What is carbohydrate intolerance? Do each of us have a personal tolerance or intolerance of carbohydrates? Does this also vary by source of carbohydrate? Learn how evolutionary tools may explain appetite regulation and carbohydrate metabolism and offer ways to regain carb tolerance through diet and lifestyle modifications.

In this episode, we explore how carbohydrate intolerance works. We look at the evolutionary template (basically the Paleo template), neuroregulation of appetite, carbohydrate tolerance, insulin resistance and sensitivity, and the factors that drive all of these.

Once the person is insulin resistant, particularly when they are heading down this road towards prediabetes and potentially diabetes, there is without a doubt one intervention that seems to work remarkably well. That’s reducing carbohydrate level to a point where it’s no longer toxic to the individual.”
– Robb Wolf

Robb Wolf (@RobbWolf) is basically the man responsible for bringing Paleo to the mainstream, in part via his New York Times Bestseller, The Paleo Solution. He also has a new book out, Wired to Eat, which covers many of the topics discussed in this episode.

Robb is a former researcher biochemist and review editor for the Journal of Nutrition and Metabolism, and the Journal of Evolutionary Health. He is a consultant for the Naval Special Warfare Resilience Program and has provided seminars in Nutrition and Strength to organizations such as NASA, the Canadian Light Infantry, and the United States Marine Corps.

One of the takeaways from Robb’s new book, Wired to Eat, is using a 7-Day Carb Test. That’s testing a different type of carb seven days in one week to see what these do to you, and what your personal tolerance is to different carbs, because not every one of them affects you the same way, or like it would any other person.

I ran that test myself and the results are further down this page. This gives you a concrete example of what Robb is talking about when he talks about the 7 Day Test, how to measure blood glucose and how to understand how these carbs are affecting you differently.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!

itunes quantified body

What You’ll Learn

  • Damien extends his gratitude to Robb for getting him back to eating meat in the year 2010, which greatly improved Damien’s health (03:45).
  • Robb’s book Wired to Eat approaches health from an evolutionary neuroregulation of appetite as starting point and progresses with dieting self-experiments (04:01).
  • The insulin resistance theory and how the 7 Day Carb Test is useful in coming up with personalized diet plans aimed at improving health (10:46).
  • The potential for low-carb / paleo diet and intermittent fasting to improve carbohydrate tolerance (18:50).
  • Robb’s plans for experimenting with donating blood to reduce potential iron overload inflammation (19:58).
  • The value of lipoprotein insulin resistance (LPIR) panel in determining ‘hidden’ insulin resistance, otherwise not detected by fasting glucose levels alone (21:05).
  • Anthropometric measures, such as the waist to hip ratio, are only somewhat reliable markers of insulin resistance (24:28).
  • Making use of the 7 Day Carb Test to track the process of recovering carb tolerance over time (24:53).
  • Why sleep is the most important health parameter and how HRV is useful for tracking sleep quality and overall health (29:39).
  • Integrating physical exercise into a busy life and optimizing exercise intensity (36:41).
  • The ketogenic diet offers numerous therapeutic and health maintaining benefits (41:35).
  • The role of the circadian rhythm in tuning meal consumption with the body’ demands throughout the day (45:35).
  • People to follow & material for learning more about this episode’s topics (51:39).
  • The best ways to connect with Robb Wolf and learn more about his work (53:14).
  • The biomarkers Robb Wolf tracks on a routine basis to monitor and improve his health, longevity, and performance (53:45).
  • The labs using NMR spectra technology to detect LPIR components with high precision (57:58).
  • Robb’s one biggest recommendation on using body data to improve your health, longevity, and performance (58:28).

Thank Robb Wolf on Twitter for this interview.
Click Here to let him know you enjoyed the show!

Robb Wolf

  • Main Website: Short life & career summaries of Robb Wolf and his team.
  • Paleo Diet: An introduction on the Paleo Diet written by Robb.
  • Robb’s Instagram: Where he spends most of his social media time and answers almost all posed questions.
  • The Paleo Solution Podcast: Robb’s long running podcast exploring every area of evolutionary and paleo based lifestyles as well as many of today’s chronic health challenges.

Recommended Self-Experiments

7-Day Carb Test

  1. Tool/ Tactic: This test is described in detail in Robb’s Wired to Eat book and on his blog here. It consists of consuming 50g of carbohydrate from different carbohydrate sources (e.g. rice, lentils etc.) each day for one week.The goal is to identify which carbohydrate sources have the biggest impact on blood glucose levels, and thereby identifying which ones you are least carbohydrate tolerant for.In creating this test, Robb was inspired by the Weizmann Institute of Science’s Personalized Nutrition Project. We discussed personalized nutrition and interviewed the lead researcher, Eran Segal, from this project in Episode 48.The test entails preparing 50g of effective carbs, or another carb source, and eating only one type of this meal first thing in the morning (with the exception of coffee and water).
  2. Tracking: Track the food types, your blood glucose level before you consume the food and the time at which you eat. Exactly two hours later, test and record your blood glucose reading again.Is your blood glucose at the 2 hour mark over 115mg/dl? This can indicate carbohydrate intolerance with respect to that specific food.By understanding the carbohydrates you are personally intolerant of you can reduce your blood glucose variability significantly by just removing these from your diet (while still enjoying other carbs that your body is tolerant of).

    Robb recommends that the 7-Day Carb Test is repeated approximately every 3 months, such that the time intervals are close enough to track improvements in particular carb foods insulin sensitivity, as well as tracking the body’s overall insulin sensitivity.

Damien’s 7-Day Carb Test Results

Before recording the interview with Robb I followed his carbohydrate testing protocol for some of the carbohydrates that appeal to me more.

I made a couple of modifications of the protocol to fit my profile better.

  • First, as I’m on a ketogenic diet, I also tracked blood ketones to understand the impact of each carbohydrate source on my levels of ketosis.Did a particular carb drop me below the performance ketosis threshold (1.5 mmol/L)1? Or did it drop be below the nutritional ketosis threshold (0.5 mmmol/L)?
  • Second, from my using a Continuous Glucose Monitor for the last 3 months I know that my blood glucose readings in the mornings are not stable. They rise and fall after waking very predictably, but to greater or lesser amounts depending on sleep, stress and possibly other factors.On the other hand, since I only eat once a day typically, at my evening meal, I know that my blood glucose in the afternoons is always flatline. So I ran my experiments in the afternoon knowing that the variables were better controlled. This is not the situation for most people as Robb describes in his book, so you are most likely better off running the test in the morning as he advises.

In my case the takeaways from this self-experiment were:

  • Lentils had the least impact on my blood glucose levels and ketone levels. My blood glucose had dropped back to near baseline, below 90 mg/dl, within 90 minutes.
  • White rice had the largest relative impact on my glucose levels, but didn’t necessarily have the largest impact on my blood ketone levels. It was the only carb for which I found myself ‘carbohydrate intolerant’, as it failed to return below the 115 mg/dl cut off mark. It also had potentially not even peaked at the 2-hour mark. It was still rising as of last reading, and was just over 130 mg/dl.
Blood Glucose Response to 50g of Effective Carbohydrate

carbohydrate-tolerance-glucose2

Blood Ketone Response to 50g of Effective Carbohydrate

carbohydrate-tolerance-ketones-2

Notes for Context & Additional Observations
  • Average readings of two or three blood glucose readings were taken for each blood glucose data point. From discussions with blood meter manufacturers I’ve learned that blood glucose meters have a high variance in their readings, so when you want accurate results you need to take several readings depending on the variance of the readings (two readings if the first two readings are < 0.5 mmol apart, or three readings if they are over 0.5 mmol apart). Researchers I’ve spoken to also follow this protocol to normalize readings.
  • Unfortunately I ran out of ketone strips for the last experiment which was the black beans. This was particularly annoying since the ketone response looked pretty unique for these – so I will likely rerun this particular test in future (especially as I dabble in black beans at Chipotle every once in a while).
  • I experienced some gut intolerance/ some negative symptoms from the lentils. This was the only carb that I experienced this with and seems to go against some assumptions that autoimmune/ auto-inflammatory responses are behind the largest glycemic responses to foods. The glycemic response in my case, was the lowest for lentils while it was the only one I experienced gut intolerance with.

Sleep

  1. Tool/ Tactic: Sleep is the most important physiological parameter, and poor sleep or inadequate sleep is excessively damaging to the body. Robb argues that if one feels good when going to sleep and waking up, then this is a reasonable indication that the body is performing in healthy shape. Tactics for improving sleep quality from Robb’s blog include: reducing light saturation, reducing noise in the environment, doing intense exercise earlier in the day (due to potential shift in circadian rhythm with late evening exercise), stopping all work a few hours before sleep and making a list of your thoughts before going to sleep – then agreeing with yourself that you are best able to take care of this list after a good night sleep.
  2. Tracking: In Robb’s opinion, it is key to subjectively track physiological concepts in our bodies and to make use of understanding these perceptions. For example, this entails paying attention to feeling tired before or rested after sleeping, or feeling background symptoms of inflammation (eg. in the joints). Robb discusses the use of Heart Rate Variability (HRV) for tracking sleep quality in his blog.

Tracking

Biomarkers

  • Waist to Hip RatioAnthropomorphic body markers, such as waist to hip ratio, body weight, or Body Mass Index (BMI) are useful for understanding carbohydrate tolerance, ex. as a complement to evaluating 7 Day Carb Test after a diet intervention. However, anthropomorphic markers are not very specific measures of insulin resistance. For example, people who are lean still face carb toxicity. Alternatively, people also sometimes face inflammation caused by the immune responses to other specific food types, ex. eggs or soy.
  • Fasting Blood Glucose: Elevated fasting glucose levels indicate a progression toward diabetes. Fasting glucose is usually taken first thing in the morning after an 8 hour fasting period and optimum levels range between 70 and 90 mg/dL.
  • Hemoglobin A1C: Used to identify the average plasma glucose concentration over prolonged periods. Higher levels of hemoglobin (A1C) indicate poorer control of blood glucose levels. Normal levels are less than 5.7%, pre-diabetes levels range between 5.7 to 6.4%, while higher than 6.4% is indicative of diabetes. Both fasting glucose levels and hemoglobin A1C are useful in identifying a level of blood sugar dysregulation, but cannot be used to quantify insulin resistance at an individual level.
  • HDL & LDL CholesterolHigh – Density Lipoprotein (HDL) is the traditional measure of ‘good cholesterol’ used by doctors and healthcare. Levels above 60 mg/dL are considered protective of cardiovascular disease. Low – Density Lipoprotein (LDL)) is the traditional measure of ‘bad cholesterol’ – the type which causes cardiovascular disease. Less than 100 mg/dL is considered an optimal level, while levels between 160-189 mg/dL increase the risk for cardiovascular disease. While both measures are important biomarkers, these are not indicative of insulin resistance status.
  • LPIR (Lipoprotein Insulin Resistance) Score: The LPIR Score is constructed as a weighted combination of 6 lipoprotein subclass measures and reflects the concentrations of each into one score. The final result ranges from 0 (most insulin sensitive) to 100 (most insulin resistant). Recent studies have been using the LPIR as a more accurate approach to assessing insulin resistance improvements via interventions.2
  • GlycA: A novel biomarker useful for predicting predisposition to insulin resistance and Type 2 diabetes3, cardiovascular diseses4 and inflammation-driven diseases including cancer5. Normal GlycA levels are below 400 μmol/L. Concentrations tested above this cut-off value are considered high and indicate the need to take steps towards preventing health issues.
  • FerritinSerum ferritin acts as a buffer against iron deficiency and iron overload. Levels are measured in medical laboratories as part of the workup for detecting iron-deficiency anemia. The ferritin levels measured usually have a direct correlation with the total amount of iron stored in the body. Female normal reference range is 12-150 ng/mL and for males it is 12-300 ng/mL.
  • HematocritThe hematocrit (Ht) is the volume percentage (vol%) of red blood cells in the blood. It is normally 45% for men and 40% for women. Robb checks ferriting and hematocrit as markers for tracking iron saturation which he plans to tackle by experimenting with donating blood and because these are useful in determining iron saturation which he suspects is the potential cause of some inflammation.

Lab Tests, Devices and Apps

  • NMR Lipoprofile: The LPIR score is part of the NMR Lipoprofile run by Labcorp (example report output here). It is an additional biomarker that was added to the panel more recently. The NMR Lipoprofile was originally run by the company LipoScience, which was acquired by Labcorp. As a result, Labcorp is now the company that runs the most advanced labs using NMR Lipoprotein analysis.
  • GlycA Test: The GlycA test is also offered by the company LabCorp.
  • BioForce HRV Set: BioForce HRV is a for tracking HRV which allows users to include their choice of sensors. There is a standard Bluetooth heart rate strap or a newly developed and finger sensor. Both sensors are compatible with all iOS and most Android devices and are constructed to deliver the precision necessary for accurate HRV measurements.

Tools & Tactics

Diet & Nutrition

  • 30 Day Diet Reset: A diet scheme based largely on a Paleo diet type template, aimed at healing the gut and re-normalizing the neuroregulation of appetite. Following Robb’s guidance in Wired to Eat, the 30 Day Diet Reset should be done before the 7 Day Carb Test such that the results of the test can be objective.
  • Fasting: Damien has seen improvements in his carb tolerance with the use of fasting as a tool in various formats. Having tracked his glucose and ketone levels, he concludes that the switching point of burning ketones, instead of glucose, occurs at approximately the 72-hour mark. Over several fasts, it becomes easier on the body to switch to ketogenic (therapeutic) ranges with the switch occurring quicker (e.g. 48-hour mark). The glucose/ketone ratio charts look flatter indicating a more controlled physiological response to fasting.6
  • Ketogenic Diet: A diet which restricts carbohydrate intake, over time causing the body to switch from using glucose to burning ketones as the main fuel. There are many potential benefits from ketogenic dieting. For most people who are overweight and insulin resistant, a lower carb intervention wins out as an approach to solving these health issues. A therapeutic state of ketosis is determined by reading fasting blood glucose levels (which should be below 80 mg/dL in the morning after 8h of no food intake), while β-hydroxybutyrate (blood ketones) should be higher than 0.8 mmol/L. See Episode 7 with Jimmy Moore on optimizing ketogenic diets.

Interventions

  • Donating Blood: Robb plans to experiment with donating blood, with the aim to reduce some potential low-grade inflammation caused by iron overload. He plans to track iron saturation before and after 3 months of donating blood on a consistent basis and reach conclusions based on the data. Robb compares his case to Chris Masterjohn who personally controls an iron toxicity predisposition by optimizing his blood donation schedule. Chris discusses this topic in Episode 46 of this show, an episode focused on micronutrient status optimization.

Tech & Devices

  • Blue Light Blocking Glasses: FDA registered blue light blocking glasses used for digital light eye strain prevention. These glasses are a useful way to reduce light saturation for a few hours a night before going to sleep.

Other People, Books & Resources

People

  • Christopher Kelly: An athlete and founder of Nourish Balance Thrive which is a service offering a science-based, personalized support program to help people regain optimal performance.
  • Marty KendallAn engineer with an interest in nutrition who seeks things numerically who founded Optimizing Nutrition. Marty aims to consolidate a range of paleo and ketogenic ideas into an algorithm that will enable an individual to tailor their diet and bring about health goals.
  • Tim Ferriss: An all-round successful man, who runs a podcast focused on deconstructing world-class performers – other successful people in various niches or businesses. His podcast is often ranked #1 across all of iTunes and is also selected for “Best of iTunes” for three years and running. Robb interviewed Tim in an episode of his podcast.
  • Joel JamiesonJoel Jamieson is considered among authority figures on strength and conditioning for combat sports and has trained many athletes since 2004. Joel stands behind the BioForceHRV project, aimed at tracking HRV and implementing it in optimizing exercise to the condition of your body. Joel introduced Robb to the BioForce tracking platform which he has used ever since.
  • Alessandro Ferretti: An optimum nutrition researcher who formed Equilibria Health Ltd, which is now recognized as one of the leading providers of nutrition education in the UK. Alessandro actively does Judo and Karate and has discovered that he performs efficiently with a ketogenic diet – meaning feeling energetic, being able to undertake fasts, and remain lean.
  • Bill Lagakos: A biochemistry professor focused on circadian rhythms and nutrition. Following on Bill’s work, Robb has adjusted his diet to time-restricted eating, meaning that shortened feeding windows are assumed to be beneficial for a variety of physiological reasons. Moreover, based on his research in biological (circadian) rhythms, Bill Lagos advocates the idea that more carbohydrates should be eaten earlier in the day, such that carbohydrate backloading can be avoided. Because of these reasons, Robb has adjusted his fasts to approximately 14-16h, whereas before he would 18h fasts. Following a fast Robb eats a robust full meal, but he usually times this with jiu-jitsu exercise 2-3 hours later. This is an example of optimizing both how diet volume and the intensity of exercise.
  • Chris Masterjohn: Robb appreciates Chris’s ability to dive into the biochemistry and pathophysiology of when things are right and wrong in the body, as well as to develop whole food and supplement solutions based on his research. Chris was a guest on our show in Episode 46.
  • William Cromwell: A physical chemist who studied NMR spectra technology lipoproteins, serving as Director of Cardiovascular Disease at LabCorp.

Books

  • The Paleo Solution: A book by Robb Wolf following his perspective as both scientist and coach on the benefits of Paleo dieting, and this along with exercise and lifestyle changes can change one’s appearance and health for the better.
  • Wired to Eat: A book written by Robb which starts with the 30-Day Reset to help people restore normalized blood sugar levels, repair appetite regulation, and reverse insulin resistance. This book also features standard Paleo – based recipes and meal plans for people who suffer from autoimmune diseases, as well as advice on eating a ketogenic diet.
  • Myth of Stress: A book explaining how much of what we perceive as stressful in day-to-day life is actually generated by our brain’s anxiety response, but is not actually a legitimate stressor in terms of evolutionary times scenarios, when our brains evolved the stress response. Robb interviewed author Andrew Bernstein in an episode of his podcast.

Other

  • I, Caveman Show: Robb took part in this Discovery Channel reality show where they had to live mimicking the stone – age hunters and gatherers. It took place at 8,500 feet in the Colorado Mountains.

Full Interview Transcript

Click Here to Read Transcript
(0:03:45) [Damien Blenkinsopp]: Robb, thank you so much for joining the show.

[Robb Wolf]: Hey, huge honor to be here, thanks.

[Damien Blenkinsopp]: Yeah, it’s a huge honor on my side, because you got me back into eating meat back in 2010, just as we discussed a few minutes ago. That was great and that vastly improved my health, so thank you for that.

[Robb Wolf]: Awesome, awesome.

(0:04:01) [Damien Blenkinsopp]: Yeah.  So you just released this book, Wired to Eat, which I went through, and it’s building on what you’ve done in the past, and also looking at some of the things you’ve learned over time with all the practical experience you’ve had implementing this.

What would you say is basically the crux behind this book? Is it the neuroregulation of appetite, or how would you think about it?

[Robb Wolf]: Yeah, it’s kind of two pieces. So the front of the book is really starting this conversation from the perspective of the neuroregulation of appetite.

So I’m kind of known as being one of the Paleo guys, and I definitely use that evolutionary biology, evolutionary medicine framework to inform the question and answer process that I bring to strength and conditioning and nutrition, and what have you, but it’s a starting place. It’s not the endpoint.

And I think that’s where, in some ways, the efficacy of that whole methodology has been lost. People assume that that’s where you start and stop. Whereas for me it’s always been this is the starting place.

We’re not yet able to take a Star Trek type scanner and run it from toenails to earlobes and then say okay you need to eat this and train this way. Stuff like that may happen eventually, but we’re still very much in this empirical process.

So then if we’re in this empirical experimentation process, where the heck do you start? And I throw out this really insane, over-the-top, greasy used-car salesman notion that maybe evolutionary biology can inform some of where we start this health and performance story from.

There’s this model in evolutionary biology called the Discordance Theory. That’s basically you have an organism that is pretty well matched for it’s environment. The environment can be the weather, the food, it can be a ton of different factors, it could be bacterial or parasitical. But if things change, it could be beneficial, negative, or it could be neutral.

But if we start seeing disease processes prop up that we don’t see in the natural free-living environment, or in the pre-environmental change story, then maybe there’s something to be learned from that. That’s my crazy suggestion is that possibly our genetics are wired up for a life way and a time that no longer exists, and that as great as so many of the elements of modern civilization are, there might be downsides to it.

For example, antibiotics are amazing for preventing septic illness and death, but there might be some downsides related to mitochondrial function in our own bodies, and then changes in our gut microbiome, which we’re now understanding may have huge implications for our overall health.

Again, I use this as an orientation tool. And at the beginning of Wired to Eat I’m laying that foundation with the neuoregulation of appetite. Really trying to understand if we looked at high carb diets or low carb diets, what are the things that allow people to eat in a way that they support their activity level, support a healthy body composition but tend not to overeat.

And there are some commonalities there. The efficacy of some of these nutritional approaches becomes really obvious why they work when we better understand the neuroregulation of appetite.

And the goal on the front end of this – and it’s kind of funny because it’s fairly touchy feeling stuff – but my real goal is to help people understand that it’s not your fault if you find it difficult living in the modern world and navigating the snack aisle of the supermarket. It’s totally reasonable and understandable.

Now I’m not one of the fat accepting guys either. I do recognize that overweight and metabolic issues are damaging to our health. They are a huge cost to society.

So I’m not recommending that we just roll over and die and let life have it’s way with us, but I’m suggesting that if we can unpack all that emotional baggage and understand that this process might be hard but it’s doable, then we’re starting off at a good footing.

And then the implementation part of the book is where we get really granular in a more progressive fashion. We start things off with a triage process where we do some subjective elements, such as asking how do you feel between meals, what’s your cognitive function like, how long can you go between meals and still maintain good physical and cognitive performance.

And then we get more specific. We look at things like the waist to hip ratio, we look at fasting blood glucose. We really lean heavily on this thing called the LPIR score, the lipoprotein insulin resistance score, because for me it’s kind of the most powerful direct means for understanding where we are on this insulin sensitivity insulin resistance spectrum.

And if we are more insulin resistance then we tend to do better on a lower carb intake. And there’s a lot of variability with that. But we also have people that are overweight or experiencing some other health related issues but they are actually insulin sensitive, and these are the people that tend to do better on that moderate to high protein, high carb, low fat diet. So there are examples of both ends of this spectrum working pretty well.

But we use this triage process to get a handle on where we are in that insulin sensitivity insulin resistance spectrum. We use a 30 day reset, based largely around a Paleo diet type template, to heal the gut, re-normalize the neuroregulation of appetite. And then from there we use the 7 Day Carb Test.

There we pick a battery of different carb foods and we eat an allotted amount, which is 50 grams of effective carbohydrate. We check our blood glucose at a two hour mark. If your blood glucose is at or below a certain level, that’s usually an indicator that’s a good amount and type of carb for you.

If it’s above that, then we start asking some questions about should we reduce the portion size or is this really a good food for you. Because sometimes our elevated blood glucose level is not just from the carbohydrate content of the food but it’s from the immunogentic properties of the food.

If someone is reactive to wheat or eggs or soy, they may actually get a significantly elevated blood glucose response. And it’s not from carbohydrate, it’s from the stress response that occurs when we eat a food that we have an immunogenic response.

[Damien Blenkinsopp]: Thanks Robb. A real big download there.

[Robb Wolf]: Yeah, that was… (laughter)

(0:10:46) [Damien Blenkinsopp]: Let’s talk about a couple of the things you mentioned that stood out.

First of all you were talking about insulin resistance.

Do you see this as one of the cruxes of the issues? Is this one of the main factors? I know you’ve had a lot of practical experience in clinics and studies, and so on. So what have you seen in the populations out there in terms of how important the insulin resistant piece is?

[Robb Wolf]: Yeah. And this is a really contentious topis because people are still in pissing and squabbling matches about what brings about insulin resistance. Is it just in response to elevated insulin levels?

I think it was an interesting theory but over the course of time that has not borne out to be the best theory. It still seems to relate to an overabundance of energy causing systemic inflammatory responses within the cells that then tends to up-regulate this insulin resistant response.

But once the person is insulin resistant, particularly when they are heading down this road towards prediabetes and potentially diabetes, there is without a doubt one intervention that seems to work remarkably well. That’s reducing carbohydrate level to a point where it’s no longer toxic to the individual.

My analogy to this is basically photo exposure in getting a sunburn. Depending on what type of skin pigmentation you have you will be able to handle greater or lesser amounts of UV radiation before you get a sunburn. And if you do have a sunburn, there’s really only one intervention that makes sense, and that’s to reduce your exposure to the toxic levels of UV radiation.

And so that insulin resistance and the resulting metabolic derangement, which includes but definitely isn’t limited to elevated blood glucose levels, you can tackle that in a variety of ways. You can starve people down on a high carb low fat diet, and it can work. But in that insulin resistant state we tend to have a really serious dysregulation of the appetite and the tendency to want to eat a lot of carbohydrate.

And so this is where for most people who are overweight and insulin resistant that lower carb approach seems to work pretty magically. Even in these free-living populations where people can make a variety of choices, the lower carb intervention tends to win out.

[Damien Blenkinsopp]: I guess that refers to the saying carb-cravings, that we often hear.

I don’t know if you’ve seen this, but some people have a lot of difficulty with fasting. They’ll have dreams about food if they fast for 24 hours. I know friends who have fasted with me [for whom] it was a bit difficult. Or they get ‘hangry’ – I know that’s a term you coined in your book as well.

Have you found that that correlates with some of the lab tests? Is that kind of a symptom of potential insulin resistance?

[Robb Wolf]: Yeah. So here’s a good example of this.

My wife and I did this 7 Day Carb Test, and we’ve known empirically that I just don’t do as well with carbs.

I remain 100 percent gluten free because if I get a gluten dose, the first bathroom I hit will require a priest, an exorcism, and probably needs to be bricked over and never used again. So there’s no upside to consuming gluten such that I willingly do it. I get some cross-contamination stuff occasionally.

But I’ll have a little rice, or some corn, here and there. We’ll go to Mexican food or Thai food and I’ll kick my heels up once in a while. And I usually feel pretty rough. And I may feel rough for a day or two afterward.

Whereas my wife, I’ll ask her, “Hey are you feeling kind of carb headed from that?” And she says, “Yeah, it lasted for 20 minutes.” I wonder what’s going on with that.

And so we dug into that deeper, using this 7 Day Carb Test. And we ate the same amount of carbs – 50 grams of effective carbohydrate — and we picked the same foods. It was, white rice, white potatoes, sweet potatoes, applesauce, gluten-free bread, and a couple other items. And it was really interesting.

So with the white rice, at two hours post-meal my blood glucose was still in the 180s, damn near diabetic levels. Terrible. And I felt terrible. And Nicki at two hours was a 121, 122 or something like that. Just across the board, she had remarkably better blood glucose levels than I did.

So that was interesting, and it was kind of validative of what we had seen previously. So then kind of out of nowhere she said, “Hey, I’m going to do a dinner to dinner fast.” I was like, okay, that sounds good. We’ll check that out. And it was interesting.

So she did her dinner, and didn’t eat again the following morning. She worked out. We have a 10 month old Rhodesian ridgeback puppy that requires a ton of training, and she’s really diligent in training the dog, but it’s active. So she did her workout and then she’s running the dog around.

And we have two daughters under the age of five. So it’s a really active life that we both live, and particularly my wife being at home in that scene most of the time. By 23 hours she was getting hungry, but she was still totally cognitively on point. She felt good.

Right at that 24 hour mark we checked her blood glucose level, which was 71. That’s low, but a good low, particularly for a fasting scenario. And her ketones were at a 0.8. So she was already in a therapeutic ketosis range. And she was effectively just right at that 24 hour mark.

This is something that we just don’t see all that often in Westernized populations. This exact type of study hasn’t really been done specifically in hunter-gatherers and pre-Westernized societies, but what we see in those situations is these folks may go a day or two without eating.

They are hungry, they are definitely wanting to eat, but they don’t have a decrease in physical performance or cognitive function. You aren’t a very effective hunter-gatherer or horticulturalist if you are leaning against a tree drooling on yourself because you are in metabolic shutdown because you have to eat every two hours to keep yourself going.

So your question was — and I know that this is the longest answer to the shortest question in history. I seem to be good for that. But the question, was do we see specific lab values that tie into this?

What I’ve noticed is a tendency towards, if you are more insulin sensitive – and that will be determined by your total choleric load, your stress load, your sleep, your gut microbiome. There are lots of factors that go into that.

But if you tend to be more insulin sensitive, we tend to see more metabolic flexibility. If you have a higher carb meal, it doesn’t really knock you out and you don’t get super high blood glucose levels. You don’t have hypoglycemic crashes. And on the flip-side of that, if you need to go 6, 10, 12, 24 hours without eating, you may be hungry but you are still functional.

Whereas that insulin resistant individual, they do a piss poor job of dealing with large carbohydrate boluses. They get a super high blood glucose level, they get a rebound hypoglycemic response. And then when they have carbohydrates restricted significantly, the first couple of days – usually 72 hours – they’re in hell, because they have neither adequate glucose to fuel what’s going on and they’ve not yet kicked over to converting fats into ketone bodies in an effective way.

There are hormonally driven elements to this, and then there are also possibly mitochondrial considerations, where the mitochondria themselves may be damaged to a degree. It’s like taking a lawnmower that’s been out in the garage for two years, and it’s got some water in the carburetor and you just have to really rip the cord on that thing to get it to turn over and start using the fuel that you want it to use.

So let me know if I answered that. I know it was a long, rambly story.

(0:18:50) [Damien Blenkinsopp]: Yeah, I think you really did. Out of interest, because you noted that your blood sugar spiked to 180, how long have you been low carb for?

In a sense it seems like it’s not therapeutic, even if you’ve been low carb and Paleo for a long time, it doesn’t necessarily mean it’s going to mend these type of things, this dysregulation when you eat some rice.

[Robb Wolf]: Yeah, it’s interesting. Over the course of time, I’ve been able to push that carb tolerance up.

So now on my heavier Brazilian jiu-jitsu days I’ll be somewhere between 120-150 grams of carbs, and I do fine with that. But I also keep an eye on the types, and then I tend to put more of the carbs in the post-workout period, and similar to that. Whereas before 120 grams of carbs would have just crushed me.

So I’ve definitely recovered a lot, relative to where I was previously. And I’m still tinkering. I’m not sure if there’s still some gut health considerations. I’m actually just getting ready to start donating blood on a consistent fashion, because of some thoughts around some potential low-grade inflammation from iron overload.

So I’m going to play with that, and what I’ll do with that is I’ll probably go through three months of consistently donating blood, check the before and after numbers with regards to ferritin and iron saturation, hematocrit. And if we get to whatever delta we get from the start and the finish with that, then I’m going to revisit this 7 Day Carb Test and see if we get some improvements on that.

So that might be one final stone that I need to turn over and explore. I know Chris Masterjohn had talked about really reversing some significant insulin resistance. He had no idea what was going on, and he felt it was largely driven by that iron overload status.

(0:21:05) [Damien Blenkinsopp]: Wow, that’s interesting.

I have iron overload as well, and many other things like infections. So for me it’s a bit difficult to pinpoint what it is. But my carb tolerance has got a lot better with fasts.

So I’ve tracked with fasts, and I’ve seen that switching point you were just talking about, the 72 hours. It gets a lot easier and would happen a lot quicker as well. My ketones would go up faster, and glucose would go down quicker. And it’s been flatter over time. So it’s really, really interesting.

So you mentioned another panel just a bit earlier, a lipoprotein insulin resistance panel. What’s that?

[Robb Wolf]: So people are usually familiar with HDL cholesterol and LDL cholesterol. The cholesterol is a fat soluble, not water soluble, substance. So it would be like trying to mix oil and water together; it just doesn’t work that well.

But we need to move these substances around the body, so there are these things called lipoproteins, which actually are the vehicle that carries the cholesterol passenger around the body. And triglycerides are also, to some degree, carried around [by these], although they have their own carrier molecule as well. But these lipoproteins usually correlate pretty directly with the amount of cholesterol that we have, both HDL and LDL cholesterol, but not always.

There are certain folks that exhibit this phenomena called discordance, where you may have lots and lots of small dense lipoprotein particles and then a relatively low cholesterol level. And these are the folks that often, like a 35 year old triathlete and they work out all the time but they’re also a shift working firefighter or something and they suffer a heart attack at age 35 or 40.

And it’s like, wow, we never saw that coming. Their triglyceride to HDL ratio looks pretty good, which is a decent correlate or indicator of insulin sensitivity. And then their total cholesterol levels didn’t look that high, but under the hood looking deeper the lipoprotein numbers were super high.

And so there’s also a way that we can look at the lipoprotein numbers and their relative ratios. And there have been some really phenomenal correlation studies to tie this link together so that we can tie that lipoprotein insulin resistant score to the real world.

And there are some other methods for tracking that. There’s looking at fasting blood glucose, but there are limitations to that. There are ways that that can be misinterpreted both on the up and the downside. Fasting insulin is similar, it’s helpful but there are ways that can be circumvented. A1C [is another].

So we do like looking at several of these numbers, in the beginning in particular, and then checking back on them periodically, because it provides a lens. In particular a lens to help us better understand that 7 Day Carb Test. Because those carbohydrate numbers just in isolation can also be a little bit confusing.

But with that lipoprotein insulin resistant score, what we found in the police and fire populations that we work with – I’m on the Board of Directors of the Medical Clinic here in Reno, Nevada – we found that with the other methods for tracking insulin resistance we were missing people, particularly folks that were sleep-deprived and/or hyper-vigilante.

So they had consistent adrenal cortical response, some HPT axis dysregulation. Those people were insulin resistant, and often times significantly so, but we didn’t see it in fasting insulin levels. Specifically blood glucose levels may not have been that bad at that point, but we were seeing some really consistent long term insulin resistance when we looked at that LPIR score.

(0:24:28) [Damien Blenkinsopp]: So it sounds like it could be uncovering people that we normally miss.

How about the waist to hip ratio? That’s a nice easy thing that anyone can do at home. Did you also find the same thing, that it doesn’t necessarily capture people? Like you can be pretty thin and slim and have these same issues.

(0:24:53) [Robb Wolf]: Absolutely, and that’s where again we use it to build a case, but you can’t hang your hat 100 percent on anthropometric measures like that.

[Damien Blenkinsopp]: Great. Have you looked at how people can basically recover carb tolerance? Or have you seen that kind of period, the timeline?

Any indication of, say they did a 7 Day Carb Test now, when would it be useful to retest? Maybe 6 months after following a clear Paleo diet and all of your proscriptions. You talk about all of them.

[Robb Wolf]: That’s a really good question. Part of the inspiration for even doing the 7 Day Carb Test came out of research from the Weizmann Institute in Israel, and it was looking at personalized nutrition by tracking the individual glycemic response.

And what they did in these folks is they had them wear a CGM, a continuous blood glucose monitor – just a little disk that gets slapped on the back of your arm – and it measures your blood glucose levels once a minute, every minute for the duration of the test. I forget, but it was two or three weeks and they had 800 people signed up on the study.

So it was a massive amount of data; they had over a million blood glucose samples. They then did a gut microbiome sequencing on these folks, they did a full genetic analysis, and the standard kind of lipidology based blood work. And then they started feeding these people different meals. And the blood glucose responses were all over the map.

It was similar to myself and my wife, where one person would eat white rice and [their] blood glucose would go to the moon, [whereas] another person would eat white rice and they had a barely perceptible increase in their blood glucose response.

And then there were wacky things like hummus. Even though I’m the Paleo guy and legumes are theoretically problematic, hummus is protein and fat and fiber. There’s hardly any carbohydrate to it, but hummus was about a coin toss as to whether or not you had a good or a bad blood glucose response.

And the one thing that they did figure out with this was that if you determine the amounts and types of food that kept your blood glucose within lower bound levels, then your gut microbiome tended to improve and your inflammation and insulin sensitivity tended to improve over time.

So I don’t know that I have an exact timeline on this that I could relate, but what appears to happen is if you eat in a way where you’re not consistently deranging your blood glucose, which seems to have knock-on effects with the gut microbiome. There are some interesting theories around how acellular or processed carbohydrate can shift the way that our gut microbiome is existing. It’s a pretty interesting and elegant model.

But if you keep things within good bounds, then things tend to improve in kind of a virtuous cycle, and then conversely if you are consistently driving blood glucose out of what we would consider to be healthy bound, the gut microbiome tends to shift towards a more pro-inflammatory state. We see elevated inflammatory cytokines on circulation, we tend to see elevations in insulin resistance.

And in the book I make a recommendation that maybe quarterly. We don’t necessarily need to do a full reset as far as a 7 Day Carb Test, but I really recommend sitting down and just paying attention.

“Hey, how long can I go between meals and still feel good? If I do a little bit of fasting training, how do I feel with that? How’s my sleep? What’s my creakiness in my joints, what’s my subjective measures of inflammation?”

I am fairly geeked-out on the quantified self stuff, and I find a lot of it valuable, but I still like to get people back in their own skin so they can get a sense of where things are going right or potentially going wrong.

And a quarterly recheck, at least on the subjective level, seems to be frequent enough that if things are sliding sideways we haven’t slid so far that it’s terribly hard to get things back on a good track. But it’s also not so frequent that you just throw your hands up in disgust and you’re just done with the whole process and don’t pay attention to anything anymore.

(0:29:39) [Damien Blenkinsopp]: Yeah, absolutely. On my own journey I’ve quantified so much stuff, but at the end of the day it’s how you feel that matters. And you can even improve a whole bunch of biomarkers, but if you don’t feel better or feel less inflammation it’s not that helpful. It can be insightful and give you clues, but we’re still at quite a rudimentary level yet.

I actually interviewed Eran Segal in just the last episode of this podcast, actually. He inspired me to get into CGM, amongst some other people. So ever since I’ve been playing around that and have found it very instructive.

And not just for the food intake, but also sleep, which you talk about a lot in your book, and stress.

How important do you think those are in your experience, compared to the food? Because we always talk about the carbs and the food.

[Robb Wolf]: Even though I’m the food guy and we used to run a gym, so you would think that I would say that exercise is most important, or exercise and nutrition, but sleep is it. I mean, sleep is it. And here’s my argument for that.

You could eat the most wretched diet imaginable, and it’s going to be hard for you to kill yourself in anything short of a couple of decades. Some people can do it, but it takes a pretty Herculean effort to do yourself in with even the worst dietary practices you can imagine.

But sleep-deprivation is so injurious to our physiology that the Guinness Book of World Records, they will let you jump a rocket motorcycle across the Grand Canyon, they’ll let you juggle chainsaws that are lit on fire, but they will no longer entertain people trying to do unbroken longer periods of sleep-deprivation. The last two people that have tried it, they got right around that 9 to 11 day mark and they just died. And they don’t know why, but they are dead rather quickly.

So the sleep piece is just so incredibly important. The stress piece is important too, but there was a great book that I read and I interviewed the author, it’s called the Myth of Stress. It was really a fascinating reframing of this whole stress story. And so much of what we experience in day-to-day life that we perceive to be stress is completely generated between our own ears.

It’s anxiety about finances, it’s anxiety about how this meeting is going to go with our boss. It’s all these different things that really at the end of the day, we have an opportunity to either let this stuff eat us alive, or we can reframe it and just say that’s not actually a real threat, and so I don’t have anything to be worried about. So there’s actually comparatively little in the modern world that is in fact a legit stressor.

Now the caveat with that, we do a lot of work with police, military and fire, and those folks legitimately live in hyper-vigilant states a lot, because they have life-or-death scenarios that they’re dealing with every day all the time. So there are caveats to that.

But a shlep like me, where I live out on a small farm, we have some animals, I have two kids, I do the business stuff that I do, I can let myself get spun up and feel stressed out. Like, oh my god, one of the goats got bit by the neighbor’s dog.

This did happen this time last year, and the poor goat it’s eat got peeled off. But it was fine, we had a vet come out and gave it some antibiotics. We had to catch the little bugger and wrap it’s ear up for about a week, and then he was totally fine.

But when it first went down, I was like, why did we ever move out here, what are we doing, this is a waste of my time. And all this just internal dialogue and stress. Then I stopped and I was like, well I love living here. The kids love the animals.

There’s sometimes pain in the ass elements to this, but I’ve turned this from an acute event into what is now for me a long-term stressor, but I did it to myself. So I would throw out there that a lot of what we perceive to be stress is mainly self-generated.

And again, circling back to the sleep part, I just can’t think of a greater return on investment than trying to go to bed a little earlier, sleep a little longer, within the boundaries of what’s normal for you. Just blackout your room, have a really solid sleep hygiene process where you go to the bed at the same time each night.

It may not do wonders for your social life, but then again maybe it will because you may not be a cranky cantankerous prick because you’re actually well rested. So it’s hard to tell. And it’s liable to pull 5 years of aging off of you in just a matter of a week.

[Damien Blenkinsopp]: Yeah. Sleep is the hardest part.

Just curious, do you use anything to track your sleep? To try and keep a bit more responsible, or have you seen anything that works for people?

[Robb Wolf]: Really HRV is kind of the best thing that I’ve seen. Some of these actigraphy things are interesting. It is interesting, again, even though I’m a biochemist, I don’t know if I’ve weighed and measured so many things that I’m just like, oh my god I don’t want to do it anymore.

But I’ve just gotten into a point now, and it’s interesting. Folks like Tim Ferriss and some other folks I’ve interviewed with, they were like, “What’s your morning ritual?” And because I have kids, the morning ritual is super variable. I don’t know if somebody pooped their pants, and they’ve got poop from their earlobes to their toenails. That’s a way different morning than if that doesn’t happen.

But what I have found is I tend to have really good control over my go-to-bed ritual. So when the sun goes down – and this varies with the seasons, our days get longer so we stay up later – but when the sun goes down then, we installed dimmer switches in our house when we did our remodel last year and we drop the lights down to a super low level. We put on some blue blocker Swannie sunglasses.

Usually not too long after that I do a little bit of reading and I just fall asleep. And it’s like a ninja blow dart hits me. And when I’m consistent with that, and if I also happen to be tracking my HRV pretty consistently, I just see that HRV score improve. And then if I do have an off-night of sleep, we see some pretty immediate impact on that.

But the actigraphy, I haven’t found to be super helpful. If we had someone that was waking up in the middle of the night or something like that and we had some HRV score feedback. The thing about HRV is it tells you something is up, but it doesn’t tell you what that thing is.

It could be that we’re having a low blood sugar response in the middle of the night, so we get some cortisol release, and that suppresses melatonin production, so it pops us up out of sleep. So maybe we need more calories overall, maybe we need more carbs near dinner. Maybe we need fewer carbs near dinner, because some people are experiencing that rebound hypoglycemic event.

There’s not a one size fits all answer with it, but in general I just kind of gauge [when] I wake up in the morning, I stand up [and see] do I feel clear headed, do my joints ache because of jiu-jitsu and being 45, or do I feel good? And if all of that stuff feels good, then I’m pretty good to go. And particularly if that HRV score just stays nice and consistent.

(0:36:41) [Damien Blenkinsopp]: Yeah. I’ve been a fan of HRV also for a long time. I’ve been tracking it.

I also find it difficult, the same way you do. It captures everything, and if you’re someone who’s got some kind of chronic health or some issue like that on top of potentially not sleeping correctly, over-training. You’re doing Brazilian jiu-jitsu, so I’m sure that’s happened a few times.

And there are these different factors and you have to kind of piece the story together. But it can give you that overall number.

I’m just curious, what do you use, do you use a sort of an app or is there something specific you like because of convenience or something?

[Robb Wolf]: Yeah, I’m just kind of old school. Joel Jamieson hooked me up with the BioForce platform and I’ve pretty much just like hung out on that.

I know there are a lot of cool stuff out there and I do have a few others but I’m again, a little busy and kind of lazy with that stuff. I’ll check in on it occasionally, but it’s generally a deal where once I get a baseline established, and it’s a thing again that I know if I’m getting into bed, falling asleep, and waking up feeling good, everything else is fine.

And then on my training side I do a little strength and conditioning, a little bit of weight work, gymnastics, and also some low level cardio to support the Brazilian jiu-jitsu. I just keep my volume and intensity really modest on that. 80 percent of my rolling is more in a drilling and aerobic fashion, and about 20 percent is that white buffalo in the sky.

Like the 20 year old three stripe white belt is trying to take my head off my shoulders, and so it’s a battle for survival. But I don’t do too many of those. Maybe one day a week that there’s some pretty hard training that goes on.

And so long as I do that, everything is good. Everything is really, really good. I just try to make very small, incremental progress, in mainly the jiu-jitsu side, and so all of my strength work, all my conditioning work, all of that is of a remarkably low volume and intensity for the most part. Just to support jiu-jitsu.

If I feel the least bit knackered after a cardio session or something, I went too hard. Because I need to save that energy for rolling, and not for getting better at the Airdyne or something like that.

[Damien Blenkinsopp]: Yeah.

So when you’re talking about volume, how many hours are you doing of exercise, jiu-jitsu, and all kind of mixed together?

[Robb Wolf]: So jiu-jitsu is between three to five days a week, and usually an hour to two. Shorter classes if I’m time pressured, then I get the one hour class which is a mix of drilling and then a little bit of live rolling.

A couple days a week I usually will stay for a half hour to an hour of just continuous live rolling. I try to grab partners where we don’t set a timer and we just try to roll. We just try to keep moving, and it forces a pace that you could maintain for about an hour straight. And I really, really like that. You get lots of repetitions in in that regard.

And then as far as the weights and gymnastics stuff, I just drop in a little bit of gymnastics bodies, mobility and strength work during the course of my work day. Usually once a week I either squat or deadlift. Once a week I might do some heavier weighted press and pull weight room style stuff for the upper body.

But those weight room workouts, I warm up and I’m done in less than 20 minutes. Occasionally a little longer than that if I’m doing a lot of mobility work in between, but even then it’s not like I’m doing a CrossFit work out.

I have two minutes of rest between sets. I’ll do a set of weighted chins, a set of weighted dips, and then some weighted shoulder dislocates to work on my thoracic mobility in between those sets. So it’s not a frenetic pace.

And then the recovery cardio, I will go longer on that if I can. It may be 40 or 60 minutes occasionally, but a lot of those – my oldest daughter now is five years old and has gotten pretty good on her little dirt bike. So I will drive her and and myself over to a park right next to our house that has some dirt trails and she’ll ride her bike and I’ll run at a nice easy pace. So I’m outside and I’m spending time with my kids.

So there’s like somewhere between three and maybe eight hours a week of jiu-jitsu, there’s maybe two more hours total a week of weights and cardio. But I do try to do a ton of stuff. I’ll stick the younger kid in a backpack and go for a hike for as long as she will put up with it. We have a three acre farm where we have animals to deal with, and we just run around playing hide and seek, and stuff like that.

So I do a lot of physical activity running around with the kids, but in the gym stuff between jiu-jitsu and strength and conditioning and all that is less than 10 hours a week, for sure.

[Damien Blenkinsopp]: Yeah, so you keep the intensity monitored.

I just looked up the Myth of Stress. Was that Andrew Bernstein?

[Robb Wolf]: Yeah, Andrew Bernstein.

[Damien Blenkinsopp]: Okay. Bernstein. Cool. That sounds really, really interesting.

Does that tie in with the gratitude stuff? We hear a lot about gratitude and I’ve been practicing it for a little while. I think a lot of people have. Did he mention that at all?

[Robb Wolf]: Yeah. He would be a great interview. He’s a solid guy, a really, really good guy.

(00:41:35) [Damien Blenkinsopp]: Yeah. Excellent.

Okay. So I thought we’d also jump into a little bit of ketones, ketosis, and fasting, because I know you’ve played around with this yourself and your levels of carb. And it’s such a big topic at the moment.

You’ve spoken a bit about you can’t really do the really low carb and the Brazilian jiu-jitsu and that you can’t get away with it. What’s you overall feeling on the whole ketones and ketodiet?

[Robb Wolf]: Yeah, the last chapter of the book is called Hammers, Drills, and Ketosis: the one tool your doctor will never use. Fortunately, that story is changing. Therapeutic fasting and ketogenic diets are incredibly powerful as potential adjuvants or adjuncts to things like epileptic treatments, potentially working in synergy with conventional cancer therapeutics.

Just huge potential there, but it’s crazy because you don’t see people get into huge pissing matches about whether or not you should use a hammer, a screwdriver, or a handsaw to get something done. If you’ve got a 2×4 and you want to cut it cleanly into two pieces, a hammer and a screwdriver are terrible options, the handsaw is a great option. There’s just not a lot of drama around that.

But then whether or not you should be higher carb or lower carb becomes this religious doctrine thing. And there is a little more nuance to it, there is a little more depth. But just empirically we’ve seen people do pretty well at the power athlete end of the spectrum, the real short time indexing end of the spectrum, and quite low carb.

And we’ve also seen some people doing this ultra-endurance work at a pretty good level going very low carb. And interestingly that looks like catering to the ATP creatine phosphate pathway and also mainly the aerobic pathway.

Where we have a kind of deadzone, a no-man’s land, appears to be these really glycalitically demanding sports like soccer and MMA and CrossFit and jiu-jitsu. And there’s just, man you don’t see a lot of just empirical success there. You see people like me that try, and try, and try.

There are a few examples, there are a few people out there that are figuring out how to do it. Probably the highest level, most sophisticated person I’ve seen looking at this problem is Alessandro Ferretti. He’s in the UK. Man, that guy is smart.

And he is just doing some shockingly interesting work looking at [it]. And he does Judo and Karate, so not exactly the same as Brazilian jiu-jitsu but he’s found he runs great on a ketogenic diet, he has great energy, he can fast, and he’s lean. All the stuff is great, but then he will get kind of adrenalized and burned out in the process of doing too much high-intensity activity.

And what he’s done is just try to map out the volume and the intensity of the training he will be doing, and then match that with a maltodextrin solution or maybe a maltodextrin plus fructose, because there are some arguments for repleting some of the hepatic glycogen preferentially. And he does some really amazing work.

Now, for me, because I’m kind of lazy, it also looks a little bit like a calculus problem. Alessandro is like six times smarter than I am, and he runs a really well done clinical intervention, where they’re just collecting tons of data on people.

I’m kind of a knuckle-dragger. So where I’ve arrived out with all the stuff is I just tend to eat between 75 to 120 grams of carbs a day. Higher end on training days, lower end on non-training days.

But the overall story I think is ketosis and fasting hold enormous therapeutic potential. Potentially some great performance enhancement under certain circumstances, but it’s also a powerful tool. And like any other powerful tool it can be misused, or inappropriately used.

[Damien Blenkinsopp]: Yeah, Absolutely. I know Alessandro, I talk to him quite often too. He’s a great guy. I have to get him on this show soon.

[Robb Wolf]: Yeah.

(0:45:35) [Damien Blenkinsopp]: So thanks for all of this. Last thing on this carb thing is it doesn’t sound like you time your carbs at all before or after training, or anything like that. It sounds like you’re very much focused on the practical, which is probably 80 percent of society who aren’t super self-disciplined and robotic about this.

[Robb Wolf]: Yeah, I do time it a fair amount, in following a guy Bill Lagakos. He’s a professor of Biochemistry, I believe, in the East Coast, and really super sharp on circadian rhythms. And he kind of alerted me to this idea that time restricted feeding, the shortened feeding windows, seem to be quite beneficial for a variety of reasons.

But he made a really strong case for this idea that we would do better to eat more of the calories and more of the carbs earlier in the day. And I know there’s carb backloading. This becomes, again, if you want to get a contentious pissing match on the internet, just throw one of these concepts out there.

But Bill made a really interesting case that there’s an argument based off of circadian biology that we should eat more carbs, more calories earlier. And that is one thing that I’ve focused on.

So I will do, whereas before I might do an 18 hour fast, I’ll just do 14 and 16 hours now. And I will do a really robust meal, and then maybe 2 to 3 hours after that I have a Jiu-jitsu session. And then that meal ends up being much higher in carbohydrate. And I again kind of base it off the volume and intensity.

But then usually my dinner… I do two to three meals a day. Probably 80 percent of the days it’s three meals, 20 percent of the days it’s two meals, and that tends to be more the weekends when I’m just hanging out with family and I just want to be lazy and I don’t want to cook yet another meal for myself and all that.

I do partition closer to the pre-workout period but I’m not like taking a maltodextrine drink right before and one right after, and all that type of stuff. There might be some upside to that, but I have noticed for my digestion that the digestive process, for me, does much better with less frequent feedings, and less refined foods and all that type of stuff.

So I’ve had a pretty darn good degree of success with that so far. And I mean it is dead simple. I would be hard-pressed to think of a more simplistic way of eating and fueling. It is really, really simple.

But at 45 years old, I just got my purple belt last Saturday and I’m doing great on that. And body composition is good. My wife is still willing to sleep with me with the lights on most nights. So life’s pretty good in that regard.

[Damien Blenkinsopp]: Congrats, I saw that purple belt. It’s quite an achievement.

[Robb Wolf]: Thank you.

[Damien Blenkinsopp]: So is there anything we’ve missed that’s important about your most recent thinking on this subject?

[Robb Wolf]: No, I don’t think so. You did a great and thorough job asking this stuff.

Again, I would just encourage people to think about, if they feel off-put by this idea of Paleo diet type stuff, just give some thought to this. Is there any merit looking at biology and thinking about the evolutionary underpinnings, particularly when we see things go south?

If we don’t see health or other parameters that we would ideally like to have, if something significant is changed in that organism’s environment, do we have any insight from looking at what the environment preceding that event? So that’s kind of the totality of my greasy used-car salesman pitch on this stuff. Is there anything we can learn from that?

And it’s not just around food. It’s around sleep, and photoperiod, community, gut microbiome. All of these things really, when we see problems popping up, it’s this discordance model again. And modern medicine is shockingly well-suited for dealing with acute injuries and infections, and it has been an appalling failure with regards to chronic, degenerative disease.

And people may get their back up about that and say we work very hard. I don’t doubt that people do, but if you simply look at disease rates and incidence – Type II diabetes, Parkinson’s, Alzheimer’s – they’re increasing at exponential rates, yet we know more about the disease process than we’ve ever known in history.

Our iPhones, iPads and computers get cheaper and better every single year, and it’s because we properly apply the technology and knowledge that we have around that topic to improving the product and the outcome. We do not do that in health and medicine, and it’s because we do not start the story from this evolutionary biology perspective, and start having the conversation from there. Because if you do that, chasing symptoms no longer works, and filing people into these arbitrary buckets of disease or not-disease doesn’t really work anymore.

In the 1900s, the previous century, was the century of eradicating infectious disease, for the most part. This century is going to be about dealing with chronic, degenerative disease due to affluence. And it is not going to be solved by a pill or a potion. It’s not going to be solved by telling people to eat less and move more, everything in moderation. Because all of that completely ignores every element of our fundamental evolutionary biology.

[Damien Blenkinsopp]: Thanks, so much for that roundup.

To learn more about this, they can go and get your book. That’s available at Amazon. There were some bonuses or stuff. Is there anything like that still available?

[Robb Wolf]: The bonuses might pop back up again, but most of that was for saying thank you for people who were early adopters on it. But we’ll see. Maybe a couple of months down the road we might pop the bonuses back up.

(0:51:39) [Damien Blenkinsopp]: Okay, cool. Are there any other good books or presentations on this subject that you’d recommend?

[Robb Wolf]: Oh, man, if people are not following Chris Masterjohn, they’re really missing out. That guy is brilliant.

And he’s been doing a deep dive on kind of a series of different nutrients that you need to pay attention to. And he kicked the whole thing off, actually, with iron. Both the iron deficiency, anemia, stories and also the iron overload stories.

So he gets into the biochemistry and the pathophysiology of when things are right and wrong. And then he also starts off at whole food solutions and also makes supplement solutions, and man he is just doing brilliant work.

Who else is doing great work? The folks at Nourish Balance Thrive are doing phenomenal work. Marty Kendall over at Optimizing Nutrition. They’re just some brilliant people.

It’s funny a lot of them had an engineering background and either they got sick or spouse got sick, and then they got in and started looking at this stuff. And it’s interesting. They come in with no medical training biases, and after they start retro-engineering, literally, the disease process, they arrive at something that looks like kind of an appropriate carb, Paleoesque looking nutritional intervention with a focus on sleep and gut microbiome and all that.

I don’t know if that’s just confirmation bias, or really smart people applying their training to figuring out a process. But it certainly caters to my confirmation bias, so I tend to like that stuff.

(0:53:14) [Damien Blenkinsopp]: Cool.

What are the best ways for people to connect with you, and learn more about you and what you’re up to? Twitter or Facebook?

[Robb Wolf]: The blog and podcast live over at Robbwolf.com. The bulk of my social media time I spend on Instagram these days. My handle there is @dasrobbwolf, and I answer just about every single question that is shot across the bow there. So I do the best job I can to stay on top of that.

(0:53:45) [Damien Blenkinsopp]: Excellent.

Just a few more details maybe on our personal approach through using any tracking. I know we’ve already spoke about them, so just really to see if there’s anything else.

I was wondering if there’s anything you track yearly, or every six months, or anything like that that we haven’t already spoken about.

[Robb Wolf]: So, I do check-in on my lipoproteins, that LPIR score, or LDLP, LPPLA2. There’s kind of a suite of somewhat obscure lipoproteins which I keep an eye on about once a year.

And part of that is because at the end of my last book, I was pretty beat up from that. Then I went on a Discovery Channel reality show, called I, Caveman. And we had to live like Stone Age hunter-gatherers. We had stone tools, we lived at 8,500 feet in the Colorado Mountains while there was still snow on the ground.

We basically starved for 10 days until I killed an elk with a hand-thrown spear, and that was the first food we ate. But the long and short of that is I lost 18 pounds in 10 days, and was super beat up. And I ended up with some HPTA axis dysregulation. My thyroid was super low, I had adrenal issues, testosterone was kind of tanked out.

And so an interesting sideline with that was that my lipoprotein numbers were sky-high. My LDLP was 2,800 or something like that. Really, really high. And the clinic that I’m on the Board of Directors of here, we do tons of lipidology work. And the doctors were freaking out, you need a statin. And I said no I don’t, I’ve got other stuff going on.

So we did some poking around, and I actually went on some Nature Throid, which is kind of like armor but a T3/T4 thyroid deal. And I did kind of a classic adrenal restoration story, high dose Vitamin C, some licorice, some adaptin. And I quit traveling, and I started really paying attention to my sleep.

And within three months I was off the thyroid medication, testosterone had more than doubled, both free and total. And I felt remarkably better after that, shockingly. And my lipoprotein number, my LDLP, had gone from 2,800 to, I want to say, 1,100. And eventually it settled out at 800 or 900.

I do check back in on that every once in a while though, because that combination of super low testosterone and disordered thyroid. The low circulating T3 that really down-regulates your LDL receptors in the liver. So you just don’t clear LDL particles, so they accumulate in circulation. And once they start accumulating, then the potential for them to oxidize is much greater.

And then I also potentially have a little bit of iron overload going on. So I had a really kind of nasty situation brewing there. So I do check in on that, just to make sure everything is bumping along good. So I do a really thorough thyroid assessment, which is TSH, T3, T4, reverse T3, thyroid uptake, and then some of the just kind of background iodine status. And that gives me a pretty good benchmark about where that is.

And then I’ll check testosterone, estrogen, estrodiol, DHT, to kind of see where that part of the hormonal axis is. Because again, based off inflammation, fatty acid ratios and what not, you can start pushing more testosterone towards the DHT pathway, which can be problematic for the prostate under certain circumstances.

So I pay attention to those things, but it’s usually about once a year. But again, I’m a lazy cuss when it comes to that stuff. I know some people test it like once a month. I’m more of a once a year, maybe once every six months on some things. But more of a once a year deal.

(0:57:58) [Damien Blenkinsopp]: Thanks for that, very, very interesting. And the fact that you recovered, and you obviously see that as an actionable metric that you can keep up with.

I’m just wondering, which labs were there? If there’s any specific place, or are these just standard Quests, or something like that?

[Robb Wolf]: We tend to go through LabCore because LabCore ended up purchasing LipoScience, which is the [unclear 58:09] that developed the NMR technology around looking at lipoproteins. There’s other ways of looking at it, and they have pluses and minuses to them, but in my opinion that NMR spectra that looks at the LPIR score and lipoprotein count is head and shoulders above everything else out there.

The guy that largely developed it, William Cromwell, he was a physical chemist, a believe a PhD, which is basically a physicist who studies chemistry. And then he went to medical school, and he got into this NMR spectra jockeying type stuff, and developed this whole technology around looking at these lipoproteins. They have some really interesting correlation studies that they’re doing.

There’s a biomolecule called glycA, and by looking at glycA in relationship to some other lipoprotein fractions, they’re claiming that they can see things like Parkinson’s, Alzheimer’s, and insulin resistance decades ahead. And they’re still awaiting FDA approval on that. But it’s really interesting. So I tend to really put some pretty heavy weight on that lipidology side with regards to that LPIR score and that whole NMA spectra technology.

(0:58:28) [Damien Blenkinsopp]: Thanks very much, that’s very, very interesting stuff.

I think I know what you’re going to say here. If you were to recommend one experiment someone should try to improve their body health, performance, longevity, chronic health issues, whatever, with the biggest payoff, what would it be?

[Robb Wolf]: Sleep.

[Damien Blenkinsopp]: Okay.

[Robb Wolf]: Sleep. I mean, maybe a blood sugar deal I can make an argument for, but if we improve your sleep, there is nothing else that you could do that’s going to improve everything else more.

And the one caveat with that, if we have say a shift work population – police, military, firefighter, new parents, medical caregivers – who can’t control their sleep, then they really need to get a handle on the glycemic load of their diet and get it to a level that’s non-toxic for them.

But even then, the shift-workers, they need to pay even double attention to the sleep. When they do sleep, they need to sleep well. When there is sunlight, they need to get out into the sunlight at appropriate times. It becomes doubley important for them.

But the greatest return on investment anybody’s going to get on any of this health and wellness stuff is putting more emphasis on their sleep.

[Damien Blenkinsopp]: And should they just track hours slept, something simple like that?

[Robb Wolf]: Hours slept is good, but it’s more the ritualized process. When the sun goes down, then you dim the lights. And if you’re still on the computer, you flip on the f.lux, and you put on some Blue Blockers, and you set up a ritual.

To the degree that we set our lives up that we have to live and die by self-control, we’re mainly going to die. We’re going to fail. And so we have to set up a kind of a habituated process so it really takes the thinking out of it; it’s just what we do. So I would tend to focus more on that.

And then certainly if you want to keep an eye on approximate duration in bed, but that’s a whole other interesting feature too, is when you start paying an over the amount of attention to those things, then you start getting anxious about it. And I just see this damnable downward spiral in the quantified self space, where I just want to put a black bag over these people’s heads, drag them out into the woods and stick them in a tent.

And it’s like, there’s a creek full of fish. We’ve got them trapped behind a fish weir, you need to get them out by hand and gut them and cook them. Here’s the kit to make a fire. We don’t make it ridiculously hard, but you’re going to have to work to get your dinner, work to stay warm. And when the sun goes down you’re going to make a decision, do I want to sit up in the dark, feeding this fire on the limited firewood I have, or am I going to go crawl into my sleeping bag and go to bed.

They’re not quantifying a goddamn thing under those circumstances. And all of a sudden, all of the digestive issues disappear, and the sleep disturbances disappear, and they’re three body fat percentage point is lower after a week and it’s not because they’re hypocaloric, it’s just because they’re not inflamed and insulin resistant.

And so again, I try to get people to just live. I’ve really been harping on this thing of track what matters. And the longer that time goes along, I’m just finding fewer and fewer things that matter, relative to the experiential process. Be in your body, experience what is going on. Be in contact with what your emotions are, and develop a little bit of a zen and stoic process, where you can see these things occurring, and then you can choose to how you respond to it.

Whereas if we’re so tied to external devices for every little bit of feedback, then we’re essentially dependent on that. And I hate dependency of any variety.

[Damien Blenkinsopp]: Thanks so much for that, this is really, really interesting. It’s been a fantastic episode. And thanks for being so open, just giving all these details of your own experiences and your life. It’s a great, great show. Thank you.

[Robb Wolf]: My pleasure. It’s a huge honor being on. Thank you.

References:

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Is your glucose metabolism driven by your personal microbiome? Recent research reveals how the microbiome influences blood glucose, weight gain and weight loss. And how the new company, “Day Two”, is using microbiome sequencing data to provide personalized nutrition recommendations.

In this episode we discuss how personal your blood glucose response and regulation is. We look at how glucose metabolism can differ from one person to another, and how it differs based on typical measures, such as the hypoglycemic index. Most research studies try to understand what a diet or food does to an average person. But the question is whether you or any of us is an average person? Will your body respond to inputs in the same way as it will for an average person?

I found out that collecting personal data for myself is more useful than following the recommendations that come out of the studies that are looking at a statistical human person, rather than a real individual person. Data which is unique and personalized is usually most helpful to act on, especially when the derived conclusions differ from the mainstream nutrition studies proposals.

In the past, we have covered several aspects related to this episode. You may find it helpful to do some background listening on previous episodes before digging into this one. These include the blood glucose metabolism episodes, Episode 43 on Continuous Glucose Measurement and Episode 26 on Biomarkers of Aging – in which we discussed blood glucose as a biomarker of aging.

On microbiome testing and its use, we have had episodes that are relevant to this one. There is Episode 9 on Quantifying the Microbiome with uBiome and Episode 37 on Health Impacts of the Microbiome with Robert Knight, a well-known researcher.

“We study many different aspects of the microbiome as it relates to our health. This is another study where we studied another very basic phenomena, the yo-yo diet. What we showed there is actually that even after you complete a diet and lose weight, your microbiome doesn’t go back to what it was.
– Eran Segal

This is a two part episode with two guests. We have Eran Segal who heads up the Segal lab, which undertakes research in computational and systems biology focusing on nutrition, genetics, microbiome and gene regulation, and their effects on health and disease. This lab has released a series of studies over the last years on microbiomes and how they may be impacting blood-glucose regulation.

These studies have been heavily featured in the mainstream press because they put into question lots of our assumptions of how diets and food work, and how they impact blood glucose. Eran Segal earned his Ph.D. from Stanford in 2004, and in 2011 he was made a professor at the Weizmann Institute of Science, which is very well-known in Israel.

“What we do is give you a mobile application. So you get a personalized mobile app that you download, and it’s tailored just for you. It gives you a microbiome report, because we did it and we have it… We’re giving you your top food and meal recommendations. You have your top breakfast, your top lunch, your top dinner, your top fast food, because even when you eat fast food once in a while, you can still choose healthier fast food than others.”
– Lihi Segal

Our second guest is Lihi Segal – same last name but, no relation. She is the CEO and Co-Founder of DayTwo, which is the new microbiome lab-testing and personalized diet and recommendation service that has licensed, and is applying the research from the Segal lab, on the microbiome. Lihi has held a series of CFO and COO positions in start-ups over the years. Previously, she was COO and CFO of Sisense Limited, a provider of business intelligence and analytic software. She holds an MBA from Northwestern University.

itunes quantified body

What You’ll Learn

  • Studying the glucose response as a quantifiable effect food has on our bodies (05:43).
  • Post-meal glucose levels represent direct tracking of response to different foods (13:00).
  • Tracking glucose spikes and quantifying the body’s post-meal blood glucose regulation (14:17).
  • The accuracy and usefulness of continuous glucose monitoring – new devices and helping research (14:55).
  • Constructing multifactorial algorithms for personalized prediction of blood glucose response (18:53).
  • Using high-resolution microbiome sequencing to detect specific strains of microbiome bacteria (20:31).
  • Compared to BMI or blood tests, the microbiome is a more significant factor in predicting glucose metabolism in a personalized way (22:55).
  • Different microbiome features contribute to the overall prediction of response (22:56).
  • The propensity to gain weight and the effects of artificial sweeteners (26:11).
  • The microbiome’s acquired ‘memory’ regulates weight gain mechanisms (26:53).
  • Relapsing weight-gain is regulated by the microbiome, including by regulating genes involved in energy expenditure (26:53).
  • The microbiome remains stable over time, such that consistent long-term diet changes are required for profound health effects (30:20).
  • Unlike micronutrients, small fibers are digested solely by gut bacteria – but consumption of either has sustained effects on glucose metabolism (33:38).
  • Artificial sweeteners currently being examined by Segal Lab (34:52).
  • What DayTwo does as a company and personalized services to expect in near future (35:20).
  • Providing actionable information for glucose management (42:00).
  • The basic data inputs for using the DayTwo service and integrating lifestyle into personalized diet feedback (43:26).
  • Instead of being a diagnostic company, DayTwo offers recommendations under a predictive model (45:52).
  • Where DayTwo microbiome testing and output to users stands out – comparison with competition companies (46:38).
  • DayTwo collaborates with the Mayo Clinic to replicate the Israeli microbiome study on US population – calibrating the algorithm for American foods (50:59).
  • DayTwo’s success story in Israel, public recognition, service available for pre-order in the US (53:15).
  • Plans for bringing DayTwo to the UK and European markets after first tackling the US market (55:24).
  • DayTwo US release is not dependent on the Mayo Clinic trial, but more data means continuous predictive algorithm improvement (57:34).
  • Reasons why numerous lab testing companies operate in Arizona (58:53).
  • Pricing of DayTwo services and a lower US pre-order price (59:42).
  • DayTwo takes a direct to consumer approach – offering customizable nutrition advice delivery for different individuals (1:01:51).

Thank Eran Segal and Lihi Segal on Twitter for this interview.
Click Here to let them know you enjoyed the show!

Prof. Eran Segal, Segal Lab

Lihi Segal, DayTwo

  • DayTwo: A microbiome lab-testing company and personalized diet recommendation service. Lehi co-founded DayTwo where she currently serves a CEO function.
  • MyNetDiary: LabTwo’s database for the American market is on this network’s nutrition database featuring 400,000 different US-based foods.

Tools & Tactics

Diet & Nutrition

We discussed the studies that reveal several tactics with respect to weight loss and weight gain, as well as optimizing blood glucose metabolism towards health impacts. Important aspects from Prof. Eran’s team’s research include:

  • Predicting Diet Response: We discussed the health effects and potential benefits of various diet types. A key takeaway is that nutrition can be personalized based on predicting post-meal blood glucose responses.
  • The Microbiome & Artificial Sweeteners: Segal Lab has tested for the effects of non-caloric artificial sweeteners (NAS) – namely saccharin, sucralose and aspartame compounds. They determined that artificial sweeteners induce glucose intolerance by altering the gut microbiome. Xylitol and stevia are chemical formulations currently being examined by Segal Lab.
  • Post-Diet Weight Regain: Eran’s team have shown that persistent microbiome alterations modulate the rate of post-dieting weight re-gain. As a general rule, a low carbohydrate diet is most beneficial for weight loss because this diet prevents post-meal blood glucose spikes. Compared to a meal which spikes blood glucose levels, low response meals are associated with more fat burning and with losing weight over time.

Tracking

Lab Tests

  • DayTwo: This test offers analysis of your blood glucose metabolism as a response to particular food types or complex meals.
    • The most novel feature is microbiome sequencing with the greatest resolution offered on the market – known as ‘shotgun sequencing’. This method covers the entire genetic content found in a stool sample.
    • Current price in the US is $299 pre-order, but will later cost $399 as a standard price for the US market. This is cheaper compared to Israel, where the price is $500. In Israel, DayTwo incorporates continuous glucose monitoring for all users, thus requiring more for the glucose monitor everyone receives.
  • uBiome: A company which offers microbiome testing services, using 16S sequencing technology for microbiome analysis. We covered the applicability of uBiome’s service in Episode 9.
    • While it is cheaper than DayTwo sequencing, 16S sequencing does not allow looking below the genus level of bacteria. 16s sequencing looks only at one small region of RNA rather than the whole sample and for this reason does not provide the same resolution or ability to differentiate between different species for lack of information. 16S sequencing is the most popular today for cost reasons.
    • Differentiating between specific species of pathogenic vs. benign E. Coli is not possible with 16S sequencing, but is a standard with shotgun sequencing (DayTwo testing).

Devices & Apps

  • DayTwo Food & Activity Logger: A mobile application providing personalized day-to-day nutrition and diet recommendations.
    • The app offers analysis of your microbiome in report format, based on the required LabTwo testing.
    • Additionally, it features your top breakfast or lunch food components, allows searching through a food database, and makes recommendations on alterations – e.g. substituting rice for pasta whenever fit for your body’s blood glucose response.
    • Over time, the impact of using this app should be improved health by consuming food with the aim to optimize your blood glucose metabolism.
  • Freestyle LibreThis device is used for continuous glucose monitoring and the obtained data is used to determine trends in glucose metabolism. The FDA approved this product for the US market in 2016.
    • Contains a glucose sensor and a reader displaying the glucose data collected by the sensor.
    • Segal Lab is switching to this device partly because it offers greater user convenience by avoiding the finger pricking technique for obtaining analysis-blood.
    • Eran claims the device is at least as accurate as the company states, possibly even more accurate.
  • FitBit Charge: A device from the FitBit company was used in Segal Lab research to track and integrate lifestyle (sleep, meditation, exercise) into predictive algorithms for personalized nutrition recommendations.

Biomarkers

  • Post-Meal Glucose Response: Measuring blood glucose levels for the two hours following a meal.
    • The most important measured phenomena by Segal Lab and subsequently used by LabTwo for making nutrition predictions – are glucose spikes following a meal.
    • Glucose spikes are sudden rapid increases in blood glucose concentrations as a result from particular meal types, or more broadly a result of your diet.
    • Glucose spikes are associated with disease (e.g. diabetes and types of cancer). Thus, avoiding such responses is important for optimizing blood glucose metabolism.
    • Other times we have discussed post-meal glucose response is Episode 7 on optimizing ketogenic dieting and Episode 43 on continuous glucose monitoring.
  • Hemoglobin A1C: This is the most used marker for diagnosing diabetes. Its interpretative power is derived from the connection between glucose and hemoglobin – the protein in red blood cells (RBCs) which carries oxygen. Because RBCs live approximately 3 months, Hemoglobin A1C reflects the average blood glucose levels over this period.
    • The results are reported in percent (%). Higher levels of hemoglobin A1C indicate poorer control of blood glucose levels.
    • Prediabetic states range between 5.7 – 6.4% and diabetes is diagnosed above 6.5%. Optimum HbA1c levels are likely below 5%.
    • A caveat: Depending on your diet, your RBCs can have a shorter or longer lifetime. Since HbA1C measures glucose accumulation having RBCs with a longer lifetime than average leads to higher HbA1C readings despite average blood glucose being low. For example, Damien’s blood glucose is typically under 100mg/dL at any time point even after many meals due to his ketogenic diet. His HbA1C has ranged between 5.1% and 5.3% during this time however low carb diets are assumed to lead to longer RBC lifetimes. Higher carb diets are typically assumed to have average RBC lifetime.
    • Both guests share the opinion that collecting HbA1C and other blood marker data is not useful for making nutrition predictions once you have microbiome sequencing data. This is because sequencing provides sufficient data when combined with an algorithm to predict an individual’s glucose metabolism and provide personalized nutrition recommendations.

Other People, Books & Resources

Organizations

  • DNA Genotek: A Canadian company supplying microbiome collection kits for DayTwo analysis. After extensive testing, DayTwo concluded that DNA Genotek offers the best state of the art technology requiring no freezing or timing. The end result is the ability to preserve stool sample in the Day0 condition for greatest result objectivity.
  • Mayo Clinic: LabTwo cooperates with the Mayo Clinic aimed at repeating the trial in Israel at the Weizmann Institute on an American population. The aim is to obtain more data and to optimize the predictive algorithm for blood sugar response to the US population. While the trial will last for a while, LabTwo is currently able to make precise predictions for US users and the data from the trial will be used to work on similar targeted future goals.
  • FDA: The US Food and Drug Administration has placed a diabetic label on CGM technology. Thus experimenting using CGM devices with individuals is not allowed, unless diabetes diagnosis has been previously established in the test participants. LabTwo partnered with the Mayo Clinic and have successfully designed a trial including CGM devices which was approved by the Mayo Clinic institutional review board (IRB) – essentially an internal ethics committee.

People

  • Dr. Saleyha Ahsan: She traveled to Israel to take part in the study on personalized nutrition at the Weizmann Institute. Afterward, this was covered in an episode of the BBC Two Trust me I’m a Doctor show.

Other


Full Interview Transcript

Click Here to Read Transcript

(00:05:43) [Damien Blenkinsopp]: Welcome to both Eran and Lihi Segal onto the call. Thank you both very much for joining us.

So I just wanted to jump straight into your research on the glucose response, and all of the other stuff you’ve been doing in the last couple of years really because it’s all kind of related. Why did you focus on the blood glucose topic in particular?

[Eran Segal]: That’s a really good question. When we started a few years ago, we wanted to take a science-based approach to nutrition.

We thought very hard about that problem, and what we should examine. And if you think of the most common approaches in most studies in nutrition they usually consist of some dietary intervention, and then they look at weight loss, or they look at a change in some marker of a disease. And that’s great because ultimately these are the parameters that we’d like to have an effect on.

But, the challenge we found with this approach is that it then takes weeks or months for these parameters to change. You know, a parameter that measures your diabetes level, or weight. And at the end of this, you get a single measure. It takes weeks or months to change, and that measure is affected by multiple things that happen to you during those weeks or months. Both the diet intervention that you give, but also many other factors unrelated, which can be then confounding to what you’re measuring.

So, we thought that maybe one of the reasons that it’s very hard to do nutritional research, and why many researchers are failing, is because they’re looking at this single measure effected by many things. So we didn’t want to go that way. Even if we see an effect, you’re not sure you can attribute it to the diet, and if you don’t see an effect it’s very hard to troubleshoot what went wrong.

So we thought very hard about this, and that led us to look at glucose levels. More specifically, the glucose levels after a meal, what’s called the postprandial glucose response, or post-meal glucose response.

So by that, what I mean is what your blood glucose levels look like in the two hours after you eat a meal, which we can also quantify using the area under the glucose curve into a single measure representing the response that you had to that meal.

[Damien Blenkinsopp]: Right, so that’s like the total area under the curve is the total amount of glucose that was in your bloodstream during that area of time.

[Eran Segal]: Yeah, you can think of that as an approximation. I’ll tell you in a moment what we really are hoping that this is actually measuring, but that’s quantifiable into a single measure. But now we have to think about three aspects, or three features of this that really led us to conclude that this is what we want to follow.

So in a nutshell, what they are is that we were convinced by all the existing literature that this post-meal glucose response is really key to weight management. It’s really key to disease – diabetes, but not only diabetes, I’ll talk about those.

Finally, and not least importantly, that it’s very easy to measure and it’s something that, not within weeks or months but within a week, we can obtain not one, but even 50 quantitative measures of healthy nutrition in a single individual.

So first, why is it important for weight loss and weight management? This is very basic, and there’s been a lot of literature on this.

When we eat – and I’m talking about healthy people, even people who are glucose intolerant, but let’s say not insulin dependent Type I diabetics. When we eat, our body digests carbohydrates in the meal and releases them into the bloodstream.

After that, there is a response of the body by secretion of insulin, whose job is to lower the glucose levels. But in addition, what insulin signals, also, is it signals the cells to uptake the sugar that’s floating around in our blood.

And then excess sugar is converted into fat for storage because it initially is converted into storage of glycogen, but our stores of glycogen are highly limited. So very fast the remainder will be stored as fat. And this is actually known as one of the primary mechanisms by which we gain weight. In other words, this action of insulin.

So, in a sense, we would have liked to even measure directly at a continuous rate insulin, but that’s technically not possible. But in healthy people – and there’s been lots of research – by measuring glucose levels you’re actually looking at a proxy for a measurement of insulin.

And there’s been work showing, for example, that if you eat a meal that spikes your glucose levels compared to a meal that does not, then after a meal that does not you have more oxidation of fat, more burning of fat.

So the connection to weight loss is very well established. There’s also a lot of literature looking at very low-carb diets, which I think as a dietary regiment it’s incompatible with life for most people. But if you look at some of the studies when you eat a low-carb diet your glucose levels are low, and in general, those have the most beneficial effect on weight loss.

So that’s item number one why we focused on blood glucose levels because it’s very important for weight loss and management. The second is disease, and the most obvious is, of course, diabetes.

In fact, diabetes is diagnosed and defined by glucose levels. It’s defined in two or three different measures; either by the hemoglobin A1C, which measures your average glucose over a period of three months or by the glucose levels that you have two hours after you eat a meal. So something very similar to what we’re measuring.

And so, of course, you directly are playing with and improving the measures by which you diagnose diabetes. By that we can manage better the disease; manage it better in pre-diabetics, even possibly reverse it in this population. And, of course, for all the people with normal glycemic levels, we can prevent or delay the onset of diabetes.

So that’s one area where it’s important, but then separate from diabetes there’s been a lot of links to cardiovascular disease, to cancer. So in cancer, this is known as the Warburg effect. We know this for 90 years that cancer cells have a very different metabolism that much more heavily relies on glucose.

And so the thought is that by limiting the amount of glucose that you provide, you deferentially affect the growth of cancer cells compared to normal cells. And there’s been associations in the literature between blood glucose levels and cancer.

There are also been associations to overall mortality. There’s one paper that tracked over 2000 people for 30 years showing that if you responded more highly to a glucose challenge 30 years ago, you’ll live longer, basically. So there’s been links to many diseases, and so we’re very confident that it also has a strong association to disease.

And the final point is what I made before that because of the technologies with continuous glucose monitors we can now really in a single week measure 50 quantitative measures of healthy nutrition. And they’re quantitative of health nutrition because of the two points I made before.

[Damien Blenkinsopp]: So you felt that it was basically the continuous glucose monitor was a game changer because you’d be able to gather a lot more data quickly, and eliminate somebody’s potential variables coming in from the longer term studies which you can avoid.

[Eran Segal]: Absolutely. So if you think about it, we actually focused on examining the direct effect, one of the ways by which food directly affects you, and this is your glucose levels.

And from everything I mentioned before, we also believed that this is really a very critical clinical marker for weight loss and disease.

(00:13:30) [Damien Blenkinsopp]: Right. Okay, great. So you focused on the post glucose response to meals specifically, but you did mention Hemoglobin A1C. Is that something else you tracked and you found useful in these studies?

[Eran Segal]: So that’s something that we measured. We found it useful for predicting how different people respond to different foods, but it’s nothing something that you measure as a direct effect of a meal.

It’s one of those single parameters that takes many weeks to change that, again, would be very hard to develop a dietary regiment that would affect that directly because of all the confounders that I mentioned before.

So in fact, glucose levels is, as far as we know, the only reliable quantitative measure that is really super relevant that we could track, and that’s why we focused on it.

(00:14:17) [Damien Blenkinsopp]: Right. And you mentioned the area under the curve is the part that you’re interested in. So I’m guessing that you’re looking at a benchmark to what’s okay, and what goes too high in terms of that area.

You said to me when I tried to give an analogy to explain that to the audience that it wasn’t quite right. How would you explain the utility of that?

[Eran Segal]: We can just say that it’s basically looking at your glucose response and it’s quantifying how much you had spikes for glucose levels after the meal. And these spikes, as I mentioned before, is what is strongly linked to everything else.

(00:14:53) [Damien Blenkinsopp]: Right. Thank you very much. How did you find the continuous monitoring technology? Did you use a specific device, and how sensitive or accurate did you find it? There’s various monitors out.

We’ve spoken about these before, and I know people that have been using them for diabetes management and so on. So I’m just interested in your opinion on where that technology is right now, if research can be improved maybe later as it advances, or is it already as good as it’s going to get.

[Eran Segal]: So I think it was very good for our purposes. Not without problems, but I think even finger pricking is problematic, and can be variable. But, there’s also progress.

There’s a recent device by Abbot that we are now shifting to using because it’s more convenient, mainly. It’s probably as accurate, possibly even with higher accuracy – that’s what the company claims. But it’s just much more convenient, and it doesn’t require the finger pricking anymore.

But overall, they definitely capture the trends. I will say that when we measure responses to 50,000 meals you really have a very large data set, and you can afford to have some inaccuracies here and there, which all the technologies have. And still you correct for that in the algorithms.

(00:16:10) [Damien Blenkinsopp]: Great, thank you for that. Moving on a bit to what you discovered is actually driving these blood sugar regulation changes. What are the examples of the most unexpected things that you saw in the data?

[Eran Segal]: Are you talking about the factors that affect it, or even just before the surprising responses that people had?

[Damien Blenkinsopp]: I’m interested in both. If we start with what you saw that maybe you weren’t expecting, and then what you think drove that, or what you discovered drove that.

[Eran Segal]: So the first key result of the study was – and this was initially very surprising – we saw that when you give different people the exact same meal, they have very, very different responses. And this is in contrast if you eat the same meal on two different days, which is what we’ve tested on an unprecedented scale of 1000 people. This is 7000 different meals standardized that we provided.

When you eat the same meal on two different days your response is going to be very similar, but when you and I will eat the same food, our responses will be dramatically different. You can eat bread and have zero response, and I can eat bread and have a higher response than what I would have if I even ate pure sugar. So it was really all over the place.

And this was even before talking about our solution, this was very surprising. And we realized also that it has a lot of implications.

Because if we realize, again, the importance of blood glucose levels to our health and weight, then what it directly means is that general dietary recommendations are always, no matter what they are, going to have limited utility. Because for any single food that we tested, we had people who had a high response and others that had a low response.

So you can’t really make a general recommendation about food. Now there are trends. There are foods that lower glucose levels on average, for some people. And that is known; it’s what’s called the glycemic index.

I think you even touched upon that in your questions. And we also saw that in the data. So whatever foods have been reported with lower glycemic index on average they have lower responses also in our data. But if you look at all those numbers that go into making that average, they’re all over the place.

[Damien Blenkinsopp]: So there isn’t a cluster around the mean, it’s widespread.

[Eran Segal]: Exactly. It’s very spread across it. And when you measure enough people the means will be significantly different, but there is a wide spread across the means.

Meaning that we can take ice cream, for example, which on average induced relatively low glucose levels, and we can take rice, which on average, induced high glucose levels, but you will still find people that respond more highly to ice cream than to rice.

(00:18:49) [Damien Blenkinsopp]: So it’s quite surprising in those terms. So, in terms of what you’ve found or discovered that drove that. I know you tested for a lot of different things. What sort of things did you also test for in order to try and find the pattern of what was driving this?

[Eran Segal]: So we looked at many different things. We looked at body measures, anthropometries, height, weight, waist for instance and so on. We looked at several metabolic parameters in blood. We looked at questionnaires.

So we had a medical background in food frequency and lifestyle questionnaires. And the most novel component that we integrated into the study is the microbiome. So we measured all of those. In fact I will say that we found an association, a strong correlation, between variability and the response to food in all of these different groups of parameters that we measure.

And then the next step was to take all of these parameters and integrate them into rules, or an algorithm, that basically given your inputs to all of these factors, which vary from person to person, we would be able to predict how you would respond to each and every single food or food combination or complex meals.

And we showed that that actually works very well, and predicts personalized responses with very high accuracy. In fact, the accuracy that we think is even feasible because, even when you eat the same meal on different days, I mentioned your response is going to be very similar, but it’s not going to be identical.

So there is some inherent biological variability, and our predictive power is approaching that variability.

(00:20:30) [Damien Blenkinsopp]: Okay, great. The microbiome was the novel part of this. What exactly did you look at? Because there’s a few different approaches to looking at the microbiome right now.

What were you looking at and trying to map with it?

[Eran Segal]: So we looked at the most comprehensive in terms of resolution, which is just doing shotgun sequencing. So that’s basically sequencing the entire content of what we find in a stool sample. That mostly consists of bacteria, but this type of sequencing is really the highest resolution.

It allows us to identify individual genes in the bacterial composition, of which there are several millions in each and every one of us. It allows us to identify not just species, but also specific strains of bacteria.

And so there are many of these different factors that we integrated together, and used them in the algorithm.

[Damien Blenkinsopp]: Great. Is that cost prohibitive verses some of the other technologies that are used out there?

So you have the 16S, which is just looking at one part which some of the projects like uBiome are using right now to enable them to serve many consumers and make it a lower cost so people can afford it right now. Are the costs much higher for what you were doing?

[Eran Segal]: So first of all, for 16S, I will say that we didn’t want to go in that direction because science-wise I don’t think we would have gotten as predictive power.

And in fact we even showed that to ourselves in the study because it doesn’t have the resolution, and in many cases it doesn’t allow you to go below even the genus level of bacteria. So you can have the pathogenic E. coli or non-pathogenic E. coli will have identical 16S; you won’t know what’s in there. Just to give an example.

So we went for the shotgun sequencing. It is indeed much more expensive. If you talk to researchers they’ll tell you that it’s way more expensive.

I will say that what we have been working on in our labs for many years prior to this study, and then as part of the study, is to optimize this process very extensively using automation and using robotics.

We’ve substantially reduced the cost; it is still significantly more expensive than 16S. But I think our margins of error are much smaller than other researchers, and this is probably also why we were able to profile at that level.

(00:22:53) [Damien Blenkinsopp]: Okay, great. So, in terms of the microbiome – because we’re talking a lot about the microbiome and the other factors – is there a stronger weighting of the variability? Are there variants associated more with the microbiome, or are there some other factors that are really important?

The other thing that is interesting is the microbiome actually does change, and we’re trying to change it and improve it and so on in many clinical situations now. Whereas your height, age aren’t changeable.

So if you could give me a bit of background on what you found is the biggest weighting there, and maybe which is most actionable?

[Eran Segal]: Those are two very good questions.

Related to what is most important, every component that I mentioned before we can show has significant predictive power. Now of course, in terms of predictive power, some of these components are somewhat redundant with each other.

So for example we found that when you add the microbiome and some other components, then we can do without all of the blood tests, and in fact we don’t need them at all for the predictive power. They add really something negligible.

Of course we think that blood parameters are predictive; it’s just that in the context of many other parameters, they’re somewhat redundant because they can be explained and correlated with several other parameters. And so likewise with the microbiome we found that actually unlike blood, in every context that we apply the algorithm, the microbiome always had a significant contribution to the prediction.

I will say though, that of course the microbiome has the most significant contribution when you add it by itself. As soon as you add more and more parameters, this is expected. It’s marginal contribution. And also, I believe this is an area where with additional research we can dramatically improve in the future.

We already have started this process because we have a lot more information and a lot of smarter ways by which we can handle this data, which is not true for BMI, weight, blood parameters, which are very limited in the amount of information they have.

[Damien Blenkinsopp]: Right, because there is basically truckloads of data we’re going to be taking out of our microbiomes, because there’s so much in there.

[Eran Segal]: And when we and others continue to research and identify key genes in the microbiomes that are helping in the breakdown of certain products, production of different metabolites that affect us, and we know better how to zoom in on different features, we’ll be able to improve the predictive power from it.

(00:25:25) [Damien Blenkinsopp]: Great. So in terms of the level, you mentioned that the technology that you’re using goes right down to the strain level, and the species, and genus, and so on. But where do you see the patterns?

Is it on the genus level, the species level? Is it just one species that can completely change how we respond? Or is it at a very high level like bacteroides, or something like that?

[Eran Segal]: So there are significant associations on all levels.

And I can say that it’s not a single species that is really dominating. We actually have this in our paper; we have many different features from the microbiome each make a contribution to the overall prediction, but together there’s dozens of these features. Together they make a significant contribution.

[Damien Blenkinsopp]: Right. It’s really a multifactorial analysis.

[Eran Segal]: Yeah.

(00:26:10) [Damien Blenkinsopp]: Okay. You did a paper before 2014 on the artificial sweeteners, which also got a lot of coverage. That was interesting also.

And in that one I believe it was the high bacteroides and the lower clostridiales which showed that you had a higher propensity to gain weight, wasn’t it? Rather than just blood glucose regulation.

[Eran Segal]: Yeah. So yes, we did see an overall effect there. But also there we developed an algorithm that could predict susceptibility, in that case, to consumption of artificial sweeteners. And that was also multifactorial basically using dimensionality reduction of essentially all the species that we had in the sample.

(00:26:53) [Damien Blenkinsopp]: So the most recent paper you are looking at is also looking at regaining weight after dieting.

For example, if you go on a diet and there’s this typical yo-yo effect where someone goes on a diet and they just regain it all back. I’m wondering is that related to the microbiome or what’s going on? So if you could relate what you’ve been looking at there and what you found?

[Eran Segal]: Yeah.

So we study many different aspects of the microbiome as it relates to our health. And this is another study where we studied another very basic phenomena, the yo-yo diet that you mentioned. And what we showed there is actually that even after you complete a diet and you lose weight, your microbiome doesn’t go back to what it was.

So it’s very well known that as you gain weight your microbiome changes, and what we showed is after you lose weight your microbiome doesn’t revert back to the original state. And that memory, if you will, of the microbiome is in fact sufficient to induce and enhance weight gain once you stop the diet.

So I would say it’s another work further establishing the causal link, and providing more insights into mechanisms by which the microbiome plays a key role in our health, and specifically with respect to metabolic states and diseases; in this case relapsing obesity.

[Damien Blenkinsopp]: In that study did you find any mechanisms? Is it specific species? I think you were talking about metabolites in there as well.

[Eran Segal]: Yes. So this work was in fact work in animal models; this was work in mice. And the advantage of is that we can really go deeper into mechanisms, unlike in humans where it’s much harder.

And so there, we also did a metabolomic profiling, and we identified metabolites that were missing after you lose the weight. And when we administered these molecules back, we in fact were able to cure the mice of the phenomena of relapsing obesity.

[Damien Blenkinsopp]: Wow.

[Eran Segal]: And more important we actually showed that these metabolites in fact regulate genes in the host, in the mouse, and they regulate genes that affect energy expenditure. So these mice, when they have less of these metabolites which are broken down by bacteria, when the bacteria break them down, these mice are going to have less energy expenditure and therefore more weight gain.

[Damien Blenkinsopp]: Wow. So I guess you don’t understand why that energy expenditure is going on. There’s probably quite a complex downstream process that follows.

[Eran Segal]: Right. That’s quite complex, but we also had some insights in the paper as to that as well, and we found some genes that regulate that process in brown fat tissue that are directly affected by these molecules. And these molecules are made less available because the bacteria in mice that had a previous history of obesity, in fact, were breaking down and taking away these molecules more.

[Damien Blenkinsopp]: Wow, so it’s actually the introduction of new bacteria for the weight gainers, which is taking away these substrates.

[Eran Segal]: So in this case, it was metabolites. So there are specific metabolites that are broken down by bacteria, which we showed here, we call that post-biotics as opposed to pre-biotics.

[Damien Blenkinsopp]: Right, by adding the bacteria that’s missing or making taking away the ones that are causing the problem.

(00:30:17) [Eran Segal]: Yeah. Those can be technically more challenging in some cases, but in general yes.

I also want to relate to, you asked me before about the stability, or how much the microbiome changes. And we have several studies on that; in fact, some are not even published. What we find is in fact the microbiome is actually much more stable, perhaps, than most people think.

So in fact your microbiome, unless there is very dramatic change in health or weight, is probably going to be very stable even across many years. We have data on that. And what I mean by stable, it means you will still look more similar to yourself even after following some dietary interventions, at least in the short term, than you will to other people.

Now, having said that, we also found that short term dietary interventions in fact do change the microbiome, also in consistent ways, across different people. So while you’ll still remain in the neighborhood of what your microbiome is, still some functions will go up, some will go down. Those can be consistent across multiple people who consume the same type of dietary intervention.

[Damien Blenkinsopp]: Right.

Just as a takeaway from that, do you think the microbiome is going to be an important area of work? Basically learning how to modify it, push it in another direction in order to solve things like weight gain, blood glucose regulation. Is that your hope?

[Eran Segal]: Absolutely.

So the more we find causal effects for the microbiome on our health and weight the more this should be a target for intervention. But of course that will require further studies to understand what is casual and also how to change it.

And I do believe that with – and this has also been shown – that with long-term changes in diet, you will in fact achieve changes in the microbiome. But with short term dietary intervention the changes will be consistent, but they will be more subtle and you’ll still remain in your own neighborhood.

And what that means in terms of the research that we did, it means the algorithm is going to give you essentially the same predictions, even in a very stable fashion, across even some small, short term dietary interventions because your microbiome is essentially going to be very much the same.

[Damien Blenkinsopp]: Right. So if I test one month, and then I test six months later after doing a series of interventions – maybe not too intense, something like courses of antibiotics, things like that might be more intense.

[Eran Segal]: Antibiotics is probably a different story. That can have a dramatic effect.

I’m talking about even if you change your diet for a few months, your microbiome is not going to change a lot. If you maintain a very different diet after a prolonged period of time – I can’t give you exact numbers, but a long time – then you will see change.

And at some point, those changes may be large enough you may want to test yourself to make some modifications to the diet. But, for a very long period of time, without dramatic interventions it should stay pretty much the same.

[Damien Blenkinsopp]: It might be interesting if you do a course of antibiotics, because people have to from time to time, to redo the test and see what it predicts afterwords. Maybe some of the food responses are going to be different.

[Eran Segal]: Absolutely. And I think after antibiotics you will have very significant changes, and those could affect the prediction.

(00:33:37) [Damien Blenkinsopp]: Yeah. So the last thing, just going back to the artificial sweeteners we spoke about. Because they did see that those had an impact on the microbiome over time.

Do you think smaller things like that, basically micronutrients or small fibers, not necessarily macronutrient profiles, but those kind of things could have longer term impacts on the diet?

[Eran Segal]: Absolutely. I would say some of them could even have bigger effects than macronutrients. So fiber, for example, is something that is digested solely by our gut bacteria, so definitely could, and this is known, have alternations and will overtime have sustained effects. So yeah, absolutely.

I think the way we think about it now, and even drugs. We and others have shown that the drugs that you take actually also affect your microbiome. Any substance that you intake, although depending on the substance, might just go through your gastrointestinal track, meet the trillions of bacteria that are there.

They have 100 times more genes than we do. They could definitely break down these products, they could convert it into other products. I would think of it right now, anything that you intake could definitely affect your microbiome.

(00:34:50) [Damien Blenkinsopp]: Yeah. Alright. Thank you very much for that. Just a last few things.

A lot of people take xylitol and stevia. It wasn’t in your original study, and I was just wondering if you knew anything about that. Because the other ones, aspartame, saccharine, and there was another.

[Eran Segal]: Sucralose.

[Damien Blenkinsopp]: Sucralose. Yeah. It was a bit of a negative view on them in terms of what they were doing to the microbiome. Have you got any information or did you see anything on the other two?

[Eran Segal]: We are studying those now.

[Damien Blenkinsopp]: Great.

Eran thank you so much for your time. It was really useful.

[Eran Segal]: Okay, great.

(00:35:19) [Damien Blenkinsopp]: Excellent. Okay, Lihi, let’s talk about DayTwo and what you’re doing there.

So basically you’re taking the work done by Eran and his co-researchers and you’ve been turning that into this algorithm service to help optimize people’s diets. Could you give me a bit of an overview, how you look at it? What the company’s doing and how you see it going forward over the next year or so?

[Lihi Segal]: Yeah, so we licensed the technology in an exclusive way about a year ago, in the summer of 2015.

And then what we’ve been doing since then with the help of both scientists, because our founders are scientists and they’re on the management team and very deeply involved in the company. And so there’s a lot of hand-holding in that sense on the scientific level as well.

But what we’ve been doing, we built a team up of machine learning experts in DayTwo and also developers, and we really dove into the algorithm.

As you heard, on the research level the first thing they took 30 metrics in the blood, they did the microbiome, both 16S and the full shotgun. What we really tried to do is once we have all the results is really look into the algorithm and see what is that minimum set of features that we need, and write it to consumer. We don’t want to send them to get anything that is redundant.

So looking into that features into the algorithm, and looking to see what we really need, how to commercialize this. So we went through a kind of learning period when we’re looking to see how we define the product, what do we need. Do we need to freeze your stool? Do we need to send you to a doctor to get blood tests, yes or no?

And where we ended up is by looking at a really minimum set; because as you heard Professor Segal say, the microbiome was very significant in any constellation that they took, and made other things redundant. So really where we ended up with on the product side is that it’s all online, almost.

So you come online and you fill in a lot of questions – not a lot, I think a 10 minute questionnaire. But, of course it has to do with your anthropometrics and your food preferences and your medical history. Any information you just fill in your questionnaire. And then we mail home a kit; just a box. In that box there is a small tube and you take a stool sample at home.

So we use DNA Genotek as our supplier of the kit. If you know them, they’re out of Canada. This is really kind of state of the art microbiome collection kit. You don’t have to freeze it, you literally just take it when you can, when it fits you. You don’t have to time it. It’s there, you take it, and then you just mail it back to us by regular mail.

[Damien Blenkinsopp]: Is it a quick swab, or are you actually taking a sample?

[Lihi Segal]: We tested a bunch of other alternatives as well, but this company really gave us the most stabilized microbiome in extreme temperatures.

It’s really important for us to stabilize it and then send it through the mail. And you don’t have to freeze it and all that. So it made it much easier on the consumer side, and it’s also very important scientifically to get the microbiome at the state it was as it was collected in Day Zero.

So we did a lot of trial specifically on that to see that what the company claims is actually right. And so we send you this kit, you mail it back to us, and then we sequence it.

We chose to sequence, as Eran said, on a full shotgun basis because we found that that resolution rate gets us the prediction into a higher level and a very good level. So we decided to do that despite the higher costs that it has.

But again, we try to put a product on the market that is very good; it’s good scientifically, we don’t really cut the corners there. So although the cost is still higher, we do expect it to go down a scale, both on the full shotgun basis and the kits.

And then what we do is give you a mobile application. So you get a personalized mobile app that you download, and it’s tailored just for you. And it gives you three things initially.

It gives you a microbiome report, because we did it and we have it. Not all our users are going to love it, but a lot of them may be curious to open it up and see. And so there’s a lot of information there.

We’re giving you your top food and meal recommendations. So what that means is that we really look into different categories. You have your top breakfast, your top lunch, your top dinner, your top fast food, because even when you eat fast food once in a while you can still choose healthier fast food than others.

We’re really trying to bring this into your day-to-day and make little changes and not turn your world upside down. And then there’s whatever alternatives with pasta, alternatives with rice. That’s really general.

And we’re really giving you your top A+ meals and scores all the way to your worst list, which has up to C-. So we’re trying to educate you through that stage. You could always go to see what your top breakfast is, what your top lunch, and all that, but then you also have the ability to search.

If we didn’t say something that you eat and you want to know what your score is, you just search for it in our database. In the US we are based on a database of MyNetDiary. So we have 400,000 different foods that are US based foods.

In Israel we are have a different database that has Israeli foods in it. So people can really find what they eat in there.

[Damien Blenkinsopp]: Right, so these are actually branded products you can buy. Is that what you’re saying?

[Lihi Segal]: Yeah, there are a lot of branded there as well, but there’s also, for example, an apple without skin.

[Damien Blenkinsopp]: Okay.

[Lihi Segal]: You also get your just general food as well, but you would find your specific brand of whatever, yogurt, that you’re eating in the specific territory. And then, so that’s the second thing. The third thing is the search and also a build your own meal kind of possibility.

So the whole point here is that we’re not scoring nutrients. We’re not saying carbs or proteins, and we’re not even going into a family of pasta versus rice. It’s very different if you eat a pasta with cream sauce or a pasta with meatballs, or you eat a pasta with macaroni and cheese.

You have to be able to score complex meals, and that is where our kind of secret sauce is, we’re really looking at your personalized response to these complex meals. And so you can just search for those meals if you want. If you’re cooking or if you’re sitting in a restaurant and you’re able to get your scores on the foods that you’re eating.

(00:42:00)[Damien Blenkinsopp]: Yeah. So just to clarify, this is just focusing on glucose management? So lowering…

[Lihi Segal]: Right. So what we aim to do is balance your blood sugar levels. So when you go on and you eat your A+ or A- foods and you eat that on a consistent basis, and you keep portion control.

So it’s not a kind of blank check to eat as much ice cream or drink as much beer as you want, unfortunately. But it does allow you some flexibility with foods that are surprising. Things you thought were unhealthy, all the sudden you understand you can eat them. And vice versa, so it’s surprising in both ways.

And then if you eat that consistently then yes, you’re going to see that we’re helping you balance your blood sugar levels.

And as Eran mentioned, balancing your blood sugar levels has an importance both in minimizing the risk for diseases of all kinds. Even as a healthy person, you don’t have diabetes but it is really important to keep your stable blood sugar levels. And also the whole thing about weight loss.

It helps you, it encourages weight loss in that sense. So you need to have a restrictive diet; you can’t eat whatever you want and think that you’re going to lose weight with this. But it does help you lose weight, it helps control your hunger, it helps control your cravings. And so it really helps you to plan and choose your foods right. That’s what we’re aiming to do.

(00:43:25) [Damien Blenkinsopp]: Okay, great. So, just to be clear. In terms of the inputs, it’s mostly filling in a questionnaire. Is there any other test apart from the microbiome sample? Or is that just the only one that they need to do?

[Lihi Segal]: No, the basic thing is that we need the microbiome and we need your questionnaire.

Now if you do have addition information, if you have your HBA1C levels then we’ll be happy to take them in. If you have more blood tests it’s always good to take in. But it’s not as significant enough so we’ll say you have to do it.

[Damien Blenkinsopp]: Yeah.

[Lihi Segal]: But on a general level, as much information as you’re willing to give us, it will always help, yes.

[Damien Blenkinsopp]: So in your algorithm, it will just take that into account as well?

[Lihi Segal]: Yes.

[Damien Blenkinsopp]: It’s just that in terms of the cost, you don’t want to add to the cost or be inconvenient.

[Lihi Segal]: Again, as Eran mentioned, it becomes redundant at some point.

And so if you have it, great, but we don’t want to get people – the cost is not that much for an HBA1C, it costs like 20 dollars in the US today. So that’s not really the issue.

It’s more just this is the basic package; you send it home, you send it back. But as we’re looking at our future products and as we interact with you throughout your day, the app is going to allow you in future versions to report to us what you ate.

And we have a lot of insight on your sleep and on your exercise. That was not published, but we have it in the data, and they haven’t published that data. He didn’t mention it, but in the research they actually had people logging in their foods, but also their sleep and also their meditations and their exercise. They had a Fitbit on everyone.

So there’s a lot of insight that we’re going to be able to give you. And when to eat your biggest meal, because people have a certain rhythm and that’s personalized as well. So when would be preferred to have a large meal of the day. In the US usually it’s dinner. In Israel sometimes it’s lunch, sometimes it’s dinner.

Certain foods that you should eat at certain times of day. So we can really interact with you over time if we have more information on how you slept last night and how much fiber you had in the past 24 hours. There’s a lot of things that go into the algorithm that, if we don’t have them, fine, but if we do it can even help us give you better results.

[Damien Blenkinsopp]: So you’re integrating these lifestyle factors as well into the computations to tell people when to eat. That’s great.

[Lihi Segal]: Your stress levels, all that.

(00:45:52) [Damien Blenkinsopp]: So I was wondering, are you able to tell the status of someone?

Say I’m glucose intolerant to an extent already, when you get the data from people without getting the HBA1C, for example, are you going to be able to know this person’s going to have to be more careful? Is any of that kind of information coming out?

[Lihi Segal]: We’re not at any point a diagnostic company, so whatever we see we will not tell you.

[Damien Blenkinsopp]: Oh, okay.

[Lihi Segal]: We don’t do health assessments on you. We’re giving you your recommendations under a predictive model.

And for example if we find things that we think you should know, then we would probably say maybe you should see your doctor, or take these results to your doctor or something like that. We would never go into actually giving you any medical advice.

(00:46:35) [Damien Blenkinsopp]: Right. The same usual thing. There’s a lot of blood glucose dis-regulation that goes on way before you get to diabetes, as Eran was saying.

So I’m just sort of interested from an algorithm perspective. I know you’re not going to publish it because there’s a medical borderline there that you don’t want to go near, but I was just interested from an algorithm perspective – can it tell how far you are along that line? Because everyone’s got a little intolerance. I’m just curious, does it offer any information?

[Lihi Segal]: I can’t.

[Damien Blenkinsopp]: Okay, fine.

[Lihi Segal]: I can’t answer that question.

But as Eran mentioned, we’re looking into on the road map for DayTwo that’s not just for the people who want to buy it right now but we are looking into various things we can do with the data that we have, the data we collect, and the things that we learn. And of course diagnostics and therapeutics are a part of that whole agenda.

And so there’s insight that we’re looking into and collecting, and can very well come out with additional products that are related.

[Damien Blenkinsopp]: So as a first stage it’s basically a food recommendation engine as the output, and of course your microbiome data.

Do you have an idea of what type of microbiome data is going to be given? I know we talked about uBiome, for instance, in the past. We had Rob Knight from some of the other tests.

We’ve looked at a few different ones in the past. Have you got an idea yet, or are there pictures or anything of what it’s going to look like in terms of the data you provide for the microbiome?

[Lihi Segal]: I can definitely go back and send you some information about how it’s going to look, more or less.

[Damien Blenkinsopp]: Alright, cool.

[Lihi Segal]: But we’re trying to go into a lot of detail. Again, we’re doing full shotgun so we have additional insight. We’re not at just a very high level; we are looking into specific types of bacteria and trying to link them. We’re looking at studies and just general information about them.

Again, we have to be a little bit careful and not tell you anything that you may be alarmed with, or if you think that you have this and you’re going to be Type II or anything like that. So of course we’re being careful in the way that we present it. But there’s a lot of interesting information.

We’re also looking to do this in a very cool way that’s going to be, at least on the web – on the mobile it’s going to be a little flatter – when you sign into your web, there’s a report that’s going to be very interactive. You can dive in and go all the way down to the strain level, and then come up. So it’s going to be really cool in that sense.

[Damien Blenkinsopp]: So is there going to be, basically are you going to give all of that data?

My audience tends to be on the high quantitative side, so some of them tend to be people who download the data and start playing around with it in Excel. So will you have that kind of data?

With uBiome, for example, they have two aspects of that. They have the raw data they provide for you to download, and then you can put it into software to actually interpret yourself, like biometrician software.

And then they give you graphs which are basically summarized. So there’s not all of that information there, it’s a bit different, and it’s according to their perspective. So in comparison, what will you provide?

[Lihi Segal]: No, I don’t know to tell you that we’re going to give you all of the raw data. We probably could, but we haven’t finalized that down to the core of it. But again, we have it.

We’re going to have, as I said, the report and the very interactive tool so you can explore it. And the infographics is really cool. People are just playing here with it when they’re too tired to code. So they go and start planning that. But we could also provide the raw data, for sure.

Again, I think our users as opposed to uBiome users, uBiome users are mainly people who purchased it because they were curious about the microbiome. Our users, most of them, if I need to kind of guess or what I see, the microbiome is what gets them to say, oh this is really interesting.

This is personalized for me, I have my personalized microbiome; these people are scientific based, it’s not just that somebody came up with a diet based on my blood type, there’s science here. I don’t think that a lot of them are going to be very interested in downloading the file of the microbiome and things with it.

But we could definitely allow that, or be able to do that, if we see that there’s a need for that from our users.

(00:50:58) [Damien Blenkinsopp]: Yeah, cool. Alright. I saw there was a mention of a Mayo study on your site?

[Lihi Segal]: Where did you see that mentioned, by the way? I’m trying to figure out how did that get to you. We didn’t publish…

[Damien Blenkinsopp]: Well I don’t know, I think it was just mentioned. Oh, I know where I found it.

I was looking through your FAQ and there were some directions for Mayo study people on how to find the information.

There’s a leak there.

[Lihi Segal]:L: No, it’s not a secret by far.

We are recruiting people in the Mayo clinic now, and DayTwo is all over it. We just didn’t issue the press release saying that yet. But that’s been approved and it’s on it’s way as well.

So, what we’re doing, I’m happy to share, it’s no secret. But what we’re doing with the Mayo clinic is a clinical trial that is very similar to the clinical trial that The Weizmann Institute has done in Israel.

And so we’re recruiting 500 people and going through the same process of putting exactly the same device that was used in the trial in Israel and giving them test foods that are American foods, like a bagel and cereal, and really having them log their foods and providing all that information, and a lot of blood tests. So we’re really replicating the trial.

We’re just going to do that because we wanted to make sure we’re providing relevant recommendations after we have a basic cohort of US people. It doesn’t have to be the entire 500 completed, but we just, as the Israeli one was all Israeli, with Israeli microbiome and Israeli food, we just wanted to make sure that we’re able to calibrate the algorithm and it also works on a US based population with US foods and all that.

So we’ve already kicked that off. It’s a great collaboration for us to do this with the Mayo clinic, obviously. So we’ve already connected people. If any of your users are Rochester or Minnesota based people they can go and be part of that clinical trial.

[Damien Blenkinsopp]: Right. And it will be literally a copy of the other study so they could look at the other study to see what it would entail as well.

[Lihi Segal]: Right. There’s a bit of new information there as well. So that’s the reason we’re doing that. And also to start a collaboration with the Mayo clinic for other things as well.

(00:53:14) [Damien Blenkinsopp]: Great. Do you have a timeline for that? In terms of when you might get results eventually?

[Lihi Segal]: The timeline for US, it’s opened for pre-order. I know you probably entered through the UK, so you didn’t see that, because it’s IP based.

But if you were in the US you would see a pre-order. If you were in Israel, you could also buy and start getting it. So we started selling in Israel already.

The US is open on a pre-order basis, and we’re going to start shipping kits out to people in the beginning of 2017.

[Damien Blenkinsopp]: Okay.

[Lihi Segal]: It’s just around the corner.

[Damien Blenkinsopp]: Okay. So there are people already using this service in Israel, and it’s functioning.

[Lihi Segal]: In Israel we started the whole process of getting the evaluation, the kits, out to people and getting them back and sequencing them. We’re just starting to get, we’re in the final stage of getting the application finalized, and then getting the recommendations for people.

But there are a lot of people already who are using it because they got recommendations, whether from the Weizmann Institute Study or through us.

They’re not using the fancy application with the ‘Build Your Own Meal’, but the results and all of that have been around and have been used. Actually the BBC had a great show – I don’t know if you’ve seen it.

[Damien Blenkinsopp]: No.

[Lihi Segal]: The BBC has a show called ‘Trust Me, I’m A Doctor’.

[Damien Blenkinsopp]: I don’t watch TV here, unfortunately.

[Lihi Segal]: Oh, okay. So anyway, ‘Trust Me, I’m a Doctor’, it’s a doctor that has a show and she features clinical trials. And so she actually participates in the clinical trials that she features on her show.

So after the publication itself, she approached the scientists. She came to Israel with her colleague and was profiled and went though it, got food recommendations. Then she went back home and only ate what she was supposed to eat, lost weight and felt great, her energy levels [were up].

She was all psyched about it, and featured it on the BBC in a great show. I’ll send you the links so if you want you can see them.

[Damien Blenkinsopp]: Yes, please.

[Lihi Segal]: So there’s a lot of people who are using it, but outside of the clinical trial setting as well.

[Damien Blenkinsopp]: Okay, great. So it’s already getting around.

[Lihi Segal]: It’s getting contracts. Yes, we see the results are there.

(00:55:23) [Damien Blenkinsopp]: Yeah. Okay, so in terms of just how it’s going to be available, you’re only shipping to the US. So is no one in Europe is going to be able to do this?

[Lihi Segal]: Well, soon. We get a lot of approach on our support.

After the show was aired there was like 10,000 people hitting the website. So we know that there’s a lot of people interested. And we really want to go into selling in the UK as well. We’re just trying to be [safe], being a start up and not to jump too far ahead.

[Damien Blenkinsopp]: One thing at a time.

[Lihi Segal]: Right. So we did Israel because otherwise people will kill us here if we don’t bring it home. But we didn’t even translate it into Hebrew, it sold in English.

And we’re opening in the US because it’s an important market to start in. But we have concrete plans to get into Europe in 2017. So, soon. At least in the English speaking countries.

Really, logistically it just means that we need to get this box to people, but it’s not that simple. We will need a local database of food. So there’s some work on the server side to give you your foods and the database that fits you. We don’t think we’re probably going to need a trial to do that.

So in terms of the microbiome what we see is that the changes are not that [significant]. So there’s changes in the territories in the microbiome, but they’re probably not that apart compared to where the recommendations are. So you and I are very different in the way the algorithm predicts for us.

The microbiome is different, but it’s not that different. Anyway, it works on people. It could work on the US even without the Mayo trial.

[Damien Blenkinsopp]: So it sounds like that’s a validation effort.

[Lihi Segal]: Right, exactly.

[Damien Blenkinsopp]: I haven’t looked at studies of comparison of different countries and their microbiomes. There are some?

[Lihi Segal]: There are, if you look at the [57:12 check, unclear] that they have their graph there. So these show the US and there’s overlaps between the US, Europe, and Israel.

There are differences as well, but the differences, the way it reflects it in the algorithm is not that significant. So it works.

(00:57:33) [Damien Blenkinsopp]: Do you know when the Mayo trial, how long that’s going on for?

[Lihi Segal]: Oh, the Mayo trial will take a while. But we don’t need to complete the trial before we’re able to give recommendations. So we just need to validate it in a smaller group. But we’re there collecting data.

It’s more, you know in the US you can’t put a continuous glucose monitor on people at all if you’re not diabetic. Except under IRB kind of trial setting. So on a consumer level we couldn’t find any provider that would allow us to put continuous glucose monitors on healthy human beings without prescriptions. It’s a diabetic label from the FDA.

So we don’t have the device, and in order to really collect that data in the US we need to have a clinical trial set up and get the appropriate IRB and all that. So part of the whole doing of the Mayo clinic is because we just want more data, relevant data with glucose monitors and logging of food.

So we don’t need that to continue to start operating. I don’t even want to stop it after 500, so we’re talking about opening Arizona as a site, and Florida as a site. It’s really good just for our internal research purposes to continue to get more data.

(00:58:53) [Damien Blenkinsopp]: One quick question. I’ve noticed that Arizona comes up a lot in lab testing. I’m just wondering, as you brought it up just then, is there any reason?

[Lihi Segal]: Because Mayo has a site there. So when I’m collaborating with Mayo clinic, they have additional sites other than Rochester, Minnesota. So they’re thinking of expanding this to there and I’m more than happy to get more data.

[Damien Blenkinsopp]: I was just on holiday in Arizona and I just noticed that there are a lot of lab testing companies there.

[Lihi Segal]: It’s probably due to relevant man power and cheap, and something like that.

[Damien Blenkinsopp]: I think there’s maybe some state regulations or something that make it a little bit easier. Something like that also.

[Lihi Segal]: But again, when you sell outside of Arizona then you’re going to have to comply with the state laws anyway. So I’m not sure if that’s going to help you. But I don’t really know.

(00:59:41) [Damien Blenkinsopp]: So right now for the US is it $299 for the pre-order?

[Lihi Segal]: The price is going to be $399 but we’re opening up at $299, that’s a pre-order discount. But once we stop reordering, we’re probably going to go up to $399.

In Israel it’s 500 dollars, but we’re also doing a premium product in Israel; we’re giving continuous glucose monitors to people in Israel. So we’re giving them a fancy report on their blood sugar levels and all kinds of other stuff. We can because the device that I talked about in Israel you can put it on humans that are not sick.

[Damien Blenkinsopp]: Right, wow. That sounds like quite a service. If someone would pay 1000 dollars or more…

[Lihi Segal]: No, no, 500.

[Damien Blenkinsopp]: Oh, and they’re getting that premium service with the glucose monitor?

[Lihi Segal]: Yeah. It’s a lot, 500 dollars. It’s just more expensive than the US because of the continuous glucose monitor that we’re putting on.

[Damien Blenkinsopp]: They’re quite expensive, those things.

[Lihi Segal]: Well, they cost a few hundred. I guess in the UK it’s about 80 Euros. And then the reader and then the patch cost a little bit more.

[Damien Blenkinsopp]: I looked into getting one for myself; not for medical reasons, just to play around with.

[Lihi Segal]: Abbott Freestyle. Just take the Abbott Freestyle Libre. Just look for it. Freestyle Libre and then just order it online. And I think it costs 100 Euros or something.

[Damien Blenkinsopp]: Okay. And it’s got consumables on it too.

[Lihi Segal]: And then you have a patch. You get a round patch that you put on for two weeks. It’s good for two weeks. And then you have a reader.

[Damien Blenkinsopp]: And this is the one that Eran was talking about earlier that they’ve started using.

[Lihi Segal]: Right. So you can get that online.

We bought a bunch of them online ourselves in the UK before we found it in Israel. And once we found it here in Israel we decided to go with this product that we can also collect from people their blood sugar managements and give them all the fancy reports on all that. So it’s cool.

[Damien Blenkinsopp]: Yeah, it sounds quite exciting what you’re doing in Israel, because you’ve got more flexibility there. Are you publishing anything, maybe a bit later, about that on your customer base?

[Lihi Segal]: Not yet.

[Damien Blenkinsopp]: Okay.

(1:01:51) Is there anything we haven’t covered about the service, that we’ve missed?

[Lihi Segal]: Yeah. I think that this is kind of our direct to consumer approach. So we’re selling to you directly, but what we’re really working on is partnerships. Because what we really believe is that the way you’re going to use this is also very personalized.

Some people, the fact that we give them a fancy application that’s really cool and has a report on it and teaches them what to eat and what not to eat. There’s going to be a diet planner at some point on this. So you can really be independent in the way you manage your food.

For some people that’s going to be great, but some people really need more support. So maybe they go to Weight Watchers or they use other weight management services. And once you know as a user that there’s specific recommendations for you that are personalized for you, you really can’t tolerate generalized information anymore.

I’m saying this for myself. I go to this Weight Watchers group – it’s not Weight Watchers, it’s a local Israeli group. But I can’t hear her say to me, you should eat pretzels as a snack. 100 calories of pretzels are your snack. I’ve been doing that for 15 years, and then I found that it was my number 1 spiking snack.

And I moved to a different, totally different corn-based snack that was much better for me if I’m eating that 100 calorie snack already. So I’m snacking on that.

And what we’re thinking of doing is really opening an API with a lot of services. And so you as a user can share your information with your doctor, or with your nutritionist, or with your weight management group. Or when you take out food you want to be able to get a score. You want to log in, connect to…

[Damien Blenkinsopp]: So you could plug into a meal delivery site.

[Lihi Segal]: Think of this. Let’s say you’re ordering take-out of your food. We do this every day at lunch, just because in Israel is how it works.

And so I want to log in and connect with my DayTwo account, into that service, then get a menu and my score, A, or B. I’m already in a great restaurant, I’m eating food or I’m taking it out, I want to be able to get a score and choose right.

In the US specifically there’s a lot of employer wellness programs. All of those wellness programs provide nutritional advice, but it’s generalized. I, as a user, want my personalized advice to go with me.

So, that’s kind of the partnerships that we’re doing. Some will bring us customers, some we will bring our customers to them. And we’re building a marketplace around this.

So literally, think of that that we’re not competing with anyone. That’s the strategy that we built. We want to enable anyone who wants to use this personalized service to use it in their application and services.

[Damien Blenkinsopp]: Great, to make the information more widely available.

Lihi, it sounds great. I’m sure there are insurance companies and so on who would be interested in that as well. I know they’re getting more interested in these wellness programs.

[Lihi Segal]: Of course.

[Damien Blenkinsopp]: Okay well thank you very much for your time today. I really appreciated it.

[Lihi Segal]: Sure. Thank you so much.

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Ketone bodies, whether gained from fasting, keto diets, MCTs or exogenous ketones have many potential applications with benefits ranging from performance, to health, to longevity and mitigating symptoms and risks of certain diseases.

There is growing evidence that ketone bodies, whether they come from fasting, keto diets, MCTs or exogenous ketones have potential applications across many areas from longevity to performance, to health and mitigating some of the risks and symptoms of certain diseases like cancer and neurologically inclined deceases. As such the whole ketone body area is what I call a high leverage area due to the many potential upsides.

So I’ve personally been investing more time into experimenting in this area as the payoff for that effort, looks pretty promising. You’ll have noticed that I’ve done a fair amount of fasting and since late 2015, that also includes the exogenous ketones and playing around with the ketogenic diet. More to come on my results with all of those in future episodes.

This interview is a very in depth look at many of the applications of ketone bodies and the nuances of their use in the body.

Ketones have a unique effect of being… anaplerotic… [This] helps to generate the bioenergetic intermediates [including] the Krebs cycle intermediates… to energize the brain when fuel flow is kind of low.
– Dominic D’Agostino

Today’s guest is Dominic D’Agostino. Dominic has something that I found relatively rare but makes for extremely valuable interviews. He has a combined prospective coming from both research and self-experimentation. He has a considerable amount of lab work and research specifically done into ketogenic diets, ketones, ketone driving supplements and a growing number of applications. And he has done a lot of his own self-experimentation for many years in this area.

Dominic is currently an associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida, and he’s also a senior research scientist at the Institute for Human & Machine Cognition (IHMC). His research is focused on developing and testing ketogenic diets, ketone supplements, and amino acid formulations for a broad range of therapeutic and performance applications.

His laboratory uses in-vivo and in-vitro techniques to understand the physiological, cellular, and molecular mechanism of nutritional ketosis and supplement formulas. His current efforts are focused on evaluating different methods for inducing and sustaining nutritional ketosis and how this can be optimized to the specific individual and applications. So, we’ll see in today’s interview that there are a lot of nuances and it’s a bit more complex than just boosting your ketones.

Dominic’s research is supported by the Office of Naval Research, The Department of Defense, Support Supplement Companies, and Private Foundations.

Special Note: In the interest of full disclosure, since late 2015 I own a company (Ketosource.co.uk) that develops ketogenic and ketone driving supplements, foods and drinks for the UK.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know if you want more on this topic in the comments!

itunes quantified body

What You’ll Learn

  • Using exogenous ketones to mitigate some of the impairments of sleep deprivation (all nighters, or jetlag) (5:50).
  • How the stress response from scenarios like jetlag will kick you out of ketosis (and can be compensated for via exogenous ketones) (13:00).
  • Dominic’s background research and how his career has evolved to working on ketone bodies and ketogenic diets and their applications (14:50).
  • Recent research with mice that may indicate that ketosis reduces anxiety (17:00).
  • Screening a range of different naturally derived exogenous ketone agents for their therapeutic and performance benefits (18:40).
  • A once to twice per year fast or nutritional ketosis protocol for potentially activating a range of beneficial genes (37:50).
  • The press-pulse ketone body strategy for the management of cancer (40:40).
  • The benefits of the ketogenic diet for the management of epilepsy over the pharmaceutical alternatives (49:20).
  • Using the ketogenic diet to restore normal appetite regulation (50:15).
  • The various health, performance and longevity applications for ketone bodies (52:00).
  • Potentially reducing tremors in Parkinsons and Alzheimers with the use of ketone bodies (57:10).
  • Evaluating the legitimacy of recently raised safety and effectiveness concerns related to ketone salts and MCTs based on scientific facts and their track record over the last two decades (1:01:10).
  • How racemic exogenous ketones suppress glucose more effectively than non-racemic exogenous ketones (1:13:40).
  • Using MCT oil powder as a staple product for coffee, baking and protein shakes to boost the ketogenic profile of your diet (1:16:00).
  • Avoiding liquid meals in order to be able to elevate protein intake higher while remaining in ketosis (1:18:00).
  • What a typical ketogenic day looks like for Dominic in terms of blood ketone measurements from morning to evening and how he optimizes it (1:20:00).
  • How Dominic has identified his optimum ketone and Glucose-Ketone Index ranges for mental performance (1:21:00).
  • To standardize and control for your blood ketones and glucose you need to be fairly sedentary (1:34:10)
  • Dominic D’Agostino’s recommended self-experiment with the largest potential upside with the tactic to test and biomarkers to track (1:42:00).

Thank Dominic D’Agostino on Twitter for this interview.
Click Here to show him some appreciation for doing this interview!

Dominic D’Agostino

Recommended Self-Experiment

  1. Tool/ Tactic: Start Intermittent Fasting with fasting windows of 18 hours and eating windows of 6 hours each day. Dom recommends listening to Matt Mattson’s talk on IF before you start.
  2. Tracking: Get some baseline lab tests before you start the IF and again 3-4, and/or 6-8 weeks afterwards to see the positive impacts. Your lab tests should include fasting glucose, triglycerides and hs-CRP.

Tools & Tactics

Diet & Nutrition

  • Well Formulated Ketogenic Diet: The high fat, low carb, moderate protein diet that puts you into ketosis with typical blood ketones of between 0.5 and 3 mmol/L depending on execution and the person. Not suggested for children, teens or people in their 20s with good insulin sensitivity in general.
    Foods Dominic Makes Particular Use of:

    • Coconut Cream: Combines the fats with some of the fiber from the coconut flesh. Coconut cream is also known as Coconut Butter.
    • Ghee (Clarified Butter): Butter that has had the dairy proteins removed to leave solely the fats. As such it is considered dairy-free.
    • Wild Sardines
    • Sour Cream with Live Cultures: Didn’t find a link to this – if you know a good source please let me know in the comments.
  • Fasting Protocols

  • Intermittent Fasting: Sometimes referred to as short-term fasting due to the typical 16 hour to 20 hour fasting window. Dom noted that he has spoken to a fair number of high-performing CEOs doing this routinely recently.
  • Fat Fast: A modified intermittent fasting protocol whereby you restrict caloric intake in the fasting window (e.g. 18 hours of day) to some fats, exogenous ketones and/ or MCTs instead of a pure fast (no food or calories). Dom finds this method effective and that he tends to be less hungry going into the eating window (i.e. 6 hour window).
  • Periodic Fasting: Typically refers to fasts spread out by once per week or once per month. We’ve done past self-experiments on the once per month periodic fasting protocols via a 5 day fast, 10 day fast and fast-mimicking diet.

Supplementation & Drugs

Exogenous Ketones

Dominic’s lab has looked at a variety of exogenous ketone formulations in different scenarios and applications. Amongst their papers are included improved blood lipid profiles1 and non-toxic metabolic management of cancer2.

MCTs and C8 (Caprylic Acid)

  • Brain Octane: Pure Caprylic Acid (C8) from Bulletproof Nutrition.
  • Keto8: Pure Caprylic Acid (C8) oil from KetoSports.
  • Quest MCT Powder: MCT powder that Dom is using as one of his staples mixed into coffee for example.

Dominic’s Sleep Deprivation Effects Mitigation Cocktail

  • Exogenous ketone: Take your pick from one of the exo ketones listed above. Is beneficial to combine with MCTs such as C8 or MCT powder.
  • Caffeine: Needs no introduction – use coffee or your other favorite
  • Huperzine A: A nootropic herb used for cognitive enhancement via modification of acetylcholine levels.

Drugs

  • Metformin: A drug which is used to improve blood sugar regulation in diabetes. Researchers are looking at its wider applications with cancer treatment as it has been found to inhibit insulin secretion.
  • Ringer’s Lactate: The long term use of this racemic solution was noted as evidence as to the safety of racemic ketone salts.

Tech & Devices

  • Hyperbaric Oxygen Therapy: Increasing the amount of oxygen in the body with the use of a hyperbaric oxygen tank which uses air that is more highly saturated with oxygen and which is compressed. Dominic has worked on research with Doctor Thomas Seyfried looking at its application for cancer therapy in combination with ketogenic diets3.

Tracking

Biomarkers

    Glucose/ Ketone Metabolism

  • Glucose: Dom suggests aiming to keep values between 60 and 80mg/dl and that if you can maintain this all other biomarkers should be fine.
  • Glucose Tolerance (OGTT): The Oral Glucose Tolerance Test is a glucose challenge test whereby you take a certain number of grams (e.g. the typical standard is 75 or 100 grams) of glucose and test your body’s ability to regulate glucose and bring your blood glucose back into normal range over a certain time period (e.g. 2 or 4 hours). Dom used the OGTT to assess his insulin sensitivity – the more insulin sensitive you are the quicker your blood glucose returns to normal fasting levels e.g. between 60 and 80mg/dl optimally.
  • HOMA (Homeostatic Model Assessment): An alternative method to the OGTT used to assess insulin sensitivity/ insulin resistance.
  • Glucose-Ketone Index (GKI): This index was conceived by Thomas Seyfried and discussed in detail with him in episode 16. It assesses the weighting of the metabolism towards ketone vs. glucose. Lower values are ketone driven metabolisms and higher value (especially over 20) can be associated with heavy glucose metabolisms associated with chronic disease. Dom brought a new angle to this marker with an optimum everyday target he shoots for of between 2 to 4. Previously we discussed Thomas Seyfried’s recommendation of undertaking a 5 to 7 day therapeutic water fast once or more times per year targeting a GKI value under 1.
  • Lipids

  • Triglycerides: Dom believes this is the most important biomarker to watch. Optimum levels estimated as below 40mg/dl.
  • HDL: Higher HDL levels are said to be protective and beneficial. Dom’s value are around 90 mg/dl.
  • LDL: Dom believes keeping values in the normal to normal high reference range are perhaps optimal. This puts levels at approx. 80mg/dl to 110mg/dl. We previously discussed LDL in more depth in episode 7.
  • Other

  • hs-CRP (high sensitivity CRP): CRP (C-Reactive Protein) is a very common marker of inflammation that is used to assess cardiovascular risk amongst other things. It tends to drop on a ketogenic diet. Dom’s values have been between 0.1 and 0.2 since he quit dairy (Note: Damien’s levels are also at this level).
  • IGF-1: IGF-1 was discussed in more detail in our FMD episode. Dom’s IGF-1 values dropped significantly after quitting dairy.
  • Heart Rate: Typically heart rate is measured as the biomarker Resting Heart Rate (RHR) for standardization, which is an average of the beats per minute. See episode 1 to understand the use of RHR.
  • Blood Pressure: Optimum ranges are for systolic between 90 and 120 and dystolic 60 to 80 expressed as for example 110/70 mm Hg.

Lab Tests, Devices and Apps

Devices for Measuring Glucose & Ketones

The different approaches to measuring ketones provide different perspectives on your ketone metabolism. These can be looked at in terms of the ‘window of snapshot’ that they represent. Some methods have a snapshot of a longer duration, so provide more of an average reading, while others provide a direct status of that exact moment.

Moving from the more average-based value end of the scale to the more direct status end you have:

  1. Measuring ketones via the urine (via the ketone body acetoacetate) has the longest snapshot with it representing your ketone values over the last 5 to 6 hours.
  2. Measuring via the breath (the ketone body acetone) has a smaller snapshot window of the 2 hours leading up to the measurement.
  3. Measuring via the blood (via the ketone body beta hydroxybutyrate) provides you a snapshot of your ketone level at that exact moment.

The various devices available for glucose/ ketones testing and mentioend include:

  • Urine Ketone Strips: . Both hydration status and becoming keto-adapted interfere with the measurement values provided by this. Dominic recommends starting with urine test strips as they are the cheapest and effective until you get keto adapted.
  • Ketonix Breath Meter: Currently the only breath acetone meter. If you are moderate to high on this meter you are effectively in ketosis (i.e. typically over 0.5 mmol/L). Dom recommends this in particular for epilepsy since breath acetone has been correlated with seizure control.
  • Blood Glucose & Ketone Monitoring Systems
  • Precision Xtra: The most popular meter for testing blood glucose and ketones in the U.S. Has a broader reference range than the NOVA providing values for lower blood glucose levels instead of the LOW error.
  • Freestyle Optium Neo: Freestyle Optium Neo is the upcoming replacement for the PrecisionXtra, it comes from the same company and has similar functionality – the only difference in the meters seems to be a rebranding exercise.
  • Novamax Plus: Novamax Plus is a slightly cheaper meter with some greater accuracy and sensitivity concerns than the Precision Xtra or Freestyle Optium Neo.
  • Dexcom G5 CGM: A Continuous Glucose Monitor that Dom is about to start experimenting with for blood glucose optimization. Peter Attia has also been using this tracking device recently to optimize blood glucose regulation. We discussed continuous glucose monitoring and the devices available in episode 43

Other People, Books & Resources

Books

People

Researchers

Other Mentions

  • Tim Ferriss: Has been experimenting with the breathe hold extending effects of ketone bodies via ketogenic diet and exogenous ketones.
  • Ben Greenfield: Has been experimenting with using exogenous ketones for free-diving.

Organizations & Companies

Other


Full Interview Transcript

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(05:32) [Damien Blenkinsopp]: Dom welcome to the show.

[Dominic D’Agostino]: Thanks for having me, Damien.

[Damien Blenkinsopp]: Yes, it’s great to connect. So you’re just back from a trip to Budapest and you just told me that you’re doing something to bypass the jet lag?

(05:42) [Dominic D’Agostino]: Yeah. Sometimes depending on circumstances I try to prioritize sleep and try to get between six to seven hours sometimes eight on the weekends if I can. But in the absence of sleep, I like to test certain things.

Usually happens once every month or two or I’m going to have to skip one night completely and have to get thrown right back into the fire of work again. I’m doing that now, and testing some different exogenous ketones in combination with caffeine and some Huperzine, and a few other little things in a stack formula that I’m working on.

It seems to be working because I’m functioning and I’ve been able to manage my tasks in a way that allows me to get stuff done.

[Damien Blenkinsopp]: So, this could be a new jet lag formula? Or if you want to keep going on sleep deprivation and work for a night or something…

[Dominic D’Agostino]: Yeah. So, inevitably people will come to the situation where they have to meet a deadline and stay up all night to get something. I don’t recommend doing it all the time because you can get burned out. There is no pill that you can take that will substitute for sleep.

But there are ways to extend your productivity and performance with two or three days of no sleep. I don’t like when those situations arise, but I worked on ways to mitigate some of the impairments that accompany that.

(07:13) [Damien Blenkinsopp]: That’s excellent, that sounds like another application for exogenous ketones I had not thought of. I know there are a whole bunch I want to discuss with you because it seems like there’s quite a few of them. So now if you want to work all night, they can help with that.

I’m tempted actually, what is the mechanism behind that specifically for sleep, is it just a pure energy thing or?

[Dominic D’Agostino]: As far as sleep? Mitigating sleep?

[Damien Blenkinsopp]: Why would exogenous ketones help with?

[Dominic D’Agostino]: Yeah, I think there are several ways that they can help. You can formulate things to provide energy to the brain. There’s various, what we call tricarboxylic acid cycle intermediates, including alpha-Ketoglutarate, creatine – is actually something that could be beneficial to the brain when energy reserves are low, and ketones have a unique effect of being anaplerotic. So if something is anaplerotic it helps to generate the bioenergetic intermediates which include the Krebs cycle or also called the TCA cycle intermediates.

Essentially just helping to energize the brain when fuel flow is low. Many of the TCA cycle intermediates are also precursors to neurotransmitters. For example, alpha-Ketoglutarate is a precursor to glutamate, and then from glutamate through glutamic acid decarboxylase we make GABA.

So, ensuring that we have efficient energy flow to the brain and sort of stimulating anaplerotic reactions and bioenergetic reactions we can replenish the neurotransmitters. Being in a state of ketosis too, can also be glycogen sparing.
I always had the opinion that when we sleep, part of the function of sleep not only restore neurotransmitters but to also restore brain glycogen levels.

Glycogen is actually stored in the astrocytes of the brain. Astrocytes are not just for support cells they have a really important function that pertains to glutamate recycling and sort of dynamic interactions with the synapses and recycling of neurotransmitters and restoring brain glycogen levels is a function when we sleep.

I think we need to look into this more but I have a theory that being in a state of strong ketosis could prevent some of the glycogen depletion that accompanies a normal day in a person that is normally sort of carbohydrate fed.

Where the brain is sucking massive amounts of glucose but if you’re ensuring that it gets a steady fuel flow of ketones it’s going to be glycogen sparing in that way. Sort of like what Jeff Volek is doing with the athletes and it showed in a recent metabolism paper, that being keto-fat adapted and keto-adapted can actually be very glycogen sparing. If you look at the muscles of lead athletes on a carbohydrate restriction, amazingly their glycogen stores are topped off in the muscles.

I think the same thing is happening, I see no reason why it wouldn’t happen in the brain. Our energy reserves in our brain tank, adenosine goes up, neurotransmitters are depleted – we want to sleep. Being in a state of ketosis can slow that process, and exogenous ketones can be a tool in a toolbox to help with that.

[Damien Blenkinsopp]: That’s really fascinating. It’s like the biochemistry of sleep, we’re getting tired and I think we understand on a very basic level but you’ve just broken down quite a few mechanisms which lead to us needing to sleep and how to counter them.

[Dominic D’Agostino]: Yeah, sleep is a really complicated subject. I did my Ph.D. in a pulmonary critical care department that was also a sleep lab. So I sat in on a lot of rounds and meetings with residents and fellows about the mechanics of sleep.

It’s just a fascinating subject, and something I’ll probably get more into research wise. But I do teach the medical students about obstructive sleep apnea and central sleep apnea, that’s some of the research that I did in my Ph.D.

(11:22) [Damien Blenkinsopp]: Excellent, and you’re on a keto-diet as well right still?

[Dominic D’Agostino]: Yeah. I maintain that but I also like to cycle a little bit because I think a lot of the therapeutic and performance enhancing benefits can be achieved with nutritional ketosis but I also think it’s good to have relative changes.

Not to stay on something all the time, but to adjust your macronutrients a little bit, and also maybe your calories a little bit, and occasionally fasting. These relative changes can produce some pretty good performance and therapeutic effects.

[Damien Blenkinsopp]: It’s kind of like exercise like promoting metabolic flexibility, is that where you’re coming from?

[Dominic D’Agostino]: Yeah, that was what I was going to say and relate it back to a hormetic effect where relative changes are good. For a while, I just stayed on the exact same ketogenic diet for a long time and I started adjusting and playing around with different supplements and I realized it’s good to sort of adjust the diet and even adjust your calorie levels sometimes. My life is variable, it kind of fits on with my lifestyle too.

[Damien Blenkinsopp]: I feel the same way. I’m probably doing the something a bit more varied these days. So, it’s just interesting, you said you are basically stacking exogenous ketones for sleep on top of your keto diet. Does that push your levels quite high?

[Dominic D’Agostino]: At least doubles or maybe triples where I would be. I have noticed in the past that if I just stick to my normal diet and I cross time zones. I’ve been in at least a dozen time zones for the last month and a half, two months.

When I do that and I miss a complete night of sleep, coming from Southeast Asia completely flips circadian. I realized that I get a stress response from that I think my cortisol goes up, my sympathetic nervous system can be activated. And I notice that can kick me out of ketosis a little bit or I’ll have levels that are — I would predict there would be much higher based on the macronutrient profile that I’m eating and even fasting.

So, I find that exogenous ketones can sort of help in those situations where I put my body into an unaccustomed stress.

(13:36) [Damien Blenkinsopp]: That’s very interesting. I’ve started to use some of the supplements, exogenous ketones for different scenarios a bit like that situation but we can talk about that later. So, I wanted to give people a background, would you say your focus area is ketones, ketogenic diet? Is that what you’d call your focus area of research?

[Dominic D’Agostino]: Yeah. I’m classically sort of trained as a neuroscientist. I did my PhD in something very specific, it’s patch clamp electrophysiology where you measure from individual neurons and you record the membrane potential, firing frequency input resistance of individual neurons, either in cell culture or in a brain slice, and studying pharmacology and the metabolic activity. I became very interested in observing fundamental neuronal activity.

I became very interested in the metabolism that was supporting that. I realized that the life that I was seeing on the amplifier of the oscilloscope, these neurons firing was completely a result of the electrochemical and the electrical gradients between the neurons, they’re like little batteries.

That was generated completely by the metabolic activity so cells they need to maintain negative 56 kilojoules per mole of energy and they will do anything to do that. Some substrates and some means of generating ATP are more efficient than others. In my early work, I was actually looking at lactate.

I was interested in Ringer’s lactate, so racemic Ringer’s lactate is actually used on the battlefield and also in surgery when people have a lot of massive blood loss. Lactate is extremely efficient fuel, and I studied hypoxia in the brain and ischemia, and I was interested in lactate for that. That got me interested in this whole idea of developing and testing metabolic substrates to preserve and enhance brain energy metabolism in the face of extreme environments.

Our work for the last decade has been funded by the military. So I’m interested in particular situations that would accompany military operations, like a navy seal using a closed circuit rebreather with high levels of oxygen. He’s susceptible to a limitation of his mission, would be oxygen toxicity seizures so the fundamental neuroscience that I learned in my Ph.D.

I applied that to developing and testing metabolic base therapies to preserve that cognitive function and metabolic resilience in the environmental extreme of high-pressure oxygen. That’s sort of a fun thing to do because there’s many ways to do it. I’m always looking for the next, or the optimal formula, of ketones and that’s why we don’t focus on any one particular exogenous ketones. We screen a variety of ketogenic agents or formulas of them to identify the one that’s most neuroprotective or anticonvulsant.

Now, we do cancer studies and we do wound healing, performance applications – and it might be a different ketone for different applications and we’re testing that now. In Budapest, we actually presented some really interesting work on anxiety. So if we induce a state of nutritional ketosis, the anxiety levels go down pretty significantly. In a rodent model, they’ll spend more time in like an open-arm of an elevated plus maze.

Perhaps that reduced anxiety can play a role in reducing seizures too, so it’s another variable that we need to look at. I probably went off on a tangent. My background was neuroscience and now I do what I would call a nutritional neuroscience or metabolic based sort of strategies to target neuronal processes and neuroprotection.

(17:43) [Damien Blenkinsopp]: How many years have you been doing this now?

[Dominic D’Agostino]: I started neuroscience research as an undergraduate in 1997. So, it’s going on about — 1996 or 1997 — so about 20 years now I’ve been into neuroscience research. The office of navy research, post-doctoral fellowship, was the first large grant money that I’ve got, and that was 10 years ago.

It took me about four years to recognize that the most potent strategy for oxygen toxicity for mitigating that, which I was being funded to do would be a ketogenic approach. Then the ketogenic diet at that time was recognized as something very obscure even just six years ago. So the funding agency really wanted a ketogenic diet in a pill per se.

In addition, to our ketogenic diet research which I feel is also very important we have developed these synthetic and actually naturally derived ketogenic agents to mimic the effects of fasting, the ketogenic diet, and also to further augment the therapeutic efficacy of the ketogenic diet. If the ketogenic diet can only get you to one to two millimolar, and we boost it in another one or two millimolar with exogenous ketones. We’ve realized that, that can be very beneficial.

Not everyone can follow a ketogenic diet including performance applications or for therapeutic purposes.

[Damien Blenkinsopp]: People find it quite hard. I don’t think it’s relatively complex to get into it. I speak to a lot of people who think they’re in ketosis but they’re not.

[Dominic D’Agostino]: Yeah, I do too.

(19:25) [Damien Blenkinsopp]: It’s a little bit tricky I think. So, alas comes the supplementation and so on which could make it easier. I think what’s really awesome about you, you self-experiment as well in addition to your research.

You’re always looking for this stuff and I know you’ve been on a keto diet for a long time, when did you start that?

[Dominic D’Agostino]: Yeah, that’s the fun part of this research that I’m really excited about. Well looking back, I did low-carb diets for a while because I was always into powerlifting, fitness, and nutrition. So, I would experiment, and I was under the impression that being on ketosis was bad.

When I did a low-carb diet or what I call the ketogenic diet, I remember smelling like ammonia. Because it was basically a very high protein, zero carb diet, with a normal amount of fat. Then I got educated I guess, being connected with the folks at John’s Hopkins who are using this on a clinical setting. I read the book by John Freeman and Eric Kossoff at John’s Hopkins, which is a great book, ‘The Ketogenic Diet’ for epilepsy and other disorders that’s out there.

There are one or more popular books on Amazon. I realized wow I didn’t know what a ketogenic diet was. I didn’t realize it has this fascinating history. You know written with Travis Christofferson, we wrote a three part of series on Robb Wolf’s blog about the ketogenic diet the history. When I actually got into the 4:1 ratio ketogenic diet, the John’s Hopkins which is like 90% fat.

And I transitioned into a state of nutritional ketosis, it was kind of difficult in the beginning. After about two or three weeks I adapted quite well and started realizing the neurological benefits. The appetite suppression was pretty extreme it was difficult for me to maintain my weight even.

(21:16) [Damien Blenkinsopp]: In terms of losing weight?

[Dominic D’Agostino]: Yeah, because my protein level was really high. I think I was getting probably 300 grams of protein a day which is really high. So, I had to drop that down to about 100 grams of protein a day to hit those macronutrient ratios.

Probably about 120 grams a day of protein, which was a relative change that was really low. When I reduced my protein to 1/3 but elevated my fat, and I still kept going to the gym. But at the time my academic career was sort of going full steam and I was in the gym less, but still making it once or twice a week.

My weights that I was handling on major exercises were maintained so I realized that being in a state of nutritional ketosis had a pretty profound anti-catabolic effect. So, I figured I’d be wasting away if I wasn’t getting my body all these protein. But I was amazed that I could eat.

I even started experimenting and went down to like 60 or 80 grams of protein a day. Even after a couple weeks and months I was able to still move the same weights.

So it really blew my mind that shifting the metabolic physiology to being more fat and keto-adapted had this sort of protein sparing anti-catabolic effect. Which makes sense if you look at it through like an evolutionary lens.

So if we stop eating and we didn’t make ketones to fuel this big, highly energetic organ in our head. If the ketones weren’t providing fuel for our brain we would liberate a lot of gluconeogenic amino acids from the skeletal muscle, and we would quickly waste away probably in a week or two, for a lean individual. That’s important to recognize in the context of using a ketogenic diet for a weight loss strategy and also for body composition.

For example, athletes that need to make weight which many sports do — wrestling, boxing, mixed martial arts – keeping that power to weight ratio is important. We think from the studies that we’ve done, we actually just got a study approved finally for publication yesterday showing elite level athletes or advanced lifters that the ketogenic diet is quite effective for body composition alterations and preserving strength and muscle strength and performance.

So that should be out pretty soon in general strength and conditioning. We realize that the ketogenic diet has far more applications than just pediatric epilepsy, which was it’s original application. We’ve probably studied about 10 different applications now in our lab.

(23:59) [Damien Blenkinsopp]: Excellent. So I wanted to run through some of those applications. First of all taking a step back because you mentioned lactate earlier. I think the majority of us assumes that glucose is the main metabolism. Then we learned about ketones and we think maybe there’re two substrates that we’re using for metabolism.

As I understand it, it’s a lot more complicated right? That we’re using a number of different fuels at any time?

[Dominic D’Agostino]: Yeah. I think the big ones for brain metabolism, which our laboratory originally focused on and now we’ve branched off, would be glucose would be the primary fuel for most people. Then ketones are sort of a backup fuel.

If you’re on a ketogenic diet, you’re running this hybrid engine and you’re using both fuels at the same time. With ketones probably the most efficient of the two. Then lactate too.

When we exercise, we mobilize a lot of lactate and put a lot of lactate back into the bloodstream through what’s called the Cori cycle. We convert that back to glucose and then replenish liver glycogen or muscle glycogen. But that lactate can also go past the blood brain barrier across which is called the monocarboxylic acid transporters and provide a source of energy for our brains.

Lactate metabolism in the brain can also occur under conditions of oxygen deprivation, so it may be beneficial. That was also an interest in my earlier work, using lactate to preserve bioenergetic processes in the absence of oxygen. What we call hypoxia or anoxia, which is a complete lack of oxygen.

Interestingly ketones can generate more ATP per oxygen molecule consumed. In a hypoxic situation, ketone metabolism may also be able to preserve the bioenergetic state of the brain. That’s something that we’re also looking into hypoxia and ischemia protection of the brain with various fuels, ketones, lactate preventing or an alternative substrate to glucose.

In certain situations, neuropathologies and even a hypoxia, stroke, a brain injury for traumatic brain injury can cause a quick impairment of glucose utilization of the brain. By internalization of the GLUT3 transporter and also inactivation or reduced activity of Pyruvate dehydrogenase complex, the PDH complex, can be impaired under certain conditions of brain injury. Even certain viruses that cause neuroinflammation can impair this rate-limiting step for glucose metabolism.

So, alternative energy substrates are a way to bypass that glucose block.

(26:37)[Damien Blenkinsopp]: It’s like a diversification strategy?

[Dominic D’Agostino]: It is, in diving we always talk about being redundance. You need a level of redundancy to ensure safety. I think the brain does that pretty nicely. So we achieve that with fasting.

We have an alternative energy substrates being utilized in the absence of glucose. It’s interesting to be able to delve into that and understand what happens during fasting in different states. From my perspective, it’s a fascinating field of research to develop naturally derived or synthetic agents that can mimic those processes.

(27:17)[Damien Blenkinsopp]: Right. Because we are on a ketogenic diet do we also use fatty acids directly for energy substrates or do they have to be turned into ketones first?

[Dominic D’Agostino]: Yeah. Hepatic gluconeogenesis will be in a state of fasting, completely dependent upon the liberation of fatty acids from adipose tissue. Fat mobilization is directly almost correlated to a ketone production in that fasted state.

Our heart can use fatty acids more efficiently than glucose – our heart is an awesome fat burner. The skeletal muscle is an awesome fat burner especially in the keto-fat adapted athlete, the liver, various organs can use fatty acids quite efficiently. The long-chain fatty acids do not readily cross the blood-brain barrier.

Short chain fatty acids do, and medium chain fatty acids can actually cross the blood-brain barrier. So, that was actually an interest of mine and we did some brain metabolomic studies where we took out the hippocampus of some rodent models that we looked at. We saw a high level of the C8 and the CA10 MCT that we administered to the animals.

I think if you look at the ratio between the blood levels and the brain levels. I think there was a kind of like a 1:5 ratio, so that wasn’t readily getting through but a lot of it was getting into the brain. Of course, the brain was metabolizing it.

Our numbers might have not correlated precisely in a 1:1 ratio in that way. But it’s clear that our body can use fatty acids as fuels, and it’s an incredible fuel for our mitochondria. Because it metabolized exclusively in the mitochondria through oxidative phosphorylation.

(29:03) I would say ketone molecules are I’d like to call water soluble fat molecules, sort of an excessive beta-oxidation or accelerated beta-oxidation in the liver, contributes to the accumulation of acetyl-CoA which drives ketone production, and hepatic ketogenesis. So the acetyl-CoA essentially condenses to form acetoacetate. Then beta-hydroxybutyrate and these spill into the bloodstream.

So it’s interesting that the liver is a massive ketone producer but it lacks certain enzymes that prevent the liver from using the ketones as an energy source so it lacks succinyl-CoA transferase for example.

So, the liver will produce massive amounts of ketones. Then dump it into the bloodstream primarily for our central nervous system to maintain energy flow to the brain, then the central nervous system, and probably the heart too. The liver is a greedy organ, if you fast and you eat, the amino acids and glucose will basically stay in the liver and the liver will take what it needs and put whatever is left into the bloodstream.

But with ketones since the liver does not metabolize ketones it puts them immediately in the bloodstream when it’s burning fat for energy. Looking at it through an evolutionary lens, that function is to ensure that our brain gets adequate fuel flow. In the absence of food, if our brain tanked because we’re hypoglycemic, we wouldn’t be able to hunt.

So, being very lucid and having our brains energized during a period of food deprivation ensure that our species survived. The humans that weren’t able to do that did not get on and live. I think we’re sort of hardwired in a way to function optimally when we’re in a fasted state and that’s important to recognize.

Also, in the context of a society that’s programmed to give three high carbohydrate feedings per day. The metabolic program that is activated during fasting is largely silenced because of the societal norms, associated with our macronutrient profile, but also our eating pattern which is frequent feedings throughout the day.

(31:22)[Damien Blenkinsopp]: Yeah. One of the reasons I ask this is because I’ve had some fear and scared feedback about fasting for instance, which is a bit more of an extreme situation like ketogenic diet normally. One of the things I did was publish some of my own information on YouTube and I got some crazy comments from people saying I was going to die because my glucose was low.

I think it was 3.3 millimolar or something about 54-55 mg/dL. My mother’s a nurse and she saw the numbers and she was quite shocked at the time as well. Everyone thinks that we’re driven solely by glucose metabolism that’s the only thing they look at. So I think it’s really interesting that we have several various fuels that we can be going on, turns out that the glucose isn’t that important.

Someone else just sent me the numbers recently and they were the lowest I’d ever seen, like I was doing a fast and she got 1.8 millimolar with her glucose. I don’t know if you’ve seen anything that low.

[Dominic D’Agostino]: I did. Well, when I fasted for a week I tried some strategies, I probably shouldn’t talk about it here.

[Damien Blenkinsopp]: Okay. In case someone else does it.

[Dominic D’Agostino]: Yeah. After fasting a week, I was staying around the mid-fifties to low fifty’s and occasionally I would dip into the high forty’s depending on my activity and things like that. I did some strategies — I’ll label it as “strategies” — to lower it down to a level that the meter didn’t read, so it just actually was flashing low.

The lowest my meter was able to read was 25 or 26 mg/dL. I assume 25 that’s the limit. I spent a good part of the day with it flashing low and unable to read. I was using the Nova Max meter, and I was using the Precision Xtra Meter and also using the Neo Meter, so I had three different meters and I was scrambling.

[Damien Blenkinsopp]: Is that the Freestyle Optium Neo?

[Dominic D’Agostino]: Yeah. The freestyle like a lower profile sort of meter than the Precision Xtra. So I had three different meters, and I was measuring and I was like, “Oh no I don’t even know what my glucose is. All I know it’s probably under 1 millimolar range.”

I was starting to feel a little bit — using different pharmacological strategies to lower it — but I realized that I was at a level that was universally fatal for everyone if I didn’t have my ketones elevated.

[Damien Blenkinsopp]: Right. But if you had been admitted to the hospital, they’ll put you on the emergency ward most probably if you walked in like that.

[Dominic D’Agostino]: Yeah. During this particular day, I was preparing for a lecture, I was writing a grant it was really a productive day. As I was working I was doing these things and I would do measurements and work for a little bit more and it just goes to show it was a very dramatic demonstration an alternative energy source.

For me, that has tremendous implications therapeutically for someone that’s experiencing insulin shock or a neurological disease with impaired glucose metabolism. So we worked very closely with the glucose transporter type 1 deficiency association. It’s a rare disease where the brain does not have glucose available due to deficiency of the GLUT1 transporter.

There are many different diseases like that. I was also inspired by the work of George Cahill, there was a study that was published in 1967. The first author was Oliver Owen and they fasted subjects for 40 days.

In another report that wasn’t originally published with the original report. I found it in another book they administered insulin, 29 IU of insulin they gave IV. In these fasted subject they lowered the glucose down to 1-2 millimolar and kept it down there.

[Damien Blenkinsopp]: So it’s like 35 mg/dL somewhere around there?

[Dominic D’Agostino]: It’s not even that it was about that 25 range that my meter couldn’t read. So one millimolar would be 18 mg/dL. That inspired me, I was thinking if these subjects can fast for 40 days I could do a week.

It’s about five years ago or so that’s when I did the week long fast and did some experiments on myself. One of the most interesting things that happened to me was my breath hold time. So at the time I was outside a lot.

I was in and out of the pool, taking short walks and trying to stay active, keep my mind off of food. Because the main challenge was just the pleasure of eating was not there. I was swimming I was under the pool and I realized, “Wow,I had been down for quite a while”, and I wasn’t gasping for air.

I got back up to the surface and my girlfriend was there at the time, now my wife, and I started testing my breath hold time. I was like, “Keep an eye on me.” Normally I could do over a minute about 90 seconds, but I was able to stay down for three to four minutes which is remarkable.

I don’t have any kind of specialized training. I’ve been wanting to take a freediver course. I know Ben Greenfield did and we exchanged emails when he was going through that because he was trying exogenous ketones. But I found that after one week of fasting, I had a profound prolongation of my breath hold time. I think that’s fascinating to me.

Fasting does definitely start to shut down your metabolism. I think my body temperature probably went down a degree or two so the metabolic demands just weren’t there. But I think our drive to breath has a lot to do with our CO2 sensitivity.

So there’s receptors in the ventral respiratory group and the ventral surface of the medulla that sense CO2 levels and drive the urge to breathe. We also have the carotid bodies, at the bifurcation of the common carotid artery that sends oxygen and CO2 and they also mitigate or they also play a role in the drive to breath.

I think there’re interesting mechanisms going on there. A desensitization in some way or in combination to just altering our metabolic physiology. I think that has some practical benefits for different sports, maybe military operations.

I want to study that a little bit further with adaptations that happen during fasting.

[Damien Blenkinsopp]: Yes, very interesting. I’m wanting to go and test that out with freediving.

[Dominic D’Agostino]: A number of other people have, I think I might have mentioned it once or twice very briefly, not as descriptive in other podcasts but other people went out there and did it.

I think Tim Ferriss did it. I’m not sure if he’d blogged about it yet but he sent me quite a few texts and emails just saying that dramatically enhanced his breath hold time. So, I’m pretty sure it’s a real phenomenon.

(38:15) [Damien Blenkinsopp]: Very cool, to kind of round that conversation off. I get these emails, like I said, some people are scared because they get injured in fasting particularly a very low glucose levels of 30-35mg/dL.

Do you think that’s something to be concerned about or is it absolutely no problem? Typically, they have ketones like six millimolar, somewhere around there at that stage?

[Dominic D’Agostino]: I wouldn’t recommend that for a long term sustainment of life. Because there are a lot of biological processes that require glucose: red blood cells, your kidney, certain immune cells, and even biosynthetic processes like the generation of certain neurotransmitters are in some part glucose dependent. I think it’s good to get into that level and I’m going out on a limb by saying this to be a mainstream sort of medical college.

I actually think it’s very good to be in a state of nutritional ketosis with sustained hypoglycemia for a period of time, and to do that at least once a year, preferably a couple of times a year. I think what really kicks on a genetic program that activates so many biological processes that I think could be protective from enhanced insulin sensitivity to autophagy, to activating a number of different genes. There’s certain ones obviously, ampakine is activated, mTOR is suppressed.

You put tremendous metabolic stress on glycolytic cancer cells or pre-cancer cells that we may have in our body, sort of an immune activation. I know Dr. Adrienne Scheck is doing some work with the ketogenic diet and she’s doing some elegant work on the immune activation, and from the gist of it and from other bodies of literature it supports the idea that the immune system becomes hyper-vigilant, to recognizing and attacking existing cancer cells when we put our bodies into the state of fasting.

Either prolong fasting or even the ketogenic diet. I think it’s good to do that sometimes. But say if you’re on the ketogenic diet all the time in the state of moderate ketosis and then you fast.

You probably won’t get the same benefits as a person who’s on a high carb diet and did a fast. It would be a lot harder for that person who is on a high carb diet to do a fast. It would be greater stress because it’s that relative change or that pulse.

Thomas Seyfried and I we’re going to work on, it was originally his idea. We talked a lot about this press pulse phenomenon for the metabolic management of cancer. The press would just be a mild state of nutritional ketosis and the pulse could be periodic fasting or some of the things that we’re interested in. Such as hyperbaric oxygen therapy that could be pulsed exogenous ketones to further allow for a greater hypoglycemic response.

Also, you could pulse various cancer-specific metabolic drugs like 2-deoxyglucose, or dichloroacetate, or 3- Bromo Pyruvate] could be used. The press would just be nutritional ketosis and that would metabolically compromise a lot of the highly glycolytic, which corresponds to highly aggressive cancer cells.

(41:41)[Damien Blenkinsopp]: When you say press that would be like something chronic that you’re doing?

[Dominic D’Agostino]: Yeah. We know that being in a state of nutritional ketosis causes suppression of the hormone insulin. The cancer cells that light up on a fluorodeoxyglucose PET scan, a FDG-PET scan. The PET [or PET-CT] scan is really the gold standard technique.

I would say when it’s coupled with the CT scan allows you to precisely locate where that hypermetabolic activity is. So the PET-CT is an incredible, gold standard tool to assess the location and aggressiveness of existing cancer cells. The greater the standardized values that are coming out, like 2.5 would be sort of the normalized value.

If you have a PET scan showing SUVs of a 100 or 250, those cancer cells are very aggressive.

[Damien Blenkinsopp]: So they show up as the big red and yellow blotches?

[Dominic D’Agostino]: Yes.

(42:47)[Damien Blenkinsopp]: Yeah, we spoke to Gene Fine on a previous episode he was talking about the PET scan.

[Dominic D’Agostino]: Oh yeah. Actually Dr. Fine, you probably know he did a study for 28 days. He did a study with a ketogenic diet and he selected patients based on their PET scans. The topic that I was going to touch on is that insulin suppression correlates with ketosis.

I think even the title of his paper didn’t even mention the ketogenic diet, it was something like insulin inhibition therapy can be used to target cancer. It didn’t even talk about the ketogenic diet. But if you read the paper, he basically used the ketogenic diet to suppress the hormone insulin as a therapy for managing these hard to treat cancers or people who have failed the standard of care.

So, that would be the press that I’m talking about. The ketogenic diet limits glucose availability to the cancer cells. It suppresses the hormone insulin which drives IGF-1, mTOR and other factors that cause cancer cell growth and proliferation. I don’t know if Dr. Fine talked about it, but he has a number of publications.

I was inspired by his work and I actually got us to look at exogenous ketones and the effect on cancer cells. We find that if you limit glucose, suppress the hormone insulin and elevate ketones, the ketones themselves have anti-cancer effects. So, we did a study, we published in the International Journal of Cancer.

The first author was my graduate student at the time, Dr. Angela Poff, she’s now a research associate following up on this work. We gave ketones to highly aggressive cancer cells that have a glioblastoma-like origin. When we grew the cancer cells in the presence of ketones, even in the presence of 25 millimolar glucose, it inhibited, it dramatically slowed down cancer growth and proliferation.

(44:47) We did a viability testing where we looked at live cells and dead cells and the ratios of that. We found significantly more dead cells when we grew the cancer cells with ketones even in the presence of glucose. The take home was that ketones were probably turning down or shutting off a lot of some of the glycolytic mechanisms and there’s previous reports suggesting that ketone metabolism can turn down glycolytic metabolism.

So, that would be the press.

[Damien Blenkinsopp]: It sounds like a signal even for the cancer cells?

[Dominic D’Agostino]: Yes.

[Damien Blenkinsopp]: For them to switch them off even if they can’t use the ketones?

[Dominic D’Agostino]: Yeah, we think so. Now, we need to mechanistically dissect those kind of signals that are happening with the ketones because they do high-level sciences. Our lab approaches things a little different. We don’t sort of identify a target and then work up from that.

We screen a lot of things at the top and find out what works. Then, once we found out what actually causes animals to live longer or produce a neuroprotective effect then we go and try to find the mechanism.

(46:00) [Damien Blenkinsopp]: That sounds like a little bit like the pharmaceutical drug research process where they screen many many molecules for doing something. Correct me if I’m wrong. It seems like maybe it’s an efficient process to find things that work by just screening a lot of things and then focusing on the things that are working.

[Dominic D’Agostino]: Okay. So, it’s a little different, with pharmaceutical companies they actually target a mechanism or a biological kind of process and enzyme.

[Damien Blenkinsopp]: So they’re all looking for an end result right?

[Dominic D’Agostino]: Yeah. We’re testing a bunch of things, we don’t even know how they work. We’re testing various ketogenic exogenous ketone formulas and we don’t even have the pharmacokinetic nailed down yet. We don’t even know specifically how they’re metabolized.

We feel that it’s really important to get this research done so we can get these therapeutic agents out there as fast as possible. We screen a lot in various agents, first in human or first in animal, and then we identify what works. But the mechanisms, the metabolism is incredibly complex.

What we find is that it’s not working through one particular mechanism, it’s many different mechanisms working in synergy. The ketogenic diet, you have an increase in the GABA to glutamate ratio or ATP production you have a greater bioenergetic potential of the mitochondria. You have more TCA cycle intermediates.

The list goes on and on. There’s a science paper showing that ketones beta-hydroxybutyrate is a HDAC inhibitor. We published a nature medicine paper showing that inhibits the NLRP3 inflammasome and that’s independent of metabolism.

(47:41)[Damien Blenkinsopp]: So it’s like a huge dynamic system? There’s no way you can see all of the mechanisms going on there? As you’re saying you looked for the end effects and then you started looking for the mechanisms.

All of these mechanisms that you just brought up and started piecing them together to see how it worked after you’ve got the end result that you wanted.

[Dominic D’Agostino]: Yeah. The important thing is that it works and then the secondary important thing is to find out the mechanism. Because once you do know the mechanism, if the majority of the therapeutic effects or performance enhancing effects are due to a particular mechanism, out of many mechanisms. Then we can tweak the molecule of the formula, the pharmacokinetics, to further enhance that particular mechanism.

Then we can go back and tweak the formula, or the molecule to make it hydrolyze faster or to increase the sustainment of it, or deliver it in a certain nanoparticle formula to a particular tissue or something like that.

(48:37)[Damien Blenkinsopp]: So we’ve already spoken about quite a variety of basic applications, benefits of ketone based metabolism, and ketones. Could you just go through the top ones in your mind, maybe the ones that we haven’t already covered? So I know a lot of people are focused on weight loss for instance.

[Dominic D’Agostino]: That probably goes back to what they call the ‘Banting diet’. That even predates some of the work that I first got attracted to in epilepsy. So, epilepsy that would be the big thing.

The ketogenic diet, the only thing that is used for standard of care in mainstream medicine is the management of epilepsy. I always harp on this too, the ketogenic diet is grossly underutilized as a tool for managing epilepsy because it works when drugs fail.

It works in about two-thirds of the population. Imagine the efficacy of it if it was the first line of therapy. If you have a child that’s two or three years old and you load them up with anti-convulsant drugs, we know that these anticonvulsant drugs cause developmental delays. It’s even more important in pediatric epilepsy, I think to start with the ketogenic diet.

I just like to throw that out there. We’ve already talked about epilepsy. So, epilepsy would be the big one and obviously weight loss. You have the original Banting diet. Then Atkins came out with what he said was his famous diet but it was really a playoff with the Banting diet. It allows for effortless weight loss because when you’re in a state of nutritional ketosis the ketones function to control appetite.

It prevents your appetite from controlling you. We don’t really know the mechanisms that regulate appetite control, are incredibly complex. But we think that the ketones are essentially telling the brain it’s in a fed state, that’s the simplistic way to put it.

(50:32)[Damien Blenkinsopp]: Okay. Ketones get converted back into fat? Because people know that you basically pee ketones out when you first get onto a keto diet. Is that one of the mechanisms also?

[Dominic D’Agostino]: Well, yeah. If you collect all the urine of someone that’s on a ketogenic diet and then you look at how many calories are there, it’s pretty marginal. I think Atkins even advertised, “Look you’re peeing out fat, you’re peeing out calories.”

But it only came down to like 50 to a 100 calories or something like that. I think the big effect, the metabolic advantage really, is not that you’re burning more calories. I think there’re different organizations out there that we’re trying to prove if there’s a metabolic advantage to being in ketosis.

I think the big advantage that we need to focus on is appetite regulation. Our current diet of processed carbohydrates contributes to appetite dysregulation. The ketogenic diet is very effective at restoring sort of normal appetite behavior because there’s no fluctuations in blood glucose.

If we’re on a carbohydrate based diet and we go hypoglycemic that’s going to trigger an intense craving for carbohydrate re-feed to re-establish that glycemia. That’s completely abolished on the ketogenic diet.

So when you’re on a well formulated ketogenic diet, the craving that you’d have with hypoglycemia is going to be significantly attenuated if not abolished. We talked about weight loss and type 2 diabetes pretty much every disorder out there. Let’s think cancer, even kidney failure, neurological diseases like Alzheimer’s disease and many other pathologies are sort of linked pathophysiologically to the metabolic dysregulation and also obesity type 2 diabetes.

If a diet does promote a healthy weight loss and sustainment of that weight loss, it’s going to be therapeutic for many other disorders. Some of the things that we study include Alzheimer’s disease, ALS, we have a really active cancer research program in the lab. I have two Ph.D. students right now studying.

One is looking at Metformin and other cancer-specific metabolic drugs but combining it with a ketogenic diet. His main thing is to locate drugs. But we think some drugs will synergize with the ketogenic diet.

In another project is looking at the ketogenic diet or exogenous ketones and branch chain amino acids to mitigate cancer cachexia, which is muscle loss or wasting, so we’re looking at that. Exercise performance we’re looking at that. The most recent data that I’m really excited about because of the pretty robust effect as far as some of the behavioral models that we use.

One particular model is the elevated plus maze which looks at anxiety. We found that being in a state of nutritional ketosis that was induced completely with exogenous ketones stimulates in the elevated plus maze which is like a rodent going out on a catwalk. You can go into a cave or come out into an open area where you’re on a plank and you’re elevated in the air.

It’s a very anxiety producing situation. In our rodent models validate as a very useful model. We’ll spend much more time on the open arm and less more time hiding in the cave. We think that has significant implications for military personnel with PTSD and anxiety in general, and a lot of depression too is also sort of a comorbidity there with anxiety, a lot of depression, and anxiety fueled.

[Damien Blenkinsopp]: You’re saying that they’re willing to go out walk on the plank, take that risk and feel comfortable with it?

[Dominic D’Agostino]: Yeah.

(54:28)[Damien Blenkinsopp]: Do you measure it by time spent on the plank?

[Dominic D’Agostino]: Yeah. Less anti-social behavior I guess. We set up this elevated plus maze and then we have a whole video imaging system above it. We keep the animals as low stress as possible.

We have the same person working with the animals so they’re not experiencing different smells, and things like that. The room is very very quiet. We pay attention to circadian, light on light off things.

There’s a lot of variables that need to be controlled and then we image them in the absence of ketones. We see how much time they’re like in the middle, in the open arm, closed arm and our video camera system sort of can track all that. We have various programs and algorithms that do all the calculations for various things.

We do a bunch of animals just on a standard high carb diet. Then what we’ve been doing is testing various ketogenic agents, or various exogenous ketone and ketone formulas that would be administered 30 minutes prior to being put in this elevated plus maze, and being there for a couple of hours. Then we’ll track all that information, it’s all done blinded.

We have one person who’s, usually two people part of the project that’s administering the agent. The person that does the analysis does not know what the animal is receiving. We’ve got a pretty robust effect with a few of the ketogenic agents on reducing this anxiety behavior.

That’s some new data that we just presented literally less than a week ago in Budapest. That’s what I’m just returning back now. So we want to follow up on that. We used one dose, we need to determine what would be the optimal dose.

There’s a lot of work that we still need to do to optimize that and maybe think about putting together a formula that could be beneficial for people.

(56:30)[Damien Blenkinsopp]: Very cool. One of the ones you didn’t mentioned is Parkinson’s, is that something?

[Dominic D’Agostino]: Yeah. There’s an earlier study I think that was done by Dr. Theodore B. VanItallie. Dr. VanItallie is like 96 years old. We still communicate on the phone and through Email.

He was one of the original ketogenic diet researchers. He did a small sort of pilot study showing that people with Parkinson’s disease can follow a ketogenic diet and that being in a state of nutritional ketosis reduced the tremors associated with Parkinson’s disease and prevented some of the symptoms. Not a cure, but it could help manage some of the symptoms associated with Parkinson’s disease.

There really hasn’t been a good follow-up study to that. I know there was a ketone ester that was developed at NIH and a study at Oxford. There was that group that had a clinical trial open. But I think they might have had some problems recruiting people into that clinical trial, that opened a few years ago.

I know there was a clinical trial looking at the effects of exogenous ketones on Parkinson’s disease. And if we weren’t tied up with so many other projects I would be jumping on that. Because I was able to observe on Alzheimer’s patients when they took a medium chain triglyceride supplement, or even exogenous ketones. They would have pretty dramatic tremors.

And some Parkinson’s disease-like symptoms can be manifested in people with Alzheimer’s, especially advanced Alzheimer’s. I was able to observe and also got feedback from caretakers that when they induced a state of nutritional ketosis it really rapidly stops the tremors associated with that. So, that needs to be followed up on.

The pharmaceutical industry dictates a lot of what studies are done. Because you need a strong financial backing on top of a university, or chain of universities that supports this kind of research. On top of a review board, an IRB, that will prove this kind of research using these nutritional metabolic substances. There are many hurdles that need to happen.

Then you have to recruit patients on top of that and convince them that it’s not a drug but it’s a nasty tasting food that could potentially benefit you. They were like — well, it’s easier for a child, a son or a daughter [who] is bringing in their mom who is typically in a situation — 80 or 90 years old.

They’re not going to want to try to formulate some nasty tasting shake to do that. It’s much easier to just give them a pill. These are some of the things you see, the feedback that you get from people who are trying to implement these kinds of nutritional protocols in patients.

There’s a lot of hurdles. A lot of people ask me, “Well, if it’s so effective, how come science is not using the ketogenic diet or exogenous ketones to treat all these disorders?” I could write a book on the reasons why, but nutritional research is so hard to do.

Because nutrition is really tied into the lifestyle thing, and getting institutional support, getting the expertise needed, ensuring that patients are following through and complying with the protocol. All of these things are hard to do. A supplement, in theory, is a lot easier but we’re at the very initial stages. Because these are just new entities that just developed.

(1:00:16)[Damien Blenkinsopp]: Right, it’s only two and a half years you’ve had the ketone salts for instance, and the esters a bit longer?

[Dominic D’Agostino]: A little bit more than that. I would say the ketone ester was actually developed probably about 20 years ago, if you look into the animal literature. Then they were dropped because it was thought that they’re very expensive to produce and they taste like jet fuel.

Some of the people that originally developed these things, like Henri Brunengraber. He’s like a hardcore metabolic physiologist-scientist who develops a lot of remarkable things. But he kind of drops it and moves on to the next thing.

There’s also sharing the chair of his department and running a billion other things at the same time. So, I dug up some of this research and realized, “Wow, why didn’t anyone follow up on this?” Then I saw some of the work that was funded by DARPA, showing that they were the secret project.

They were using these ketone esters for warfighter performance enhancement. I found some patents and some files on that. I was like, “Well, this is what I need to explore, for use of CNS oxygen toxicity.”

Not only can the ketones potentially mitigate the oxygen seizures but the ketogenic diet was super effective. Even independent of the ideology of the seizures that it tends to work which is really remarkable. But instead of giving an anti-convulsant drug to a warfighter, which can dull your senses and impair your physical and cognitive performance.

You could be giving an anti-convulsant neuroprotective substance that enhances the physical and cognitive performance. It seemed like a win-win situation. I’d rapidly grasped this idea and just went into this manic state of writing grants and writing proposals, and digging up all the research.

Then, I was calling my program officer and I was like, “You need to hear this information and what I’m going to tell you.” We actually had a little meeting at our university and he was like, “We have to do this.” He was very generous to fund some of the initial basic science proof of concept research that demonstrated the efficacy of this ketone ester in mitigating oxygen toxicity.

It worked better than anything we had ever tested or anybody had ever tested, even drug wise. That’s going back in 2009 or 2010. From there, I’m really in safety because I’m really scared about bringing something to market that could potentially harm someone. I know there has been some discussion out there about the quote and quote dangers of a racemic beta-hydroxybutyrate salt.

People need to recognize the difference between someone’s opinion and scientific fact. The scientific fact is that racemic beta-hydroxybutyrate salts have been used for decades for treating a disorder called MAD, Multiple acyl-CoA dehydrogenase deficiency. I get Emails from the patients or from the parents that are treating their kids with this, and it’s like a miracle for them.

I also get Emails from parents that are treating their kids with glucose transporter type 1 deficiency syndrome with a racemic beta-hydroxybutyrate (sodium beta-hydroxybutyrate), which is actually a prescription you can get in Europe.

But they’re also using these commercially available ketone salt products which would be the ones that you might be familiar with. There’s KetoCana from KetoSports, Pruvit makes Keto OS, Forever Green makes Ketopia. The Kegenix product which is the one I’m testing now. It’s a really excellent exogenous ketone product.

This idea which was talked about in various podcasts, I think in Bulletproof podcasts and Ben Greenfield’s that racemic sodium beta-hydroxybutyrate was dangerous and ineffective. It is an opinion and there’s no science to back it up.

If you go back and listen to the podcast you’ll hear the speaker actually reference no actual studies. So, it has an intellectual property supporting the non-racemic, so that needs to be acknowledged and appreciated.

What is appreciated from my end, the science backing up the efficacy and the safety are really profound – like I’ve said on expert panels to approve some of these molecules. And no toxicologist or physiologist could find any evidence that racemic, which is the DL version of beta-hydroxybutyrate, was dangerous in any way.

For example, if you’re a medical doctor or a combat doctor on the field and you’re treating soldiers that have a loss of blood or you’re in the emergency room just talking to the ER doctors, use the Ringer’s Lactate and that’s Racemic lactate.

So, L-lactate would be the natural lactate that you would find in your body. The DL would be in an enantiomer or a mirror image of that lactate. Both of the lactate molecules get metabolized to energy. So, the same things happen with ketones. So the D and the L version get metabolized to ATP, to energy.

A lot of the metabolism has been worked out with very elegant tracer based fate association studies by Dr. Brunengraber at Case Western. Lactate Ringer’s has been used in millions of combat troops and emergency rooms. If there was a danger to using a racemic metabolate, there would be a lot of dead bodies around – and that has not been the case.

Actually, it’s FDA approved, it’s widely used and accepted, and it was even studied the difference between L-lactate and Racemic lactate before it became a standard of care. Actually, it was looked into, and it had exact same effect.

So, if you use the Racemic versus the L-lactate have the same effect at preserving the metabolic activity of the tissues and being protective in that way. So, that needs to be acknowledged that when statements are made, that they could be an opinion and not validated by scientific facts.

The ketone supplements that are on the market now that I’m aware of are very safe and from feedback, they’re very effective. I don’t support any particular ketone supplement that’s out there. I’ve tested all of them and they tend to elevate my beta-hydroxybutyrate and the .5 – 1 millimolar range for one dose.

So, for me to really boost my ketone levels up, I have to take a packet and a half, or a dose and a half, which I can tolerate pretty well. But I think there’s a lot of room for improvement and the products that are out there.

I hope to work with these companies, hoping that they will fund research to support the further development and evolution of these products for different applications.

(1:07:30)[Damien Blenkinsopp]: Excellent. Thanks for going through that because that’s something I have my eye on as well and wanting to get some more facts. Something else that was thrown out, a couple of things was that the racemics were less efficient or were ineffective?

We also have all of the MCTs which people are using to kick up their ketones as well. We have the C8 and C10 of the MCTs, there’re various products around. Another statement that was said they were undesirable and you should avoid those as well unless you really had to take them.

For instance, if you have Parkinson’s it was okay to take them but otherwise you shouldn’t be really taking them. But a lot of people are taking these. Right now, there’s a bulletproof brain octane. I’m sure a lot of people are taking that.

KetoSports has got their own product that I’ve been taking for a long time personally. I don’t know if you have got any comments on that?

[Dominic D’Agostino]: Yeah. I study a lot of very expensive exogenous ketone products. But the more I look into medium change triglycerides, especially the C8 oil which is digested and assimilated much differently than long-chain fatty acids. When you consume it, it basically perfuses the liver.

I mean it goes right to the liver via hepatic portal circulation. It goes right through to liver and is burned as energy. So, they’re poorly astrophied, which means they’re not re-astrophied back and packaged into chylomicrons, like long-chain fatty acids.

Once they reach the liver, it’s basically an obligate oxidation. The medium chains are almost completely oxidized to ketone bodies. Some of them will spill into the bloodstream because we find them in the brain tissue and other tissues.

But it’s independent of the various transporters too. For the medium chain triglycerides to get into the mitochondria there’s various CPT-1, for example, is not needed to get the MCT into the mitochondria. So, they bypass a lot of these rate limiting steps.

And you consume them, it goes right to the liver, you generate a lot of beta-hydroxybutyrate and some of that gets into the bloodstream. So you have the combination of ketones and the medium chain triglycerides going right to the mitochondria. And that can be very therapeutic and beneficial for many different disorders.

You have to realize that the person making that statement that MCTs are dangerous or ineffective, has some underlying personal interests in advancing the commercialization of his particular exogenous ketone, and that needs to be appreciated and understood.

From our perspective, we’re interested in testing that particular ketone formulation and 20 other, and finding out the truth, finding out which is most effective, which is safe. When it comes to the racemic, and the statement that racemic beta-hydroxybutyrate is not as effective. We have not found that out to be the case.

Actually, the first ketone ester that we studied for oxygen toxicity was a monoester of the R-beta-hydroxybutyrate we have formulated. And that did not prevent CNS oxygen toxicity, which actually was very strange to me. But the more research I did I found out that you needed to elevate both the acetoacetate and beta-hydroxybutyrate in the blood to mimic some of what happens naturally, physiologically.

The acetoacetate through spontaneous decarboxylation to acetone, or maybe it has it’s own metabolic effect independently. The elevation of acetoacetate was absolutely critical. It also in the presence of beta-hydroxybutyrate but it was absolutely critical to elevating both ketone bodies to get the anti-convulsing effect.

We published that in the American Journal of Physiology and showed the pharmacokinetics and seizure work with that. So, we screened a lot of agents and found out the particular ketone ester that we found to be most effective was 1,3-Buntanediol acetoacetate diester]. So it was 1,3-Buntanediol that was racemic, so it would make racemic beta-hydroxybutyrate.

But even the non-physiological enantiomer gets broken down and converted to Acetyl-CoA and some of that goes back to the physiological enantiomer so it all gets broken down and metabolized similarly to Ringer’s Lactate which is used in millions of patients.

But the important thing about that particular molecule is that when it’s consumed orally it gets hydrolyzed and it rapidly liberates the acetoacetate. Then the 1,3-Buntanediol gets metabolized in the liver and elevates beta-hydroxybutyrate. So you have both ketone bodies elevated in the blood. We find that it’s absolutely critical to get a certain level of acetoacetate to get the anticonvulsant effect.

(1:12:30) One thing I didn’t talk about was Angelman Syndrome, which is characterized by impairment of motor function and also drug resistant seizures. It’s extremely effective in an animal model of Angelman Syndrome.

If you look at Angelman Syndrome and the ketogenic diet, you come across case reports showing that it basically puts Angelman syndrome patients into remission, at least for seizures. So, it’s highly efficient for that.

So, the first ketone ester we studied was this R in the enantiomer, the hydroxybutyrate, and it was not effective. So it was actually the racemic version of a ketone ester that was most efficacious.

But we’re interested in exploring all different pathologies and finding out which one. So, we have not found out that the R and enantiomer is any more efficacious for any other disorder than the racemic. I think that’s important to acknowledge.

We also found that medium chain triglycerides tend to formulate really well with this exogenous ketones. Not only are they carriers but we think they enhance the transport across membranes and they improve the pharmacokinetic profile, two of many of the ketones salts. So when it’s formulated with MCTs which have the nice advantage of also being ketogenic.

One of the benefits of racemic, the other enantiomer, so there’s D and L. The L-enantiomer tends to impact the liver in a way that reduces hepatic gluconeogenesis. So, you have this hypoglycemic effect that is very well characterized by our laboratory and other peoples laboratory.

[Damien Blenkinsopp]: So you’re saying that ketones go up and the glucose goes down?

[Dominic D’Agostino]: Yeah. It’s more pronounced with the racemic and we don’t know why that is.

(1:14:22)[Damien Blenkinsopp]: Is that beneficial to some of the applications more than others? Weight loss for example?

[Dominic D’Agostino]: Yeah for weight loss, maybe for seizures too. We know that reducing glycolytic metabolism can be beneficial for seizures but also for cancer. As I mentioned, we have pre-active cancer research program.

The lower we can get glucose or glucose response to a meal, the lower we can reduce that, the better therapeutic efficacy we think the agent will have. If we formulate the agent with food, so every time our animal models will eat the food they’re getting a dose of it.

Instead of injecting into the animal or ‘gavaging’ it in the mouth for our cancer studies, we actually take these ketogenic agents and formulate it to about 10 to 20 percent of the weight of the food. Then we count the macronutrient ratio, and then they eat it.

Every time they’re eating the food they’re getting a dose of ketones with the glucose. Because we do a lot of our studies formulating with a high carb diet. Because we want to find out the therapeutic effects of the particular agent and distinguish that between the ketogenic diet.

But we also published a study, about a year ago, where we formulated the ketogenic diet with the ketogenic agent. We did this with a ketone ester and found that it further enhanced the anti-cancer effect of ketogenic diet.

(1:15:48)[Damien Blenkinsopp]: Okay. I’ve got a few questions about this. There’s some MCT powders on the market which combine glucose. Me coming from a ketogenic perspective, that’s not something I want to take with the MCT powder. There’re other powders which don’t have the glucose.

Is there anything to think about or is it not really an issue? Because there’s this effect of the ketones pushing down the glucose anyway? Would it have zero effect? I haven’t tested it myself yet.

[Dominic D’Agostino]: Yeah, the MCT powders on the market like Quest Nutrition?

[Damien Blenkinsopp]: Not Quest, they don’t. It’s basically the generic ones. There’s this cheaper one, generic one, where they’ll put glucose syrup in it and some other glycemic ingredients.

[Dominic D’Agostino]: Yeah, with my interest in the ketogenic diet and staying in ketosis, I would rather get my carbohydrates from things like vegetables, salads, blueberries and dark chocolate. Basically encompasses my carb intake there. So I would avoid that.

A staple product that I use, I have it right by me right now is the Quest MCT oil powder. I did a little bit of beta testing for them as they brought that to market. We went back and forth, and I tested that a lot.

I consumed a lot of that and I did tons of the blood work and got to the point where I was really impressed with the product. There’s not too many products that I consider staple products, maybe about a half a dozen in total that I keep with me all the time.

That MCT oil powder is great, it’s very versatile. You could use it in baking, you could put in my coffee, you can add it to protein shakes to further boost the ketogenic profile of your shakes.

[Damien Blenkinsopp]: Do you take that with you? I take this stuff as well, I’ve got it right next to me as well in my coffee [unclear (1:17:32)]. What I was going to say is that you take that on top of your ketogenic diet?

But I think an interesting thing, I talk to people and they’re taking the exogenous ketones or the MCT powder as a normal diet, or the body builder’s diet where it’s high protein, and they’re not doing a keto diet.

Then there are other people who are interested in getting keto but finding it difficult. They’re using it to ease into the keto diet. So there’re a couple of different applications people use them for different things. I’m just wondering what you’re ideas are in those scenarios.

Dominic D’Agostino]: Yeah. If I put the Quest MCT oil into my coffee or shakes or things like that. I generally try to avoid liquid meals, because liquid meals digest totally different. The only liquid meal that I have would be my coffee, and I would put in some coconut oil and MCT on top of that.

Occasionally, I put in butter or coconut cream. I’ve been using coconut cream instead of full cream. The benefit is that I can elevate my protein a little bit more. I generally eat two meals a day now that I’m home and not traveling.

My meal in the evening is about twice the calorie count. So, I get about a third of my food calories in the morning and about two-thirds in the evening, but I get a lot of fat calories during the day I guess. Because I’ll make my coffee and whip it up and then bring it in a thermos, and drink that mostly in the morning. Then I’ll have a little kicker in the afternoon maybe.

That fat balm, I guess if you want to call it that and occasionally take some exogenous ketones too during the day, if I’m testing different products. It just adds to my total fat macronutrient ratio.

I probably get — with the coconut cream, the butter, and the MCT oil powder — probably get about an extra 100 grams of fat from that. So that allows me to eat a little less fat with my meal in the evening, and that makes it maybe a little bit more palatable because I could add some more protein.

On a typical schedule, I will do my physical activity in the evening. Then I’d like to couple that with a little bit higher protein intake.

(1:19:51)[Damien Blenkinsopp]: Right. So using the exogenous ketones or the MCTs to offset gluconeogenesis? Is that the idea?

[Dominic D’Agostino]: Yeah. This morning I had three or four eggs cooked in coconut oil. I usually have sardines, oysters, chicken, or steak from the night before. Then I’ll have a little bit of green vegetables cooked in fat, and that will be my breakfast.

It will be roughly under a thousand calories, somewhere around 800 – 1000. Then, I’ll get 1,500 – 2000 calories in the evening. During the day, I might even get an extra 500 – 1,000 just of fat or ketones.

I stay semi- fasted, so if I eat 6am or 7am I feel the best when my ketones get highest between like 3pm and 6 or 7pm.

(1:20:53)[Damien Blenkinsopp]: Okay what levels of ketones would you have then?

[Dominic D’Agostino]: I say high but it’s not really that high. In the morning when I wake up it’s maybe 1.0, sometimes .5 if I ate more blueberries or chocolate the night before. Right now, approaching noon, it would start to creep up about 1.5.

Then towards the end of my work day, I’m usually approaching about a 2.0 – 2.5 or somewhere around there. If I’m lucky I budget my time where I can go to the gym so I will be typically be working out. Then if I go home I’ll do some stuff, take my dog for a walk, do some sprints, and that’s when I feel most energetic – when I’m fasted, and in ketosis.

(1:21:40)[Damien Blenkinsopp]: Right, and you’re saying your blood ketones would be 2.5 or something like that and you’d feel that’s when you’re most energetic? Or you feel your best at that time?

[Dominic D’Agostino]: Yeah. I try to subjectively do this too. Basically, I would carry my meter, and I would be like, “When do I feel most energetic, and lucid?”. Then, I would measure my glucose and ketones at that point.

And I find that basically if my glucose is about 3.5 millimolar and my ketones are about 1.5 to 2.0 is when I personally feel the best, as far as energetic. So that would be a glucose-ketone index if we use the Thomas Seyfried’s calculation, of about 2.0. When you’re approaching 1.0, you’re starting to get into that therapeutic range.

But I think for all intensive purposes, for the normal person, if you keep between 2.0-4.0. It would be very abnormal for someone in a normal society to even approach that. If you’re hitting that then you’re doing really well.

You’re in an altered metabolic state. If you can sustain that, I think you’re going to get a lot of therapeutic and performance benefits from that.

[Damien Blenkinsopp]: So 2.0 – 4.0 in the GKI — glucose-ketone index — from Thomas Seyfried?

[Dominic D’Agostino]: Yeah.

(1:22:58)[Damien Blenkinsopp]: Which we covered in his episode in the past. Yeah, the only time I’ve got below 1.0 is when I’d be fasting. I’ve tracked full days as well, every half an hour I’ve tracked, it looks pretty similar to yours.

I’ve heard you say before that over 5.0 millimolar, in terms of ketones has some metabolic downsides. So, I was wondering about the ranges. Are there ranges that people shoot for between this 2.0 – 4.0 basically? You don’t really want to be lower?

Right? Say on the GKI, you don’t want to be going down to 1.0 unless you’re fasting or doing some pulse?

[Dominic D’Agostino]: Yeah, unless you’re really in a total fasted calorie restricted, deprived state, I think between 5.0 and 6.0. I think there was a report in a 60 day fast up to 8.0 millimolar. So that it may be beneficial there for just maintaining that energetic flow to the brain.

But if you’re on an isocaloric diet not calorie restricted. I think staying between 1.0 – 2.0 is probably good. If you’re mildly calorie restricted or maybe towards the end of an intermittent fasting, the fasting portion of an intermittent fasting day, approaching 3.0 may be optimal.

I based this upon thousands of blood measurements that I’ve taken and literally hundreds of blood measurements from other people. Between 1.0 – 3.0 millimolar I think is good. We’ve even seen it in animals, once you dose them up to about over 5.0 they start hyperventilating.

You create a mild metabolic acidosis that needs to be compensated for, so that you get the hyperventilation, they start getting even drunk and sedated, when you really start getting up there and has signs of ketoacidosis. In cases where they’re sedentary, that could be the reason. If you’re approaching 5.0 or 6.0 millimolar and you’re in an all-out sprint, you’re using that.

So maybe in the case of an athlete approaching the higher numbers could be beneficial if you train for that. But say you’re not trained for that and you dose up really high. Your body perceives it as a foreign acidic-metabolic substrate that has to neutralize, your bicarbonate compensates, and you have respiratory-renal compensation that needs to compensate for that.

I just had this discussion in metabolism and physiology with some people that I really respect. They were making the argument that anything above 4.0 or 5.0 is really going to be toxic to the body. I didn’t argue against that but we agreed upon — and there’s some pretty sharp minds in the room — anywhere between 1.0 – 3.0 was probably optimal.

As you know staying in 2.0 – 3.0 range is really hard to do with diet. But staying in a 1.0 range is pretty easy to do with a diet. I do a modified Atkins or modified ketogenic diet, and that’s pretty easy.

Then if I add a little bit of exogenous ketones or some C8 on top of that. I can easily boost that up to 2.0 – 2.5. I think that would give me a metabolic, performance, and cognitive advantage. I’m pretty sure about that.

So, that’s what’s exciting to me. So, not using exogenous ketones in the place of a low carb diet — but you might be able to do that too — I’m actually thinking about doing some experiment of getting off of my ketogenic diet for a period of time.

Not going super high carb but just being out of a state of nutritional ketosis and then adding supplements back in and then doing some blood work and see what happens there. I just haven’t got around to doing it because I enjoy eating ketogenic so much.

[Damien Blenkinsopp]: Right. Once you get into it for a while it’s like you don’t have to eat very often.

[Dominic D’Agostino]: It’s almost like I dread doing it.

(1:26:51)[Damien Blenkinsopp]: I was testing some of the supplements, the different supplements. I don’t think I didn’t do it very well. But what I was doing I was eating in the evening basically a high-carb meal lots of rice to put myself out of ketosis.

I did this for about a week and then tested different supplements in the morning. For the first reason, I don’t think it was a great control because I am basically keto-adapted now. I tend to pop straight back into ketosis relatively quickly.

I’d like your feedback on that whether it’s a decent control. Maybe I’m no good as a control because I’ve been just keto-adapted for a while and also may be I’d have to go for a few days ‘carbing’ it to make it a bit more realistic. What are your thoughts on that?

If you’re trying to do some normal, the first thing is, going back to your point about exogenous ketones. You’re saying like if someone just takes it straight off as some people are doing right now. They’ve been on a carb diet the whole time.

Then they can’t necessarily utilize those because they’re not keto or fat adapted. How long does that take? Should we be taking a lot of these when they haven’t really had that much exposure?

Do they have to take them over a period of a week or longer in order to start getting more benefits from taking them?

[Dominic D’Agostino]: Yeah, that’s a good question. Interestingly, we can use exogenous ketones even if we’re not keto-adapted at all, and that was our first study that we did for CNS oxygen toxicity. It was actually rats eating a standard rodent chow which is 60-70 percent carbohydrates.

We gave a single dose not even feeding it chronically, 30 minutes prior to doing a deep oxygen dive. It worked remarkably well and that really surprised me. So, taking a little bit of a step back, we use the R-enantiomer of the beta-hydroxybutyrate, and it didn’t work.

But then when we found out the ester that did work, that particular compound worked remarkably well. That kind of changed my thinking because I approached it with the understanding or the bias that you really need to be keto-adapted. But if you are adapted to burning fat and ketones for fuel, what has been shown is that you do up-regulate the transporters and the enzymes associated with ketone metabolism.

So, you will theoretically be deriving more benefit from exogenous ketones if you have been previously adapted to a ketogenic diet. I think from a practical standpoint, say you’re on a ketogenic diet and you choose to transition to eating carbs for some reason and then you throw ketones back in. Since you’re adapted to a ketogenic diet already, I think you’ll use those ketones more efficiently even by following a carbohydrate based diet.

We have some evidence to indicate that glucose disposal is enhanced in the presence of ketones. So, it may actually be enhancing insulin sensitivity. The glucose goes does, if you have animals eating a high carb diet and you bolus exogenous ketones, the glucose goes down remarkably low. Much more than you even get with something like Metformin.

What we don’t know why that’s happening, we want to look at the liver metabolimic profile. I think it could be influencing the liver in some way, and may be decreasing hepatic glucose output. Really it’s your liver that dictates your blood glucose, it’s all happening in the liver.

So, if you turn down gluconeogenesis in the liver, you would see a decrease in blood glucose. But also if you’re enhancing insulin sensitivity you would be facilitating glucose disposal and peripheral tissues with ketones. I know Dr. Richard Veech at the NIH has written about that and suggested that ketones actually do enhance glucose uptake and insulin sensitivity.

I get the question, what if you throw ketones on top of carbohydrates? What are the cells going to use? I think the cells will use what’s available to them and we know that the brain might not be able to use the certain types of fatty acids but they can use MCTs.

If you have glucose and ketones in the blood, your cells, your muscle cells, brain cells will be using both fuels. There’s some evidence that suggests that it will be using the glucose more efficiently in the presence of ketones. Because we know ketones can lower reactive oxygen species.

Excess ROS production can decrease insulin sensitivity and cause protein nucleic and lipid peroxidation that can inhibit glucose transporter processes. Even translocation of glucose transporters to the membrane or even PDH complex could be sensitive to the Redox state of the cell.

Ketones tend to normalize or prevent an oxidative environment that could potentially impair glucose transport and insulin sensitivity.

(1:31:56)[Damien Blenkinsopp]: There’s such a wealth of information in this area. It’s not like ketones are a panacea, but there’s just so many applications we’ve spoken about today, so I could go on talking to you for absolute forever. I’m conscious of your time also.

I wanted to round off of a bit of what you do more in terms of optimizing yourself and what you think is effective. For instance, in terms of blood ketones, you said you’re tracking your blood ketones. Have you used the other methods, the urine or the breath method?

The strips for the blood can be a little bit inaccessible in the UK, in the US sometimes, and also they are really expensive. The price varies. I’m sure you have your own ways of getting them but for everyone else it can be a little bit difficult, particularly in the UK I’ve found.

What do you think of the breath? There’s the Ketonix looking at the acetone instead. Do you think that correlates with the blood ketones, and it’s an okay way to try and optimize or not?

[Dominic D’Agostino]: Yeah, it’s a good question. I get this frequently. What I would say the breath, if you’re measuring moderate to high on a breath acetone meter you’re definitely in ketosis. I like it, and I wish it was more quantitative because I’m a numbers guy.

I think we’re all sort of what’s your number? There was like a ketone competition in the lab and my friends like, “You know what’s your ketones today?”. So we like numbers and I wish the unit could be designed.

I believe [unclear (1:33:20)] who’s working on a quantified meter. I like it, and I think it’s great for kids that are trying to manage their epilepsy because breath acetone has correlated with seizure control. So if you give this to a kid and he blows in it and he sees colors and he gets excited, I think that’s great.

It’s giving you a relative level but it’s not a precise level. But it’s also a snapshot of your level of ketosis over the last couple of hours. So your blood, beta-hydroxybutyrate can change.

I’m standing here in front of my desk and talking to you and relatively sedentary. But if I was to go and take a brisk walk on the other side of campus which I do occasionally to get things signed. I’ll come back and measure my ketones, and it’ll be cut in half.

It’ll go from two to one, or below one, just from brisk walk where it should be increased right? Because I should be mobilizing fat, I’m burning fat. But I’ve burnt those ketones for fuel during my movement.

(1:34:25)[Damien Blenkinsopp]: So then it goes into glycogen? I’ve seen this before and I didn’t understand it, that’s why I’m pretty curious.

[Dominic D’Agostino]: Well, it’s burned as fuel. Ketones are substrates, so they’re going to be burned up as fuel. And yes, you may mobilize glycogen from the liver so your glucose can actually go up. You might have some lactic acid from your muscles and through the Cori cycle goes back to the liver and you get some glucose in the blood.

The stress, the sympathetic nervous system from moving and running across traffic and navigating or whatever you do when you walk, that can contribute. What I really found that’s most important is you need to be completely calm and sedentary when you make these measurements to get accurate measurements to prevent the variability.

We have this issue with our rodent studies, we need to pull the food from them for about four to eight hours, to normalize the blood glucose. Because you have some that are nibbling on food, some that have gorged, others haven’t eaten. So the glucose is going to be all over.

To standardize and normalize glucose, you need to remove their food for a little bit and the numbers are tighter. The same thing applies for measuring ketones, especially blood ketones, you need to be fairly sedentary to do it. I really like the urine ketone strips, got a bad wrap, but I like the urine ketone strips.

They’re still used by John’s Hopkins. So, before you go spending a lot of money on getting ketone strips for the meter. You want to first confirm that you’re actually in ketosis on a urine strip.

If you’re registering 15 or 40 mg/dL on a ketone strip then it’s like, “Okay, at least if I take a blood measurement now. I’m going to register something on my blood meter and it’s going to be ‘I’m in ketosis’.” I remember the other meter, I think it’s the Novamax meter, would just give you this annoying, ‘low’, it won’t even read your number on it.

One person went out and bought a couple hundred hours worth of strips and have like 17 lows on there, and have come to find out you’re just eating too much protein or they think it’s okay to drink fruit juice. I forgot what the situation was.

Well first change your diet, then go out and get some urine ketone strips. Once you’re actually in ketosis on the urine strip then go back to the blood meter. And come to find that they tweaked their diet a little bit.

They did it until they were measuring ketones on the urine strip and they went to the blood meter, and bang they get 1.2 and they get all excited. So they could’ve saved a lot of money.

(1:37:04)[Damien Blenkinsopp]: Right. Because the urine gets a bad wrap, because it stops working once you get more keto-adapted. But when you’re first on a ketogenic diet and you’re trying to check that, that’s not going to happen. Right?

[Dominic D’Agostino]: Hydration state too, also plays a role, and less ketones will spill into the urine over time because you’ll conserve them as fuel. The transporters change a little bit. But if your hydration — if you’re drinking lots of water those people who carry water around with them and drinking.

Your urine ketones may register pretty low. Sometimes I wake up dehydrated and I would check my urine ketones will be quite high, whereas my blood ketones would be quite low. So, that’s just an indication of my hydration status.

It’s also a snapshot of what your ketones were over the last four, five, six hours because that urine is collecting in your bladder over time. So it’s sort of a snapshot of what’s happening through the course of the day, whereas your blood ketone is a snapshot of your ketone level at that point in time.

(1:38:04)[Damien Blenkinsopp]: Right, just a bit of information more about you and what you do these days? In terms of tracking things, it seems like you’ve tracked a lot yourself. Are there things that have stood out for you?

Overall, the time that you’ve tracked yourself and you found really useful insights from? Any quants or anything you’ve changed something you do in your life because of that?

[Dominic D’Agostino]: Yeah, I think initially when I started doing the ketogenic diet it was very dairy based. I was taking lots of creams, a stick or two. Two sticks of butter a day. So, I had a really high intake of dairy fat, probably about 200 plus grams of fat per day of dairy.

My LDL went up pretty high and my triglycerides went down a little bit but not really low. Then, I started replacing some of the dairy fat or the whole cream with coconut cream, and just using a little more coconut oil, getting more avocado in from my fats.

I still get dairy fat, by a sour cream that has live cultures in it. I’ll probably get about 50 to 70 grams of fat per day from dairy instead of like 250 grams of fat which I was getting initially. My lab test has improved. I guess you would say, I think my insulin sensitivity is better.

My glucose I can get lower glucose numbers now after eliminating some dairy. My triglycerides are really low now, they stay at 40s to 50s, I think it was 36 at one time. My HDL has improved and better and it’s really high, like 90 something.

My LDL went from really high to normal, but normal high. Now, which I think is completely normal and actually maybe even optimal. My IGF-1 levels are really low now compared to when I was on dairy.

I think dairy may have been contributing a little bit to some insulin resistance or maybe I was just getting a surplus amount of calories. My CRP levels also are the lowest now than they’ve ever been. I mean it’s like 0.1 or 0.2.

[Damien Blenkinsopp]: Right. Basically nothing, that’s the bottom of the range.

[Dominic D’Agostino]: Yeah, it’s like totally bombed out. I just feel better. If I eat a lot of dairy, I do wake up a little bit slightly congested, stuffy in my nose but it’s not bad.

I wouldn’t call it an allergies, and it could be due to allergies. But eliminating that has sort of helped, not eliminating, but reducing the amount of dairy. I don’t get in a whole lot of dairy protein. Maybe a slice of cheese here and there but I limit that. I limit casein. I don’t take away protein anymore.

The dairy that I get is primarily dairy fat. I was actually thinking about, I get very little butter, but I was going to switch to Ghee, and do some clarified butter. The triglycerides I would say for people to look at, for physiological biomarkers, your heart rate, blood pressure, sleep is an important one.

I wear the FitBit Charged. It’s really fun to look at my heart rate during the course of the day and in my sleep, and those sorts of things. I have a Dexcom that I’m going to put in. And I want to…

[Damien Blenkinsopp]: Is that the latest one? Is it the 4 or 5?

[Dominic D’Agostino]: Yeah.

[Damien Blenkinsopp]: I know Peter Attia is playing with that.

[Dominic D’Agostino]: Yeah, the 5 I think it is. So, I’ve just been traveling I just wanted to wait until I was put it in one spot and I can test it. I’m interested in trying that, and maybe working with some companies too, to do a glucose and ketone Dexcom.

I’m hoping to try that. That would definitely fit into your show. Yeah Quantified Self, and get some data for that, that would be good. As far as looking at physical biomarkers, you want to look at blood pressure, heart rates, sleep, and all these things improved when I got on a ketogenic diet.

I think there were various reasons for that. The lab test, the simple ones are probably the most beneficial ones. Triglycerides are the things that I look at the most. My HDL I think is important, and CRP, and of course your blood glucose. If you’re keeping glucose levels between 60 – 80, and doing that pretty much all the time.

Everything else is going to be good, that’s what I find.

(1:42:35)[Damien Blenkinsopp]: You said you did an insulin sensitivity, was that the homo or was it something else?

[Dominic D’Agostino]: No, I didn’t do that. I did the glucose tolerance.

[Damien Blenkinsopp]: Okay, the challenge.

[Dominic D’Agostino]: Yeah. I did like 50 grams, 75 and 100 grams I think. I think that was like over four hours, the 100-gram ones. Yeah, you drink the nasty Slurpee glucose and look at that. I’m extremely insulin sensitive. I dispose of glucose very fast.

I can also get a little bit of a hypoglycemic effect. If I’m on a ketogenic diet, and I go off of it. For example, I get some rice, sushi, or something like that, I will dip down into the low 50s and bounce back up again – very, very insulin sensitive.

(1:43:18)[Damien Blenkinsopp]: Thanks for that. If you were to recommend one experiment. I can guess what you’re going to say. So, we should try to improve the body whether it’s health performance longevity with the biggest payoff.

What would that be? How should they track it to make sure it’s getting that payoff?

[Dominic D’Agostino]: It depends on the person really. I don’t think low carb ketogenic diets are ideal for people in their teens or early 20s because they may be extremely insulin sensitive. I know I have tons of friends and I’ve even measured their glucose levels, and they’re great.

They stay pretty low, the glucose levels and they have adapted really well to a high carb diet. They wouldn’t want to do a ketogenic diet. So, maybe you’re expecting that kind of answer.

But, I think periodic fasting would be an important thing to do. I’ve been talking to some high-level CEO people and they tell me, “Well, I’ve been doing this anyway because I’m so busy. I wake up and I just work all day, and just go home and eat at night.”

But if your pattern of eating — like my patter of eating — I was obsessed with eating every two hours especially when I was really into lifting. I felt I had this preoccupation with food, preparing my meals, carrying it with me. I think it’s very liberating to not have to do that and to realize that your performance, energy levels, are not going to tank if you eat one meal a day.

If you were to do a short term fast, initially, and to do that every once in a while. I think, not only is very good for your metabolic health. I think it’s also good for your state of mind because it tells your body. It tells your mind that you don’t have to be sort of psychologically dependent upon food.

I would go five or six hours, and I’ll be like, “I’m starving I have to eat something.” I have been around people that are like that. My wife is kind of like that, she’s an incredible carb burner.

But if we’re traveling and she’s gone four to five hours without having a meal. I could see it in her mood and in everything. But that’s fine we’ll stop and get something to eat, and usually we’ll have coffee or something like that. But it’s interesting to see, and she sees it in me, “How could you go this long? Aren’t you hungry? What’s wrong with you?”.

She understands it now. She’s watched me do so many tricks and everything. If you’re not a big fan of being hungry. If you’re not a fan of having to eat every two or three hours because you’re hungry. I think doing some intermittent fasting would be a really good experiment for you to do.

I actually interviewed Mark Mattson at IHMC. So, I’m also a research scientist at Institute for Human and Machine Cognition. We interviewed Mattson, I think you did too for a podcast. He really went into the benefits of intermittent fasting and he’s at the National Institute of Health.

If you get a chance, he gave a brilliant lecture, presentation. If you go to IHMC lectures and look up Mark Mattson, he gave a great talk on this. He talks about all the health benefits.

If you do embark — if your listeners embark on [an] intermittent fasting experiment it would be interesting for them to track their blood glucose levels, their ketone levels, their triglycerides and their c-reactive protein. I think in each one of those biomarkers, if you want to call them that, will improve with intermittent fasting. I’ve seen it.

(1:46:51)[Damien Blenkinsopp]: You’re saying the 16-hour window or one day? Because you said short-fast, do you mean like a one day, 16, or 20 hours?

[Dominic D’Agostino]: Yeah. You could do every other day eating. But I think the easiest thing to do for most people would be, what I’d do if I do intermittent fasting maybe once or twice a week now. I eat two meals a day but like once or twice a week I’ll eat one meal a day, and it varies depending on what I’m doing and testing.

But it will be 18 hours of fasting and 6 hours of eating. Actually I get home late, so it ends being about 20 hours of fasting and four hours of eating. So, it will be 7pm – 11pm. I’ve done it [with] water and abstained from putting fat into my coffee.

I’ve also done what I would call ‘fat fast’, so I would put in some MCTs in my coffee and maybe get a ketone supplement during the day. I would still call that a fast because it’s basically non-glycemic.

[Damien Blenkinsopp]: Yeah, probably has very similar ketone and glucose effects.

[Dominic D’Agostino]: Yeah, I actually find that it’s optimal. So, I would call that a modified intermittent fasting protocol, where you would get in some fats and exogenous ketones during that fasting period. I’m a little less hungry once I go into that eating window.

I think that’s good too, so I tend to not over eat that much. My body is still strongly in a state of ketosis that has probably enhanced a bit with the supplementation. It tends to dampen my appetite a little bit so I’m not as ravenous.

But I don’t generally don’t get that ravenous anyway when I eat. But, I would experiment with that the intermittent fasting. I think it’s so easy to do. I mean intermittent fasting is easier to do than the ketogenic diet that’s what I find with people.

So, do some experiment, get some initial blood work, read up about it, listen to Mark Mattson’s talk on [the] IHMC website and you’ll find it there. I’m sure there’s a lot of blogs on the subject and do blood work before and three to four weeks after.

You’ll see pretty big effects, especially six and eight weeks after. You’ll see even bigger effects on your lipid profile and metabolic biomarkers.

(1:49:04)[Damien Blenkinsopp]: Excellent thank you so much for that, that’s a great one. Where would someone look to learn more about your topic? Are there any good books or presentations on the subject you’d recommend if they want to learn more about the whole subject of ketones and ketosis?

[Dominic D’Agostino]: One of the go to book that I would recommend is Jeff Volek’s ‘Art and Science of Low Carbohydrate Performance’. It’s a mandatory reading for students entering the lab just to get a hand on what the ketogenic diet is. The Ketogenic Diet Resource is a website maintained by a friend of mine, Ellen Davis, and I think has a lot of good information on it.

But I maintain a website to throw up links, compile links in there called ketonutrition.org. If you click on resources from the homepage, it will take you to dietary consultants, books, publications, list of podcasts, and lectures on there on a variety of subjects that hit on pretty much all the topics we’ve discussed. I probably need to get on there, but it’s relatively updated. I’ll probably update that in the next month or two.

Metabolic Optimization too, that’s a website that I started with Travis Christofferson who wrote the book ‘Tripping Over the Truth’ which is an excellent book that covers the metabolic theory of cancer. Travis and I maintain the website Metabolic Optimization, and we have Thomas Seyfried on.

We’ve had Adrienne Scheck, we’ve had Bruce Ames actually was our first guy. We’re going to line up a bunch of other speakers on metabolism so that’s another area where they can look up information on these topics.

[Damien Blenkinsopp]: Great, thanks for that. Are you active on Twitter? Where could people also connect with you and keep updated of what you’re at?

[Dominic D’Agostino]: I tried to post at Twitter maybe once or twice a week, not like super active. But on Facebook I post a little bit more. My page is maxed out, I got 500 or 5,000 people following me.

So I’ll probably create a more public page. But you could still follow me because I post things open to the public. I will post usually one or two studies per day, or podcasts or lectures per day on my Facebook page which should be very easy to find.

It’s always sort of topics relevant to the interests or the topics that we covered today. Sometimes I dual post on Twitter and Facebook, important things that pop up as far as studies and lectures and things like that.

(1:51:39)[Damien Blenkinsopp]: Excellent. Of course, we’ll put links to everything you’ve mentioned here in the short notes. Is there anyone besides yourself? You’ve already mentioned a few people, but was there any you would pull out and you would recommend if people wanted to learn more about the subject? Are there are some other people that you would recommend also?

[Dominic D’Agostino]: Yeah. My colleagues, there’s so many of them. I try to stay very active in collaboration. It’s really good for scientists to collaborate to help get their work out there. Also, to get other people to validate the findings that you did in the lab.

So, I know you’ve had Thomas Seyfried. He’s a great friend and colleague of mine. Adrienne Scheck is a fantastic scientist and a pioneer in ketogenic diets and moving the ketogenic diet into clinical trials at Barrow Neurological Institute.

There’s some of the mentors that even got me into this field — would be Dr. Eric Kossoff. He’s a neurologist at Johns Hopkins. He’s been a pioneer in using a ketogenic diet for kids with epilepsy, so look him up.

John Roe who’s a neuroscientist and pediatrician. He was originally at Barrow Neurological Institute and he was the first scientist I ever connected with to discuss this. The use of the ketogenic nutrition for oxygen toxicity.

Dr. Richard Veech he had a profound influence on me when I first got into this area of ketogenic diet and discovered exogenous ketones. It was his reviews on the subject. So if you look up on some of his reviews on ketones and the therapeutic effects of ketones, they’re really good.

Susan Masino has been really supportive of our work and she’s doing some really innovative work looking at the effects of the ketogenic diet on adenosine. Adenosine is a neuroprotective substance that’s elevated, has anti seizure, anti-convulsant, neuroprotective effects.

So, we actually have a lot of these speakers [who] will be coming to our Metabolic Therapeutics’s Conference which will be held either the last week in January or the first week in February. We had a number of speakers, we had Eugene Fine, Colin Champ, David Ludwig, David Diamond, he was a colleague of mine here at USF and [we] talked about cholesterol and statins.

We had Eric Kossoff, Adam Hartman, and a bunch of scientists. So, I would tell your listeners to go to the Metabolic Therapeutic’s website. We’re in the process now of sending out the invitation for speakers.

And pretty soon, I think we might have a preliminary site set up for that, but we’ll be updating that soon with all the different speakers and the topics that are going to be talked about. We really try to emphasize basic science, so you’re going to find lectures on neurophysiology, cancer biology, proteomics, tracer based metabolomics.

Performance — Jeff Volek will be there talking about performance. It will be a mix of things related to not just the ketogenic diet but metabolism in general.

[Damien Blenkinsopp]: Sounds fantastic so anyone can attend that?

[Dominic D’Agostino]: Anyone can attend that, yeah. We should have the registration going up soon. The problem that we had is that last year the venue was small. We wanted originally to keep it small, to cap it at about 250, but we had to turn so many people away.

So, this year we’re going to blow it up a little bit and probably have about maybe 600 – 700 people, hopefully in the same venue. But we’re going to get the whole hotel. You’re going to find a lot of great companies there that are producing these exogenous ketones.

So, Pruvit is going to be there, probably Forever Green, the company Kegenix – they make a great product that I’ve been testing recently during my travels. KetoSports hopefully will be there, and Quest Nutrition has a big footprint in our conference and they have been incredibly supportive of our work.

Scivation, who’s really the leader in branch chain amino acid supplements, will be there. Let me see, we have a lot of good sponsorship supporting this area of research. It’s really exciting to me that it’s becoming so popular it’s easy to find companies that are now emerging that are interested in developing products that can enhance nutritional ketosis.

So it’s fun to see a market for this evolving. They’re are creating products that I think will be very beneficial to patients even that are following nutritional ketosis for managing a disease process.

I do get Emails every single day from patients that are using these products that made a world of a difference. They couldn’t get into ketosis and once they did or their trial did, they started getting all these benefits from the ketones.

[Damien Blenkinsopp]: It’s a super exciting area, you’re very lucky to be right in the center of it.

[Dominic D’Agostino]: Yeah. I do feel lucky.

(1:56:48)[Damien Blenkinsopp]: Just as a quick anecdote, I gave some MCT powders and C8 to my mother because she has tremors. They have been getting worse over time, and they are so much better it seems. She was really surprised by that.

But it is an exciting area, they have so many crazy benefits, so broad compared to the other things we looked at. Which is one of the reasons I’ve covered it several times in different episodes, fasting, ketosis, all of these.

Whereas most topics I don’t cover in many episodes but this one has just so many applications, it’s just interesting. I think it’s worthwhile for people to learn more and more about it.

[Dominic D’Agostino]: Absolutely.

[Damien Blenkinsopp]: Dom, thank you so much for your time. I really appreciate it, we’ve covered such a wealth of topics. I know there’s so much more you could talk about. So, thanks very much for your time.

It’s been great talking to you.

[Dominic D’Agostino]: Thanks for having me Damien. I appreciate it.

References:

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Putting the body into ketosis and controlling blood glucose levels may prove to be effective therapy against certain cancers. This real case reveals one aggressive self-experimenter who used a combination of the ketogenic diet, fasting and other tools to control his epilepsy and send his brain cancer into remission.

This episode examines the ketogenic diet as a tool to fight against cancer. It is a follow up of the episodes on ketosis and fasting that we have done with Dr. Thomas Seyfried in episode 16, and Gene Fine in episode 36. You definitely should check those out for context before or after you dive into this one to fill in any gaps.

We are talking to someone who has actually used ketosis by a combination of ketogenic dieting and fasting as a therapy to fight his brain tumor. Our guest has gone through a variety of extreme approaches to ensure he remains in a high state of ketosis. In his case, his life depended on it. This episode is not just for those with cancer or epilepsy, but also for those interested in the benefits of the ketogenic diet. You can take some of the tools he used to improve your own state of ketosis if you are having trouble maintaining it.

[W]hen I have my blood tests . . . and [test] a number of markers for potential tumor progression, internally, I am actually much healthier than before I had cancer . . .
– Andrew Scarborough

I met Andrew Scarborough at a conference where he spoke about his experience with ketosis and its effect on his brain tumor. After being diagnosed with a type of malignant tumor called an Anaplastic Astrocytoma, Andrew underwent several months of unsuccessful chemo treatment. He decided to take his cancer treatment and management of his epilepsy into his own hands and to go the ketosis route. This decision was based in a small part on researching Thomas Seyfried’s work, which we will also discuss in the episode.

Fortunately, this decision has yielded very positive results for him, and his tumor has shrunk. In fact, it has disappeared from scans (seen below) and his doctors are now giving him the all clear. Andrew is now working with London-based hospitals to develop clinical trials for treating brain cancer patients using an optimized ketogenic diet.


Andrew's brain tumor before and after being on the ketogenic diet.

Andrew’s brain tumor before and after being on the ketogenic diet.


There are a lot of details in this podcast on how Andrew went about using the ketogenic diet, including the types of foods he ate, how he optimized the diet for his situation, the extreme measures he has taken, and how he has been able to keep up physical activity. We will talk about everything on his journey, including things like eating bugs and sheep’s brain, and quitting eating plant-based foods altogether.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!

itunes quantified body

What You’ll Learn

  • The beginning of Andrew’s brain cancer story (4:46).
  • Andrew is diagnosed with a grade 3 Anaplastic Astrocytoma (12:14).
  • After unsuccessful chemo treatment, Andrew devises a treatment using the ketogenic diet (19:19).
  • Using MRIs to visualize changes in the metabolic activity of the tumor due to the ketogenic diet (20:52).
  • Scans show complete remission since using the ketogenic diet (23:40).
  • Optimizing and maintaining the ketogenic diet for brain cancer management (26:40).
  • The biomarkers Andrew tracks to monitor the effects of the ketogenic diet (28:08).
  • The glucose-ketone index (29:13).
  • Andrew’s typical diet (32:58).
  • Maintaining a healthy 1:1 ratio of Omega-6 to Omega-3 (33:35).
  • The ketogenic foods Andrew eats (36:10).
  • Variations on the traditional ketogenic diet (41:30).
  • Supplementing the diet with insects (46:30).
  • Keeping up ketone levels and controlling seizure activity during exercise (50:16).
  • Andrew’s research on an optimized ketogenic diet for brain cancer patients (54:50).
  • More on Omega-6/Omega-3 ratios (59:15).
  • Limiting protein and fasting (1:00:32).
  • Using magnesium to prevent seizures during a fast (1:02:08).
  • Mimicking chemo naturally with diet (1:06:44).
  • The resources Andrew recommends for those facing cancer or epilepsy or interested in the ketogenic diet (1:11:47).
  • Andrew’s advice on what biomarkers to look at and where to start with the ketogenic diet (1:18:34).

Thank Andrew Scarborough on Twitter for this interview.
Click Here to let him know you enjoyed the show!

Andrew Scarborough

Tools & Tactics

Interventions

  • Hyperbaric Oxygen Therapy (HBOT): A therapy Dr. Seyfried believes may be beneficial to fight cancer but is relatively non-toxic in comparison to current treatment modalities (chemo and immuno-therapies). It exposes the body to higher levels of oxygen via having the person sit in a pressurized tank with higher oxygen concentrations. Andrew is adding this therapy to his current tools. Typically you visit centers that provide sessions inside hyperbaric oxygen tanks, however some new smaller and lower pressure HBOTs are now beginning to appear in the market that you can buy to use at home.

Supplementation

  • Ketosports KetoForce: KetoForce contains the endogenous ketone body beta-hydroxybutyrate (BHB) in sodium and potassium salt form. The compound BHB can be used as an energy source by the brain when blood glucose is low. Ingesting KetoForce raises the levels of blood ketones for 2.5-3.0 hours after ingestion. (Note: A similar product from the same company is Ketosports KetoCaNa). Andrew uses KetoForce to increase his ketone levels during gentle exercise.
  • Ancient Minerals Magnesium Spray: Most people with epilepsy have a magnesium deficiency. Magnesium supplementation has been used to reduce seizure activity in people with epilepsy. Andrew prepares his own magnesium chloride solution that he takes transdermally multiple times every day (about 230 mg per day) and during exercise, which can be a seizure trigger for him.
  • Curcumin BCM95: Curcumin is a derivative of turmeric which is an anti-inflammatory antioxidant and potentially has anti-cancer properties. Andrew takes Curcumin in tablet form with DHA because it increases the uptake of DHA to the brain.

Diet & Nutrition

  • Ketogenic Diets: The ketogenic diet is a low carb diet which raises the level of ketone bodies in the blood. Tumor cells are inefficient at processing ketone bodies for energy. The diet is commonly used to help control epilepsy in children.
  • Paleo Diet: A diet that mimics the nutrition of early hunter-gatherers, and consists of all lean meats and fish, fresh fruits, and non starchy vegetables.
  • Water Fasts: A water-only fast of at least 3 days and preferably 5 days is recommended by Dr. Seyfried as a tool to reduce cancer risk and to lower your glucose – ketone index to 1.0. They are the standard fast protocol used in most of the research studies looking at cancer inhibition or therapy for cancer patients. Learn more from Damien’s experience with a 5-day-water-fast.

Tracking

Biomarkers

  • Blood Glucose: A measure of the level of glucose in the blood at one point in time. Blood glucose is a biomarker for increased cancer risk. Therapies target reduction of blood glucose levels to limit cancer cell growth. Blood glucose levels vary throughout the day. Ideally levels should be kept below 100 mg/dL and below ~85mg/dL for fasting glucose. Andrew maintains his around 60-70 mg/dL.
  • Glucose – Ketone Index (GKI): The ratio between the concentration of glucose in the blood to ketone bodies in the blood. The calculation is Glucose (mmol)/ Ketone (mmol). Dr. Seyfried created the index as a better way to assess metabolic status. Therapeutic efficacy is considered best with index values approaching 1.0 or below. Patients with chronic disease like cancer have index values of 50 or more. Check out the episode with Thomas Seyfried here.
  • Cholesterol-HDL and LDL: The cholesterol biomarkers include lipoproteins and triglycerides which are found in the blood. There are standard markers that all doctors and labs will run, and some newer specialist labs that are more specific and accurate. There are two main types of lipoproteins, HDL and LDL. We covered these markers extensively in episode 7.
  • Omega-6/Omega-3 Ratio: Many Western diets are deficient in Omega-3 fatty acids, such as DHA, and have excess Omega-6 fatty acids. A high Omega-6/Omega-3 ratio promotes inflammation and the pathogenesis of many diseases, including cancer, whereas increased levels of Omega-3 (a low Omega-6/Omega-3 ratio of about 1) exert suppressive effects.
  • hs-CRP (high sensitivity C-reactive Protein): a marker for systematic inflammation that can be measured over a period of time to determine effectiveness of treatments such as the ketogenic diet. Ideally CRP levels should be <1 mg/L. High levels are associated with chronic inflammation, which is common in cancer and other chronic diseases.

Lab Tests, Devices and Apps

  • Glucometer: is a device used to measure the level of glucose in the blood. Andrew and Damien use the Freestyle Optium Neo Glucose/ Ketone meter. Andrew’s ketones and blood glucose levels hover around 65 mg/dl, which puts him somewhere around 0.6-0.8 on the Seyfried index. Check out episode 16 to learn more about the Seyfried Index.
  • Omega Blood Count: Measures the levels of Omega-6 and Omega-3 fatty acids in your blood. (Note: This test is only purchasable via offline retail stores such as pharmacies and health shops in the UK – an alternative test that Andrew recommends that you can buy online in US or UK is OmegaQuant.com)
  • Complete Lipid Panel: measures total cholesterol, triglyceride levels, HDL and LDL cholesterol, which are all found in the blood. High blood lipoprotein levels are associated with cancer.
  • Complete Blood Count: is a blood panel that measures the levels of the different cells in the blood. Numbers of the different types of cells vary depending on disease status and even between people. The test is often used to monitor cancer progression and treatment.
  • Magnetic Resonance Imaging (MRI): MRI scans use pulses of magnetic energy to visualize internal organs and structures. It can be used on almost any area of the body and provides information on tumors, bleeding, injuries, blood vessels, or infection. MRIs were used to monitor Andrew’s brain tumor.
  • Positron Emission Tomography (PET) scan: A PET scan is a functional imaging technique used to image body processes. A PET scan can be used to identify cancer presence and severity. A radioactive tracer, fluorodeoxyglucose, is used to tag cancerous cells so they can be visualized. Check out episode 36: Quantifying Cancer and Reexamining Which Cancers May be Inhibited by Fasts with Gene Fine to learn more about PET scans and cancer.

Other People, Books & Resources

People

  • Dr. Thomas N. Seyfried, PhD: University of Illinois, Urbana-Champaign. Dr. Seyfried’s research focuses on the mechanisms by which metabolic therapies manage chronic diseases like cancer, epilepsy, and neurodegenerative lipid storage dysfunctions. Check out Dr. Seyfried’s episode on “Water Fasts as Potential Tactic to Beat Cancer.”
  • Dr. Dominic D’Agostino, PhD: Assistant Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine, and a Senior Research Scientist at the Institute of Human and Machine Cognition. His research focuses on developing and testing nutritional and metabolic therapies for neurological disorders and cancer. His own website is Keto Nutrition
  • Dr. Colin Champ, MD: A board-certified radiation oncologist and Assistant Professor at the University of Pittsburgh Cancer Institute and University of Pittsburgh Medical Center. He is also board-certified in integrative medicine by the American Board of Integrative and Holistic Medicine. His focus is the role and effect diet and nutrition may have in cancer treatment.
  • Dr. Adrienne Scheck, PhD: An Associate Professor of Neurobiology at Barrow Neurological Institute. Her expertise is in neuro-oncology and her lab has been involved in investigating the effects of the ketogenic diet on brain cancer.

Organizations

Books

Other

  • Ketogenic Diet Resource: Andrew says this website has answers to just about all the questions you could have.
  • Clinicaltrials.gov: This site can provide you with information on clinical trials that are currently being done relating to the ketogenic diet and different cancers.

Full Interview Transcript

Click Here to Read Transcript

[Damien Blenkinsopp]: Andrew, welcome. Thank you so much for coming on the show.

[Andrew Scarborough]: Thank you for having me.

(04:39) [Damien Blenkinsopp]: Yes. You have quite an amazing story that a lot of people are very interested in hearing about. It’s always good to get the context of how this happened to you, and where it all started? Could you go into the beginning, how you made the discovery that you had this condition? How did it start?

[Andrew Scarborough]: Yes. I was studying a Master’s in Nutritional Therapy at the University of Westminster. This is before my diagnosis, and I was suffering from migraine headaches for a few months. Until suddenly I had lost my speech in February 2013, this was nearly 3 years ago now.

What I didn’t know at the time, that was my first partial seizure, and just being a man I carried on.

[Damien Blenkinsopp]: So to describe that, did you have difficulty saying words, or what exactly happened?

[Andrew Scarborough]: I went very dizzy, and then lost my speech completely for about five to six minutes, I was with a friend and we laughed about it because it was a bit strange. Because it was quite a cold day, it was February, I was just thinking when you get cold and shivering. You just stutter and loose — you struggle to speak, but it was a lot more serious than that.

I didn’t do anything about it. A couple of months later, I was experiencing very similar symptoms with pins and needles in my tongue and throat. To cut a long story short, I went on the train after a heavy gym workout. And, I felt like I actually have a lot of energy after the workout, even though I really struggled through it.

I just felt completely wiped out, even though it wasn’t the most difficult workout. I suffered more seizure activity afterwards, when I was getting on the train, very busy train actually in London to go home. And I devastatingly had a crushing headache, like my head was in a nutcracker.

The pressure was constantly building up, then I suffered a quite a traumatic brain hemorrhage, and grand mal seizure on the train, which wasn’t too pleasant, and the whole train stopped. I was rushed to hospital. There was so much blood in my brain that they didn’t know what to say, what actually was the cause.

As I was in hospital not knowing — feeling very confused not able to speak or walk at this point. I was given a CT scan and all that was shown was this massive blood in my brain. It looked like an explosion had gone off. I was still experiencing horrific grand mal seizures at this time, so I had things explained to me, and at the time, they were going in one ear and out the other, because I was so out of it.

That was quite a tough time from my family, and my first diagnosis was an AVM, which is an arteriovenous malformation. Because it looks so poor on the scans — because CT scans are quite ambiguous. All we could really see was just a tangle of blood vessels and arteries.

[Damien Blenkinsopp]: So, they thought it was an artery that had grown the wrong way, or you’d been born . . .

[Andrew Scarborough]: They saw it as being an unusual tangle of mess.

[Damien Blenkinsopp]: Okay, the arteries growing in the wrong way.

[Andrew Scarborough]: Yeah. They said, “No it’s not probably like that, it’s probably a Cavernous Hemangioma instead, which is a tangle of abnormal blood vessels, not tangled in the arteries.” Which is better because it was a bit less life-threatening, but I was given a number of misdiagnoses before. Eventually, I had an operation, because I was continually having these grand mal seizures that were starting to cause me cognitive difficulties, and my speech was getting worse, so I wasn’t able to speak at all at this stage.

(09:11) [Damien Blenkinsopp]: So, going back to the hemorrhage is that a stroke, is it the same as a stroke, or is it slightly different?

[Andrew Scarborough]: It’s very similar to a stroke, it was caused by the pressure of the tumor. Pushing against the side of my skull, and also it was between the speech movement area invading into the motor cortex, that’s why I had lost my speech completely. I had an operation not long after, in May 2013, to try and remove as much as possible, if this very vascular and invasive tumor, which was slightly larger than a size of a golf ball — but invading into the motor cortex area of my brain.

They couldn’t remove all of it because otherwise I would be completely paralyzed or dead. Because I was misdiagnosed, I should’ve had the operation awake but I was unconscious during it. The neurosurgeons said after, “Yeah we probably.”

If he has to do it again, he would have it awake so he could potentially get more out of it, but he couldn’t remove all of it because of where it was in the brain.

[Damien Blenkinsopp]: That’s interesting, what is the difference between you being unconscious and awake, are they able to get some feedback from you?

[Andrew Scarborough]: Yeah. You’re kept awake so they can monitor your responses, while they’re poking around in there to see what can be removed and what can’t, and what healthy brain tissue and what isn’t. One of the main issues with the brain surgery is it’s very difficult to distinguish what’s healthy tissue, and what’s the tumor.

[Damien Blenkinsopp]: So, this is what date now that you’ve had your surgery, and you’ve been given a clear diagnosis?

[Andrew Scarborough]: This point now? It’s two and a half years coming up to three.

[Damien Blenkinsopp]: Okay, it was a few months after your hemorrhage.

[Andrew Scarborough]: That was two months after that I’ve had the operation because they didn’t know what to do with me. There was a lot of blood in my brain, and if you think about a malignant brain tumor, it’s not a great thing if you’ve got a constant blood supply there — and it’s not a fantastic thing if you’ve had this thing that looks like an explosion in the brain, scattering around the cells, and blood everywhere. So, it just makes it more migratory, I guess if that’s the word.

More likely to spread into other areas, which is not ideal. I then had my pathology, finally, and it showed that the tumor was indeed extremely vascular. And there was still some significant scar tissue, as well as some slight enhancement there, but we didn’t know exactly what that was.

[Andrew Scarborough]: So you’re saying, is that a scan?

[Andrew Scarborough]: Yes, sorry.

[Damien Blenkinsopp]: Okay.

[Andrew Scarborough]: — This was the MRI scan after my operation.

[Damien Blenkinsopp]: Is that a straight MRI?

[Andrew Scarborough]: Yes, this was just a standard MRI, but I also had my pathology report from the amount of tumor that was able to be removed, and that came back as an Anaplastic Astrocytoma, which is a Grade 3 Astrocytoma — affecting the glial cells, the astrocytes in the brain, and quite important components of the brain. It’s not a great thing to have, particularly a high grade glioma, which is what mine was.

Brain tumors come in different gradings, so it’s like we’re staging how — with the brain it’s Grades 3 and 4 are highly malignant, and Grades 1 and 2 are slow growing. Grade 1 is typically a solid mass, that you can — if you can operate it can be curable. Even Grade 2s are known to come back, and do grow, but grow at a slower rate. But Grade 3 and 4 are the fastest growing, they grow quite fast. Mine was showing to be heterogeneous, it had quite a few Grade 3 cells in there.

[Damien Blenkinsopp]: Does that mean that it has different types of cancer cells there when you say heterogeneous?

[Andrew Scarborough]: Well, yeah. It showed numerous mutations. It’s very difficult to explain, but it showed that it wouldn’t be chemosensitive, it was negative for IDH1 which is a predictor of longest survival and chemosensitivity. It was also unmethylated for MGMT, which is a repair gene.

And that’s also — it’s not a good thing that it was unmethylated, so it was one of these gene mutations that they say is good to have for longer term survival. I also had tumor suppressor genes missing which again, with these Grade 3 tumors the timescale for survival is variable until it comes back. But in my case, I had just about the worse. It’s scenario terms with the pathology.

(14:33) [Damien Blenkinsopp]: So, did they give you a rough timeline, I guess at that point?

[Andrew Scarborough]: They said it was difficult to tell because of my age and the location of the tumor. Typically in that scenario, it’s around two years when it comes back, and that’s one of the best cases in that particular scenario. It’s a strange type of tumor because in a different scenario with different kind of pathology it can be up to five years or sometimes seven that it comes back.

It’s quite variable, but in my case it didn’t look so good, and I still had some scar tissue where there was lots of — healthy blood supply that could’ve had any enhancement that was present at the time, not great.

[Damien Blenkinsopp]: Must have been a shock, must have been a pretty big shock for you when that one came about.

[Andrew Scarborough]: Yeah, most definitely. I was told that even though my tumor was not chemosensitive that I should probably go ahead and have chemotherapy and radiotherapy, which I did for a short period because I was quite ignorant about it. I thought that it would potentially give me a bit more time.

But then once I’d looked into it I realized that it was only going to cause further mutations for me personally, and I didn’t want to see that. I started to learn my carbohydrate intake and go on a restrictive ketogenic diet after I’ve learned about it prior to my diagnosis, when I was studying a Master’s in Nutritional Therapy.

(16:17) [Damien Blenkinsopp]: Right, what was your lifestyle like before this all happened to you, and how old were you when this happened?

[Andrew Scarborough]: 27, 28. It’s difficult now thinking back, because my birthday’s at September 1, so I was 27 going on 28. It was two and half years ago and I’m 30 now.

[Damien Blenkinsopp]: So roughly 28 or 27.

[Andrew Scarborough]: Yeah. I was on a diet that I thought was healthy, so I was on a low fat, high carb with a complex carb diet, all whole foods, so I thought I was doing a good job, no processed food. I actually had quite a low body fat percentage and quite a high lean body mass. I thought I was very healthy, and I was very athletic.

I’d worked as a personal trainer for a few years. I was studying my Master’s in Nutritional Therapy and it was a shock to me that what I was learning in my undergraduate degree in Nutrition was completely useless, because I was learning all these new information that contradicted all the older information, but I was just learning about it. I thought it was interesting but it seemed to go against most of what I’ve studied for the past few years before that.

I thought I was healthy.

(17:44) [Damien Blenkinsopp]: When they gave you the diagnosis for the cancer —people at home are probably thinking, “Well is this one of those — metastasized, so it would spread to other parts of the body, or does it tend to stay concentrated?”

[Andrew Scarborough]: Yeah, well primary brain tumors typically just spread into the brain, which isn’t great because your brain is very useful. Apart from medulloblastoma, which can spread down the spinal fluid and into the central nervous system. It’s the central nervous system that can spread down the spine, and other also spread into the brain.

Mine is an astrocytoma, it would’ve just spread into the brain, and there can also be secondary tumors that come about as a response in the brain. It’s not a great type of tumor to have.

[Damien Blenkinsopp]: No, tumors are good ones to have, but it’s one of the nastier ones.

[Andrew Scarborough]: It’s the step down from glioblastoma, which is the most common type of brain cancer.

[Damien Blenkinsopp]: That always the worst, is the Type 4. . .

[Andrew Scarborough]: Yeah. I thought with my approach, with my own treatment strategy — I thought I have a little bit more time to play around with things and adjust to strict ketogenic diet. If I had a glioblastoma I would’ve pushed things a lot quicker. I did push things quite a lot, and I go to extremes with this diet and this approach.

(19:19) [Damien Blenkinsopp]: Yeah. Did you consider any other options? You said you took a little bit of chemo and radiotherapy —radiation, and pretty quickly you stopped, was that a couple of months?

[Andrew Scarborough]: I stopped after four months because I was proposed to have it for up to two years which is a long time, and I said no after a few months experiencing how horrible that was, and still having these horrible seizures. I thought, “Well, I want my quality of life to be good at least.” I stopped it, because my scans were still showing this enhancement.

I thought, “Well, we don’t know if that’s necrotic tissue or scar tissue, or if it’s the tumor activity.” But I thought that, because my tumor looked so glowing on the scan that it was potentially very responsive to carbohydrate restriction. So you do get some cancers that seem to use more glucose for energy, and you get some that actually use glutamine more for energy than glucose.

More or less they use both for energy, but because mine was so glowing up — lighting up like a Christmas tree I’d like to say, it showed that it was potentially more efficacious to just really cut down on the glucose, and see what was going to happen from that.

[Damien Blenkinsopp]: So these were all MRIs they were giving you?

[Andrew Scarborough]: Yeah, and interestingly even though it’s different from other cancers where you get a PET scan, and you can still see the enhancement there, on an MRI, that was interesting to me.

[Damien Blenkinsopp]: Do you know why that was? We spoke recently to Gene Fine who is talking about the PET scan, in the use of cancers. Do you know why you were able to see it quite clearly on the MRI in your case? Is that specific to brain cancers?

[Andrew Scarborough]: Yeah, I think from what I’ve seen in the literature it is, I don’t know exactly why that is. I guess it’s just you’re able to see the metabolic activity even with — I think it’s an iodine solution, not the good kind, the more radioactive iodine that they give you, rather than the supplemental iodine which you can get which is actually really good for hormonal control and certain cancers.

[Damien Blenkinsopp]: So, they give you an IV of that when you go to your MRI, so they can see more?

[Andrew Scarborough]: Yeah, that’s the contrast injection that they give you. Sometimes with PET scans, they do give you the — that shows up quite nicely with the contrast dye. I view my scan straight after I have them, so it’s interesting to view that.

[Damien Blenkinsopp]: Yeah. So I think its gadolinium, is that the contrast dye you’re talking about?

[Andrew Scarborough]: That’s one of them, but I don’t have that one from my scan, I have something else. I can’t remember exactly what it’s called, but I’ve had a few different kinds of scans. I’ve also had MRI spectroscopy which is a fascinating type of scan.

It works with lights, allowing you to see the microenvironment in the brain. And we’re looking at how the ketogenic diet is changing that environment within those biomarkers within the brain as I’m progressing. That’s really interesting to see.

(23:02) [Damien Blenkinsopp]: Yeah, so great. What kind of scans have you been having over time, and how frequently? And how have you seen the ketogenic diet impact that over time?

[Andrew Scarborough]: Well initially I had a standard MRI scans which were quite boring. The cancer cells, [unclear 23:19] was that wasn’t the best for brain cancer, even though it’s world-renowned for other cancers. At that time, I had the enhancement and significant scar tissue, and I had Hemosiderin, which is a blood staining, that was quite a lot of that showing on my scan.

Since then I’ve had progression in a way that I’ve been given a statement saying that I have a response, that I’ve achieved complete remission, and the enhancement is no longer present. I’ve also had significant healing of the scar tissue, and I’ve had vast improvement of my symptoms. So, I am completely off medication for epilepsy which I was told by five different neurologists — that I’d be crazy to even reduce the medication, and I should increase it because my seizure activity was so bad.

I’ve just had a linear progression of improvement in that respect, so I’m completely off medication for the epilepsy, and for that, I do a number of things which controls my seizure activity. And if I forget to do those things I instantly have seizures — it’s like being on a tightrope you have to keep up with doing all these things, I haven’t had a seizure in a long time. When I start to stop doing these things, or I slip up even a little bit I get an aura, which is a warning for me that I’m going to have a seizure.

I have emergency measures to reverse that, which I’ve devised myself largely. It’s interesting.

(25:07) [Damien Blenkinsopp]: Yeah, sounds very interesting, we’ll jump into that. So the epilepsy is a symptom, it’s driven by the hemorrhage that you had and some damage?

[Andrew Scarborough]: Yeah, and also it can provide these for an indicator of where you are with cancer with the brain. Particular with the temporal lobe epilepsy which is a typical response from a temporal lobe brain tumor. My tumor was between the temporal and frontal lobe, so I have three different types of seizures, which is fun.

Monitoring my symptoms and my seizure triggers, and my theories on what would resolve the seizures, not just the ketogenic diet but things I could do with the ketogenic diet to optimize it specifically for brain cancer management. I was able to work out what worked out most effectively for me personally and relate that to the literature as well. I was then able to go to my neurologist and say, “Well what do you think of this?”. And then when they said, “I think it’s absolutely ridiculous, there’re no science behind it.”

I was able to show the science behind it and my results. And then they could say, “Well that’s very interesting.” I’ve had success that they didn’t expect.

(26:42) [Damien Blenkinsopp]: That’s great. So when were you given the sign off, when they say, “Okay your scans are clear.” Did they say it’s in remission or do they say it’s clear?

[Andrew Scarborough]: With that kind of cancer it’s never deemed as curable and I don’t think it can be curable, but personally I think you can achieve and maintain complete remission, and maintain that status indefinitely. From close observation of the animal studies, when they come off the diet after they’ve achieved complete remission, same kind of cancers, that it comes back almost instantaneously. The unpublished human studies I know the same thing, the same occurrence.

I am very keen to stay on this very strict ketogenic diet, and I actually feel quite good on this. Internally, when I have my blood tests which I have a myriad of different blood tests just to see how I’m doing in terms of my general health. A number of markers for potential tumor progression. Internally I am actually much healthier than before I had cancer, which I find that kind of funny.

(28:08)[Damien Blenkinsopp]: So what kind of improvements have you seen, what are the biomarkers that stand out for you, the test results that have come back, and been useful?

[Andrew Scarborough]: The first thing I looked at was my vitamin D. When I was first diagnosed it was in a severely deficient range, and now it’s in the suboptimal range. People would say it’s too high now, it’s 200, and previously was 20.

I also have my triglycerides tested, I have my cholesterol done, and all those fun markers. I have a full blood count, my white blood cell count was pretty good, I can’t remember the exact figures. It’s actually better than before I had cancer, which is not typical even years after you had cancer, immunity can be compromised, so your white blood cell count is typically quite low, and I found that quite interesting.

(29:13) [Damien Blenkinsopp]: It’s great to hear about that progression. Let’s talk about the actual things that you’ve done in terms of where you started in your ketogenic diet, because I know that people said they’re ketogenic. Have you been tracking your blood ketones and blood glucose since the start? And have you seen how that’s changed as you’ve changed your diet?

[Andrew Scarborough]: Yeah. The first thing I did I went out and got a glucometer to measure my blood ketones and blood glucose, and I was comparing that to book cancerous [unclear 29:45] disease, and the glucose-ketone index that Thomas Seyfried devised and came up with, with his colleagues. I had a number of conversations with him about it, just over email, and I was amazed that he got back to me.

I found it very interesting, I started with trying to do the fast, to start with, to get me in ketosis quite quickly. But I realized with epilepsy that’s not a great idea. I had quite a few bad breakthrough seizures attempting that.

I decided not to try it that way, I decided to do it gradually and over time I managed to get into the therapeutic range within just a few weeks.

[Damien Blenkinsopp]: When you say therapeutic range what is that?

[Andrew Scarborough]: I was using the glucose-ketone index, which you use a ratio where you divide your blood ketones by the blood glucose, and you come up with a number, and you try and make sure that number is — I think it’s above one. I don’t measure it anymore in that way because I’m consistently in very deep ketosis with very low blood glucose, so I don’t have to do it anymore.

[Damien Blenkinsopp]: Yeah, we actually covered the index with Thomas Seyfried before. I think it’s a glucose divided by ketones, and there’s a couple of other little things you have to do in there, it’s not super straight forward. I put a spreadsheet up for some people who are asking, when he was talking to us he said it was under one.

So I guess that’s what you are aiming for and you seem to be saying you’ve gone…

[Andrew Scarborough]: Yeah at that time, that’s what I was aiming for, but now I’m consistently above 3.5, so I don’t have to worry about that so much.

[Damien Blenkinsopp]: Oh, in the glucose-ketone index?

[Andrew Scarborough]: Well my ketones are typically above 3.5, and the blood glucose is typically hovering around 3.5 — at the very least one to one.

[Damien Blenkinsopp]: Okay, so for the people at home, because in the US the blood glucose measurement isn’t millimolar. So you’re talking around in between 54 and 72 mg/dl, like 3-4 millimolar. I’m guessing you’re hovering around with the Seyfried Index somewhere around 0.6, 0.8.

So it’s well below one that’s what you’re saying because your ketones are so high.

[Andrew Scarborough]: Yeah. In the evenings it goes sky high, well the ketones go sky high, the glucose goes really low.

[Damien Blenkinsopp]: Do you mean from 5 o’clock onwards — it’s interesting because I saw that in some of my fast and some of my earlier experiments also.

[Andrew Scarborough]: Yeah. I guess it’s a hormonal thing that happens, and also because there’s that period of time where I only have typically two meals a day, that’s the in-between period, I guess where it goes that high. So that’s where I’ve unintentionally fasted for that period of time even though the diet’s mimicking fasting itself.

(32:58) [Damien Blenkinsopp]: What is a typical day look? What are you doing now, what is your typical day look like? I’m assuming at the moment you’ve got the most extreme version of your own program for this, is that correct?

[Andrew Scarborough]: Yeah. Typically I have 85% of fat and 15% protein in my diet, but over the last few days, I’ve experimented with 90% fat and 10% protein, and negligible carbs. Typically on my 85% and 15% protocol that I follow which is very similar to the animal studies, and quite similar to very strict ketogenic diet for children with epilepsy.

I restrict my calorie intake to 1,600 calories — calorie restriction is extremely important for brain cancer management. You probably discussed that with other people I’m guessing. What’s also important I think is the other things that I’m doing.

Personally, I think it’s very important to make sure you have correct therapeutic ratio — I like to call it of omega 3 and 6 in the blood, and I have at home testing kit for that which I send off to the lab every few months.

[Damien Blenkinsopp]: Okay, that’s interesting, is that a dry spot test?

[Andrew Scarborough]: Yeah, it is. You just have to collect quite a significant amount of blood, and it gives you a report back just saying what you’re ratios of omega 3 and 6 are in your blood.

[Damien Blenkinsopp]: Which lab are you using for that?

[Andrew Scarborough]: Well, the testing kit is by — if you go on Omegasense.com it comes up. There’s a center called the NutriCentre in London, and I just get it from there. It’s a pretty good test, very accurate.

[Damien Blenkinsopp]: Have you seen that change? This is actually the current levels ratio, it’s not like it’s your diet of the day like we were talking about — the blood glucose and the ketones which are changing all the time. It’s a more stable marker which is evolving over time, so you’re choosing for a range you want to keep it within.

[Andrew Scarborough]: I’m just trying to get us close to 1:1 ratio as possible, and I’ve experimented with a 2:1 and a 3:1 ratio in favor of omega 3 which is quite hard to do, but it’s very interesting. We know that omega 3 fatty acids exhibit neuroprotective properties and can represent a potential treatment for a variety of neurodegenerative diseases. It’s really interesting, we know that they are shown to be cytotoxic to tumor cells themselves.

Ideally, an optimal ketogenic diet for brain cancer should have, in my view a better ratio than omega 3 and 6. I think the standard ketogenic diets that are applied to humans at the moment are way to high in omega 6 which is inflammatory. I struggled when I was doing a standard ketogenic diet because of that.

[Damien Blenkinsopp]: What are you taking in order to raise your omega 3 levels? What are you doing in diet specifically?

[Andrew Scarborough]: Well, initially I was eating lots of brains because they are the best source of omega 3 that you could get, and that’s high in DHA, and one of the main fatty acids in the brain is DHA. The brain is 70% fat, and the rest is mostly water, it just makes sense to me to have in my diet mostly fat and water, that was my main reason for doing that.

We also know that the fatty acid composition of gliomas differs from that founding non-malignant brain tissue quite significantly. The reduction of glioma DHA content is really interesting to view — we know that in gliomas which is what my tumor was, and what a glioblastoma is as well. We know that they have significantly less DHA in and around them.

If we can increase that — the literature shows that it can have a very potent effect, particularly when on a ketogenic diet, in shrinking these tumors.

[Damien Blenkinsopp]: That’s great so you’re still eating brains today, is this a large part of your diet? What types of brains?

[Andrew Scarborough]: I was eating lamb’s brains, but, unfortunately, I’ve stopped eating them because of the very, very low risk of Scrapie which is like a CJD, a Mad Cow disease but the lamb form. Even though it’s a very small risk, and you probably have that same risk if you were to eat any infected tissue of that same animal, I just thought it would be a good idea to avoid it, which is a shame because it’s my favorite type of food on the ketogenic diet.

It’s a perfect ketogenic food, but my second most therapeutic ketogenic food that I found is sweetbreads which is the pancreas and the thymus gland of — in my case I get them from lambs again. I’ve done an experiment which is on YouTube, on my YouTube channel, just look at Andrew Scarborough, and look at my sweetbreads experiment, I’m testing the myoglobin of sweetbreads and it comes up very high on the glucometer for ketones.

When I test my blood after my postprandial blood glucose and my blood ketones after eating, my ketones shoot up very high, and the blood glucose stays more or less the same as before I started eating.

[Damien Blenkinsopp]: That’s interesting. Out of interest, how much do sweetbreads cost? Are they relatively cheap or expensive?

[Andrew Scarborough]: Well I mostly get them for free, sometimes I have to pay a pound for them.

[Damien Blenkinsopp]: Okay, so they are very cheap.

[Andrew Scarborough]: Yeah, because no one wants them.

[Damien Blenkinsopp]: Right that’s what I was thinking.

[Andrew Scarborough]: They’re incredibly nutrient dense, rich in trace minerals such as zinc and selenium, and they’re rich in protein, and omega 3 fatty acids. Like the brain, and like all the fish — the great source of omega 3. They also raise ketones very high.

[Damien Blenkinsopp]: Yeah, that’s very surprising. I don’t know if you’ve heard new supplement ranges which I’ve been playing around with it, exogenous ketones.

[Andrew Scarborough]: Yeah, I take those as well. I take KetoForce, mostly when I’m trying to do exercise because exercise is a huge seizure trigger for me. So yeah I play around with that.

[Damien Blenkinsopp]: It sounds like the sweetbreads are more effective than the KetoForce, KetoCaNa and the other ones.

[Andrew Scarborough]: Yeah. I actually made a supplement, a sludgy juice that the sweetbreads come in because I have them completely fresh straight after the animals are being slaughtered, well not straight after, but not long after, because they have to do a number of things just to make sure they are safe to eat. I made a supplement out of that and tested it, and it was very interesting the results, but it tasted absolutely foul.

[Damien Blenkinsopp]: Is that a downside of sweetbreads, they’re really awesome except they taste bad.

[Andrew Scarborough]: Yeah.

[Damien Blenkinsopp]: Okay.

[Andrew Scarborough]: It’s not the best tasting, you have to boil them for a long period of time, but they’re very nutrient dense and very effective.

[Damien Blenkinsopp]: How do you eat them? Have you got a quick recipe for the people at home, and they’re like, “Oh like a great thing to try out.” But if it tastes horrible is there some way to mask it.

[Andrew Scarborough]: The best thing to do is boil them for about an hour, that’s actually a short period of time typically for sweetbreads. Normally, it’s a lot longer. And then if you add tarragon to it, it actually compliments the flavor, and it actually tastes a lot nicer.

That’s one of the things I do, it goes well with tarragon. I just consume every bit of the animal, and I don’t have any carbohydrate so that’s how I get around possible nutrient deficiencies from not having any fruits and vegetables. And it allows me to not count carbohydrates, so it’s a Paleo-Ketogenic diet.

[Damien Blenkinsopp]: It’s a pure meat diet, right? Basically a pure carnivore?

[Andrew Scarborough]: Meat and fish, and fat, and that’s it.

(41:37) [Damien Blenkinsopp]: I do know there’s a little bit of story behind the reason — first you were on a ketogenic diet and you were doing more of a straight forward one with the coconut oil, and all of these kinds of things, what happened?

[Andrew Scarborough]: I noticed that with certain people with certain types of brain injury, your brain can be more sensitive to salicylates which are found in coconut oil, various vegetables and fruits, especially ones that have seeds. I wasn’t able to have avocados or any of the staple ketogenic foods that you have. I also couldn’t have dairy because I had a reaction to that, and I wouldn’t advise dairy anyway on a ketogenic diet for anyone with cancer let alone — brain cancer, because of IGF-1.

It just doesn’t make sense to me that there’re so many ketogenic diets for cancer management that have been based around dairy.

[Damien Blenkinsopp]: Right. There’s a lot of cheese, cheese is pushed quite hard…

[Andrew Scarborough]: Yeah, loads of cheese and double cream, and it’s not efficacious for me, even though I’m astounded that they get any results with these trans fat. And they do get some results, that’s encouraging for me on my — what I would call a more beneficial and effective ketogenic diet for this circumstance.

(43:06)[Damien Blenkinsopp]: Could you explain quickly the IGF-1, because there are people at home that are not quite up to speed on the IGF-1 and the dairy aspect of it. What’s the problem there?

[Andrew Scarborough]: It activates insulin-like growth factor and that can cause cancer cells to proliferate faster. One of the ways I get around that — I used to eat lots of butter, but because it’s more insulinogenic and it has milk proteins and casein. What I do is I have Ghee, which is clarified butter so the milk solids and the casein have been removed, and it’s much less insulinogenic and I actually get a much better blood ketone readings as a result as well compared to butter.

I find that interesting in itself, and we also know that compared to coconut oil, Ghee has much more omega 3 fatty acids, and coconut oil only has omega 6. If you’re basing a ketogenic diet around — just loads and loads of coconut oil which is just omega 6. Even though coconut oil is fantastic for achieving ketosis, I would advise it in moderate amounts if you can tolerate it because it’s really good.

I would say that making sure that you have enough omega 3 by having more animal fats is more beneficial in terms of the overall nutrient profile than just consuming tons of coconut oil.

(44:44) [Damien Blenkinsopp]: Right. You mentioned you eat all the parts of the animal, I’m guessing you mean all of the organs…

[Andrew Scarborough]: Yep.

[Damien Blenkinsopp]: Do you consume what you would call a variety of these? Do you try to cycle them, and the widest spectrum possible? So what other organs are you eating, are you literally eating all of the different organs on a rotation each week?

[Andrew Scarborough]: Yeah. Literally everything but mostly heart, because it’s very very cheap, it would cost me 60 pence at a time, and you get quite a substantial portion— because lamb hearts are quite fatty, there’s a huge chunk of fat on them. I can just eat them as they are, and I don’t need to add extra fat.

It’s a fantastic source of iron, zinc, selenium, B vitamins, folate, and it’s the best food source of coenzyme Q10. It’s funny how people pay an absolute fortune to get pills that have a coenzyme Q10, and I just get the best source that you could possibly get for 60 pence at a time.

[Damien Blenkinsopp]: There’s a psychological barrier about the taste, and it’s just what we’ve become used to really. I’m definitely nowhere near as far as you — I’ve been eating more organ meats and I’m trying to push it up, I just made another order today from a new company actually. I’m slowly building my way up, and it’s a taste I’m struggling with, recipes I think help with that, learning how to cook and deal with the different tastes, and just getting used to them.

[Andrew Scarborough]: Yeah. I actually did quite well to start with brains, they’re actually the most tolerable in terms of tastes because they just taste like creamy eggs.

[Damien Blenkinsopp]: Oh, I would’ve never thought that.

[Andrew Scarborough]: They taste like creamy salty eggs.

[Damien Blenkinsopp]: You just don’t look at them while you’re eating them.

[Andrew Scarborough]: No. And a number of things I do are just for entertainment, to keep the diet interesting, to make sure I have enough trace minerals. That’s why I added insects to my diet quite early on because anytime you eat the whole animal you’re getting a variety of nutrients. When you eat insects you’re consuming the whole animal — it just makes sense that it would be a beneficial thing to have.

[Damien Blenkinsopp]: How do you consume those? Because I know there are cricket bars out there in the US, how are you consuming insects?

[Andrew Scarborough]: What I do is I get the fattiest insects that are ketogenic, I get waxworms and super worms. Mostly insects that reptiles eat, I get them from a pet shop that sells them for reptiles now, I used to get them online.

[Damien Blenkinsopp]: Oh, man. Okay did you used to buy from [check 47:31 – Bug Grow], was that the specific brand — was that the only place you bought from?

[Andrew Scarborough]: Yeah, I tried a few, I tried silk worm, pupa as well — a few different insects have different medicinal properties, they’re in Chinese medicine. They’re really interesting in terms of the properties that they have. But we largely ignore that, mainly what I do now is I get them from the pet shop.

I just stick them in the freezer to kill them, and then I’ll give them a gentle wash and eat them …

[Damien Blenkinsopp]: You just eat them straight?

[Andrew Scarborough]: The problem, if you get them online is that they’ve been dehydrated and cooked so much that the nutrient profile isn’t as good as if you have them fresh after they’ve been wiggling about. I also grind them up and make my own flour after I’ve frozen them. That makes quite nice breads, I make a zero carb ketogenic bread which is very useful. People actually think it’s proper bread…

[Damien Blenkinsopp]: You don’t tell them right?

[Andrew Scarborough]: I’ve actually offered it to people without telling them, and they quite like it, and then I tell them what it is, and they want to punch me. But it’s actually surprisingly quite nice.

[Damien Blenkinsopp]: A quick story here, I was in Mexico 15 years ago and I went to Taxco. Anyway you go up into the mountains, into this old city and they were selling plastic bags full of live insects for eating. It’s something that we used to do — we don’t do in modern society. . .

[Andrew Scarborough]: If you look at anthropology, and how we evolved, it’s largely ignored especially with these Paleo diets — we evolved primarily eating a variety of insects, and in quite a large amount. It suggested that the man would go out and go hunting — would only about a 20% success rate catching these larger animals.

The woman would be mainly collecting insects for food. Seasonally they would collect nuts and berries, but it’s a fact in anthropological studies that we did consume a large amount of insects before we moved closer to the coast to eat fish, and that’s how our brains developed more. It’s an ignored fact.

(50:16)[Damien Blenkinsopp]: It’s really interesting, we’ll get there. There’ll be people writing books — maybe you, about the missing parts of the Paleo diet, Paleo upgraded. You did mention that, when you exercise you’re taking exogenous ketones, because of your epilepsy, why is that?

[Andrew Scarborough]: When I exercise my blood ketones go down, lower than my individual therapeutic reading for seizure control for me personally. I have to do that, and I also have to take another experimental treatment of mine which is proved effective, which I learned from the literature on epilepsy. It’s a magnesium chloride solution that I mix into water, and I have a specific amount that reverses auras.

An aura for me is when you have all symptoms that you’re about to have a more serious type of seizure. An aura is a partial seizure in itself.

[Damien Blenkinsopp]: Okay. Maybe you would loose your words a little bit?

[Andrew Scarborough]: I would get pins and needles in my mouth and throat, and I would feel very dizzy, and faint. I have this horrible feeling like I’m going to collapse and have a tonic-clonic seizure. When I take the magnesium solution that I take three times a day, it actually reverses that aura, it is a potent preventative measure that I found to control seizure activity extremely effectively.

People with any kind of epilepsy, their levels of magnesium drop very low, and there are certain types of the day that magnesium is at its lowest, and typically that’s when seizure threshold is also at its lowest. If we can control that, we can control seizures very effectively. Also, on a ketogenic diet, supplemental magnesium — particularly magnesium chloride are found most effective.

It acts as a natural statin, it has a beneficial effect not only on cholesterol, in a natural way not like a typical statin where it’s actually destroying that process, it’s working with your body to do it naturally. I find that it also controls blood glucose — it regulates blood glucose very effectively too. I see it as my replacement for my medication that I was on previously, and the medication interestingly actually causes magnesium deficiency as well as calcium deficiency, deficiency in vitamin B-12 and vitamin D.

[Damien Blenkinsopp]: Which medication where you on?

[Andrew Scarborough]: I was on the maximum dose of Levetiracetam, which the brand name is Keppra and Sodium Valproate the brand name for that is, Epilim. I was both on those and the highest possible amount that you could be on. You can imagine the side effects of that, and the nutrient deficiencies that caused were just quite substantial.

When you’re withdrawing from those drugs you could actually get breakthrough seizures if you don’t address those nutritional deficiencies, and those seizures can actually cause SUDEP — it’s shorthand for sudden unexpected death in epilepsy. I was told consistently that I was highly likely to have that if I was to — not only come off my medication which is what I eventually did but reduced the medication. I have to reduce that medication for a period of almost two years.

I had to do it very slowly, and adding these nutrients and trace elements so that I was not having these breakthrough seizures that were life-threatening. It was a difficult balance, but I achieved it.

(54:50) [Damien Blenkinsopp]: It makes it easier when you titrate down slowly, but still you’ve been courageous in pushing for all of these things when you’re getting this pushback which is saying it’s really dangerous. Just in terms of the exercise, how do you bump your ketones up – is it the KetoForce?

[Andrew Scarborough]: Yeah. I consume that throughout my workout but I tend to mostly just do quite a light bodyweight exercise because I don’t want to stress my body too much. Thomas Seyfried himself recommends that cancer patients don’t push themselves too much with exercise, because it just puts too much stress on the body and on the brain. Mostly I just go for long walks, in an area with lots of oxygen, and I’m actually going to start having hyperbaric oxygen therapy fairly soon.

I’m in discussions with a number of facilities about that, and I’m going to start doing case studies on patients. I’m actually working part-time at the moment with Imperial College London in Charing Cross Hospital, to start-up clinical trials hopefully next year with brain cancer patients using — what I would call an optimal ketogenic diet.

We’re looking at magnesium for these brain cancer patients, we’re looking at the omega 3 and 6 ratios in the blood, we’re looking at C-reactive protein as a marker for a systemic inflammation, and we’re able to measure that for over a period of time to see how that changes while on a ketogenic diet.

[Damien Blenkinsopp]: With cancer is that typically high the hs-CRP because of the inflammation, or is that just a. . .

[Andrew Scarborough]: Yeah. It’s typically higher than normal, but one of the main ideas of measuring that is to have a marker that you can measure over time. I’m a huge fan of testing and I know that even if these things have no effect on cancer, they have an effect on epilepsy and blood glucose management.

We know that these are prognostic factors and they’re also effective at managing epilepsy which many brain cancer patients have as a result. I’m very keen to start doing this in patients more, and I’m working very hard to do that.

[Damien Blenkinsopp]: It’s very exciting that you’re able to work in hospitals. This is starting next year you said, potentially?

[Andrew Scarborough]: Yes. It would also be featured in, New Scientist magazine early next year. My story and my approach will be featured, and that’s very exciting as well because it’s getting the message out there and we can then have the actual data on humans which is missing. It would be — as I’ve said before it will be efficacious.

We’ll be able to not just translate the diets that have been used for children with epilepsy which I don’t believe …

[Damien Blenkinsopp]: As good, as they could be?

[Andrew Scarborough]: I don’t think that they’re translatable for brain cancer patients because I think it’s just very different. For example, when I was on the standard type of ketogenic diet, they did include those ingredients. I developed symptoms that were similar to Temporal Arteritis, where my temporal arteries became so inflamed that I nearly went blind and I was prescribed steroids for it.

But instead of taking the steroids what I did is I looked at how much omega 6 I was taking in my diet, and even though my blood glucose and ketones looked fantastic, and the ketogenic diet is anti-inflammatory in itself. I was having these inflammatory responses which were only controlled and reversed when I re-addressed the balance of omega 3 and 6 ratios. That in itself is quite powerful.

(59:15)[Damien Blenkinsopp]: Interesting. Where did your omega 6 ratio start? We read studies where the standard American diet, for example, is you can get ratios of 20:1, 10:1 — quite far off.

[Andrew Scarborough]: I’ve read up to 40:1.

[Damien Blenkinsopp]: Were you not so bad because you said you had a reasonable — you were trying to have a reasonably healthy diet before. I wouldn’t expect you’d have the sad numbers.

[Andrew Scarborough]: Yes, prior to initiation of the diet, I would say I was most likely about a 10:1 ratio. But, on the ketogenic diet, it was probably quite similar actually because it was including lots of nuts, coconut oil, coconut milk, coconut cream, lots of vegetables that were high in omega 6. I just thought it could be done better — then I transferred on to what I like to call a, fishogenic diet.

I was consuming a lot more fish, and I felt instantly much better and then as I cut down on the vegetables – cut them out completely. I had an instant response where I can’t even remember the last time I had a headache, even a mild headache.

(60:32)[Damien Blenkinsopp]: Great to hear. I’m conscious of your time I know that you’re really busy currently. But there’re a couple of things — I do want to make sure we cover before you go. We didn’t speak about glutamine and I know that an important part you mentioned up front that’s something you had to restrict quite sharply. But how did you do that practically?

[Andrew Scarborough]: Well, the first thing I did was limit protein quite significantly, and I did a number of therapeutic fasts, and it wasn’t until then that I actually saw the greatest response in my MRI scans, in terms of the complete remission. One of the other things that’s quite effective is with the magnesium it has an effect on that as well. I need to find the study for that, but I can send it to you if you’re interested in reading it.

Another thing that I’m actually looking into for the long term is Metformin, because Metformin on a ketogenic diet has quite a potent effect. It has a number of mechanisms which I can’t remember all of them off the top of my head, but that’s one thing that I’m playing around at the moment. It gets an effect on MAMP and a few other things.

It’s quite hard to explain, it’s quite technical.

[Damien Blenkinsopp]: In terms of the fast, you said that’s when you really started seeing the effects, so that would mirror — we had Thomas Seyfried on here and he was talking about the importance of the fast. How many days — was that a pure water fast? Was it a seven or five day fast?

[Andrew Scarborough]: It’s interesting because I think that — when these researchers are talking about fasting for brain cancer patients particularly if they have epilepsy, what they fail to note is that there’s ionic changes that are happening in the brain when you’re doing these fasts. A patient with epilepsy can’t — especially if they have brain cancer in my opinion shouldn’t just do water-only fast.

I think that they need to do what I call, a ’magnesium fast’. When I fast I have my magnesium water solution that I make up myself, and that prevents me from having breakthrough seizures while I’m fasting because I have such low body fat percentage. My longest fast has only been nine days. I aimed for 10 but I couldn’t do more, I’ve done that a few times but I need to have my magnesium-chloride solution or I instantly have breakthrough seizures, not the good kind either.

I found out the hard way initially, but now it’s just the easiest thing that I do.

[Damien Blenkinsopp]: You’re taking specifically magnesium chloride, is that because it’s a spray kind or is it actually the magnesium chloride specifically — there’s something about the chloride which is helping?

[Andrew Scarborough]: It has something to do with hydrochloric acid and how you digest it. I’d say it’s more bioavailable and it seems to me to be just in my personal experiences that it seems to get the brain very quickly. The literature doesn’t actually say that, but personally, I found that — even though there is not much in the literature about that.

[Damien Blenkinsopp]: Are you buying a specific brand? We’ve talked about using magnesium spray transdermally, but I’m just wondering if you’re using one of those sprays? How much you’re taking of it?

[Andrew Scarborough]: It’s designed to be primarily used transdermally this particular type, and I just get it from a health food shop, it’s mainly people who do sports who take it, which is interesting and funny. I typically take about five sprays three times a day. I can’t remember exactly how much that is, for 10 sprays it’s 150 milligrams of magnesium.

It’s variable depending on how mixed up the solution is — typically around 230 milligrams in a day that I would take. If you consider our water is too high in calcium and not high enough in magnesium. It’s addressing that imbalance that we have, we know that we should have at least a 2:1 ratio of magnesium to calcium, that addresses that imbalance.

We know that in the mornings after we wake up, magnesium levels are lowest. Primarily take it in the morning, after waking up in the afternoon, and before I go to bed.

[Damien Blenkinsopp]: Have you checked your RBC magnesium levels?

[Andrew Scarborough]: I haven’t because I don’t think it’s an accurate measure. I just go by how I feel, and sometimes — I see the epilepsy as a blessing because everything to do with epilepsy with brain cancer is typically very similar to what would work for treating the cancer. If something is working for the epilepsy, you’ve got a pretty good idea that it’s beneficial for the cancer, and most of the things that I actually research about what helps in terms of my epilepsy, experimentally and otherwise.

I found incidentally that it has quite potent anti-cancer benefits as well. It’s really interesting the relationship. It’s quite empowering as well. What I would call spectacular results because I still can’t believe I’m not having these horrific seizures all the time without medication. It’s quite empowering to know that it’s potentially having the same benefit on the cancer.

(1:06:44)[Damien Blenkinsopp]: Yes, it’s pretty amazing your journey. I don’t know if you’ve come into contact with other people with similar stories to tell — I know that some other people who had cancer, you said, unfortunately, they’ve passed away — the ones you were relating to. But if you come across any other people who have been experimenting like yourself.

[Andrew Scarborough]: Yeah. I actually have a group of friends now who I came into contact with just through seeking out long-term survivors, and I have a group of long-term survivor friends who had glioblastoma many years ago, and now have no sign of disease. I have a group of friends with various other cancers who are still here now. They’ve mostly done a drug cocktail treatment on themselves, which is very interesting.

Personally, I wanted to try and copy that drug cocktail treatment but do it in a natural way just using diet.

[Damien Blenkinsopp]: When you say drug cocktail, is that chemo or is that more Metformin and things like that?

[Andrew Scarborough]: It’s more Metformin and statins, and phosphates, and various other DCA, and other very interesting drugs. Personally, the only one I’m considering is Metformin, and potentially a few others, but mainly Metformin and Curcumin which I take in tablet form with DHA because they work synergistically. Curcumin actually increases uptake of DHA to the brain.

Because we know that around these tumors, or where the tumor was – DHA is very low. We know that if you have Curcumin and DHA that’s a powerful combination. Curcumin is cytotoxic to the cells. We know that DHA is, and is essential for brain functioning.

[Damien Blenkinsopp]: You really have built a whole lot of armory against this — it sounds like you’re doing really well. On the Curcumin – there’s many forms available on the market today, you’re taking one of the bioavailable forms…

[Andrew Scarborough]: Yeah, it has piperine in it as well.

[Damien Blenkinsopp]: Okay.

[Andrew Scarborough]: It’s a component of black pepper. I have a number of strategies that I use, and I’m constantly optimizing my metabolic formula.

(1:09:14)[Damien Blenkinsopp]: Do you feel constant improvement? I don’t know if there are any symptoms because it seems like you’ve got most of it under control. Do you think you’re going to be able to repair your body, do you feel any signs of that in terms of potentially resolving the epilepsy?

Do you think this is more likely something that you’re just going to optimize and maintain so that it never bothers you, so you never get the actual symptoms?

[Andrew Scarborough]: As my brain has been visibly healing at a very fast rate on these scans while I’ve been utilizing this protocol, I’ve also found my symptoms have improved with that quite substantially as well. I had facial paresthesia constantly all throughout the day, everyday, and a number of other debilitating symptoms I couldn’t even go out and walk a few steps. The fatigue was horrendous as well.

Being able to do what I am now and this non-stop activity, and just doing so many different things, and having my seizure activity controlled in such a great way that’s much better than before — even before when I was doing all these things I was still getting more activity. I haven’t actually done that many more things if I compare to even just a few months ago. Definitely improving in quite a dramatic way, despite having to keep up with all these things.

It’s getting easier to control, to the point where I have days now that I have no symptoms at all, but if I get overconfident and I forget to have my magnesium drink or do something that’s just out of my routine, I’d definitely have more seizure activity coming. Even though it’s not to the degree that I used to have.

[Damien Blenkinsopp]: I guess really say why you’re saying epilepsy is a bit of a bonus for you because it’s early warning detection system for you…

[Andrew Scarborough]: Yeah.

[Damien Blenkinsopp]: — Whereas cancers can creep up on you and you won’t know unless you’re watching the scans and even the scans aren’t showing a small progression. So right now you can still have a small amount of cancer left, but you can’t see it. It does seem like a pretty nice little tool, even though it’s not nice to have it, in the longer term it sounds like it’s a beneficial thing for you.

[Andrew Scarborough]: Yeah, I can see it as beneficial now, I couldn’t before but it definitely is.

(1:11:47) [Damien Blenkinsopp]: Well Andrew this has been an amazing — it’s very inspiring episode today. I can really say that — I’m totally going to take some of the things that you have been trying and start testing them out myself. I would like to ask you — where to look first if they would like to learn about this topic if they’re facing cancer or epilepsy?

Are there good books or presentations on the subject, the first places to go to, to start learning themselves about this?

[Andrew Scarborough]: I would thoroughly recommend the book, Cancer as a Metabolic Disease by Thomas Seyfried. I think that’s a great starting point. For anyone starting a ketogenic diet I would recommend, Keto Clarity, that’s a good resource to use. I would also go to www.ketogenic-diet-resource.com — that has answers to just about all the questions that you could have.

For help to a dietician, if you live in the UK I would recommend the charity, Matthew’s Friends. In the US, I would recommend the Charlie Foundation which is the sister organization of Matthew’s Friends in the UK. It has recently started to see — it’s mainly brain cancer patients that they see because they get around with that by saying that they’re treating the epilepsy.

I would also go on Clinicaltrials.gov to see what clinical trials are happening globally to do with the ketogenic diet and different cancers.

[Damien Blenkinsopp]: Right, so if they’ll just search for a ketogenic diet on there…

[Andrew Scarborough]: Yeah, if they search for ketogenic diet and cancer on Clinicaltrials.gov they can see all of the clinical trials that are currently happening in terms of ketogenic diets for different cancers. It’s very exciting that more and more of these are popping up, and I hope to — I have a meeting on Thursday to discuss having proper official ketogenic diets, using the right approach in this country, and that’s really exciting new development.

[Damien Blenkinsopp]: Is that with the government, NHS or some other body that’s going to help promote it.

[Andrew Scarborough]: This is in conjunction with brain tumor research, they’re one of the very few cancer charities that actually are going all at it with this metabolic research, and they’re doing that with Imperial College London. It’s a small charity that’s doing this, it’s quite incredible what they are able to do being such a small organization.

[Damien Blenkinsopp]: It’s great they’re starting to be – some grounds building from the bottom and up.

[Andrew Scarborough]: Yeah, and I’m going to start-up my own individual research with a few of my lecturers at my university because I want to get these things happening much faster than if it’s going through clinical trial protocol. I want to do this myself with lower grade gliomas, so that we can see a long-term response to try and shrink these tumors hopefully, because they are not as aggressive, but, they still are incurable.

I want to see what effect that we can have on them rather than having to go through all the standard treatment to go through clinical trials. I think that’s very exciting going forward.

(1:15:25) [Damien Blenkinsopp]: That sounds really exciting, and I’m sure anyone who – maybe affected would be very interested to know more. What are the best ways for people to connect with you and learn about you, and keep up with you when you’re doing these things, they can stay up to date on them. Are you on Twitter, you mentioned you had a YouTube channel?

[Andrew Scarborough]: Yeah, my Twitter name is @ascarbs, and I’m on Facebook if people want to add me on there, Andrew Scarborough. I also am working on a website at the moment which is www.metabolictherapy.co.uk, and that has a holding page at the moment, but it should be live shortly. I have a YouTube channel, Andrew Scarborough, and I have a blog, My Brain Cancer Story that’s the title of it.

People search for Andrew Scarborough and My Brain Cancer Story, they should find it.

[Damien Blenkinsopp]: Excellent. We’ll put all those links on the show notes of course also, make sure all of that is there. Is there anyone besides yourself you’d recommend to learn more about the stuff that you mentioned, Thomas Seyfried, is there anyone else that people should look to?

[Andrew Scarborough]: I would look at the research by Dominic D’Agostino, also I would recommend Dr. Colin Champ, I’ve had various discussions with him online which are very interesting. He’s very interested in my approach and he is very unique, he’s a radiation oncologist who is very supportive of this metabolic treatment. Very similar to my oncologist who – it’s quite a rare thing to find – but it’s very encouraging.

There’s Dr. Adrienne Scheck, who I’m having a meeting with on Thursday she’s coming overseas from the Barrow Neurological Institute in the US, and she’s the one that does the rodent studies using the ketogenic diet. It’s great to be able to discuss with her.

(1:17:29) [Damien Blenkinsopp]: Great, great, thank you for those. Some quick items on your – just a personal approach on what you would advise people to get started with – are you still tracking any biomarkers, on a routine basis?

[Andrew Scarborough]: Only occasionally with MRI spectroscopy but we’ve stopped doing that now just because it looks a bit boring and nothing’s really changing. It all looks really good, that’s why we’re not monitoring it anymore.

[Damien Blenkinsopp]: So maybe once in every six months or once a year?

[Andrew Scarborough]: Yeah, just to keep an eye on it, but everything that you would expect to be elevated but would be a bad thing isn’t showing up – it sounds like a good thing. It’s very new research, we don’t know too much about it, but it’s very promising for the future.

Because if we can see these things before they show on the scan, in terms of enhancement or just showing in an obvious way then it’s – that can only be good for the patient really. Then we can intervene in a non-toxic way.

[Damien Blenkinsopp]: So if you were to recommend one experiment, basically you’ve done many experiments to get to this point – they’re not proven recommendations by doctors and so on. What would you recommend that someone with brain cancer or potential other cancer – what would be the first thing they should try, the biggest payoff from all of the things that you’ve mentioned, what should their first step be?

[Andrew Scarborough]: The first step should definitely be reducing carbohydrate intake. The second step would be reducing protein intake to maintenance levels, and therapeutic fasts are very important. But the main thing, I would say is the omega 3 to 6 ratio, I believe that they should be an omega 3 to 6 index, just like with the glucose-ketone index, and they should work together, as a synergistic therapy.

Because you could even argue the ratio of omega 3 to 6 is even more important than the ketones. I would also say, the magnesium is very important with that too, those three things. Therapeutic ketosis, the omega 3 to 6 ratio and the magnesium I would say are very important for brain cancer patients.

[Damien Blenkinsopp]: Great, thank you, that’s some great takeaways for people at home. Andrew, I’ve got to say this has been really amazing interview – it’s amazing all of the different avenues you’ve run-down and all of these different aspects that you found to improve your situation. I know it’s going to be an inspiring story for the audience.

Thank you very much for being on the show.

[Andrew Scarborough]: No problem, we did cover a lot but we got there in the end.

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Most of us have non-optimal blood glucose regulation today.
The impact? Reduced performance, and reduced longevity. We wrongly assume that it’s only diabetics that are exposed to these issues. This episode explores using continuous glucose monitoring and other tech to optimize blood sugar through the eyes of a diabetic self-experimenter.

How can blood sugar regulation and dysregulation be  better understood? Certainly a lot of you are aware and concerned about these topics, if you haven’t already been tracking your blood glucose or your ketones through some of the self experiments we have previously done.

There are a lot of lessons on optimization in this area. Because it is such a serious issue today, there are a fair number of interviews coming up and talking about it.

Another aspect we look into is hacking medical devices. This means not waiting for the technology to arrive from big companies. We are talking about the DIY spirit that some people are taking towards technology. Rather than waiting for solutions to arrive from the market, they are making real use of technology today, right now.

We are also looking at open-loop and closed-loop system technologies. This is a different approach to using direct feedback to optimize ourselves, our biology. I hope you see that this as exciting as well and we will look at both of those scenarios in today’s blood sugar regulation area. And finally, of course, the value of n=1 experimentation as today’s guest is an n=1 experimenter.

This episode looks at blood sugar regulation through the lens of Diabetes. Now of course this is the main disease associated with blood sugar dysregulation, and this means that we’ll be looking at more of an extreme case. This can often be helpful, though, to finding really useful tools because when you are managing something like diabetes you have to take it a lot more seriously, and you have to manage it a lot more closely, and thus you learn more about it.

So today’s episode, even if you are not diabetic — I am sure there are a certain number of you out there, because it’s very common today — it will still be very useful. I found it incredibly useful myself. And one of the reasons for this is even if you are not Type 1 or Type 2 diabetic, you most probably have some level of blood sugar dysregulation; unless you’ve checked it, and you are at ease with that level.

What I am saying here is it may not be optimum. You may have suffered some metabolic damage along the way and your blood sugar doesn’t quite self-regulate as well as it could. If you wanted to test this yourself, you could do a simple blood glucose test and see what your post meal blood sugar is one and two hour after meals. So if it was over 120mg/dL, it may be something you need to look into further, as you may have accumulated some damage and you may be more towards the spectrum of diabetes, diabetes 2 most likely.

So today we’re going to learn from diabetes 1 management – the most challenging form of diabetes. What works for this is often applicable to your own blood sugar management optimization, and managing blood sugar dysregulation in general.

The power of [Continuous Glucose Management] is not necessarily giving the most accurate reading. It’s more the power of seeing the trend. So I know if I’m going up or down, or something is changing.
– Tim Omer

Today’s guest is Tim Omer. He is a guy in the UK who got frustrated with limitations and stresses of having to manage his own diabetes 1 condition, and he set out to fix it. He is an n=1 experimenter and has made a lot of progress in this area. He has really improved his own life through better information and levering the technologies that exist.

He is not isolated in this either. You will also learn in this episode about the community working to build a bionic pancreas. That is a closed-loop system, or potentially an open-loop system, which can manage insulin release automatically or semi-automatically.

So it is really set to replace the broken part of the body, the pancreas, going forward, which is pretty exciting stuff too. For example, you can learn more about this at #wearenotwaiting on Twitter.

I came across Tim through an article in the Guardian which talked about what he was up to, and his blog HypoDiabetic.co.uk where he talks about his journey and his updates.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!

itunes quantified body

What You’ll Learn

  • Tim Omer’s personal motivation for monitoring blood sugar levels and his battle with type 1 Diabetes (05:57).
  • The basic summary of type 1 and 2 diabetes and on using insulin as therapy (06:56).
  • The effects of very high vs. low glucose levels and how diabetics optimize glucose levels (09:12).
  • Tim Omer’s realistic aim with diabetes management is to remain around the 100 mg/dL blood glucose level (12:57).
  • Long term management of blood glucose levels and sticking to healthy ranges (13:19).
  • Micromanaging diabetes – being proactive with lifestyle choices in order to avoid physiological and mental stress (14:31).
  • The difference in root causes behind the development Type 1 vs. Type 2 diabetes (20:13).
  • How switching to Paleo dieting helps increase insulin sensitivity and optimizes insulin therapy response (22:49).
  • Which are the long term risks of mis-managing diabetes (22:15).
  • Optimal ranges for blood ketone levels and avoiding toxic ketoacidosis in diabetes (26:51).
  • Defining a practical Paleo Diet and caveats with slow – release foods advertisements (29:21).
  • The advantages of switching from pin-prick devices to continuous glucose monitoring (30:39).
  • How CGM informs and empowers the patient in deciding on ways to regulate blood sugar levels (33:28).
  • How insulin pumps work and the benefits these devices offer (35:13).
  • Difficulties in obtaining CGM devices and overcoming initial psychological barriers of using such devices (38:02).
  • A comparison of major CGM devices on the market and user cost-reductions by hacking and re-engineering devices (41:48).
  • How the DIY community is advancing the use of devices and improving quality of life for diabetic patients (47:59).
  • Calibrating CGM devices to gain accurate and useful data for individuals (50:32).
  • Using CGM for detecting trends in blood glucose levels with consuming different food types (55:05).
  • Using open or closed – system devices capable of simultaneously tracking blood sugar levels and adequately administering insulin therapy (56:30).
  • The risks of being solely reliant on technology to treat diabetes and the need to self-engage in the process to achieve optimal positive outcomes (1:03:23).
  • Why the We Are Not Waiting community has taken diabetes treatment into their own hands? – explaining set goals and achieved progress (1:04:36).
  • How the artificial pancreas aims to replace the pancreas of diabetic patients and apps paving the way towards achieving this goal (1:05:46).
  • Undertaking medical and legal risks when participating in DIY biohacking devices and positive effects such movements have on the market (1:07:47).
  • Why the models for developing medical technology are outpaced by DIY communities and why feeling empowered as a patient matters in the social battle for obtaining medical devices, such as CGMs (1:11:51).
  • Tim’s number one recommendation for everyone involved in the field of medical devices and managing data to improve their lives (1:14:52).

Thank Tim Omer on Twitter for this interview.
Click Here to let him know you enjoyed the show!

Tim Omer, Hypo Diabetic Blog

  • The Guardian’s original article on Tim Omer: Describes the active role he is taking in using new technology to battle with his type 1 diabetes condition.
  • Hypo Diabetic Blog: Where Tim Omer talks about his journey and his updates.
  • Tim Omer’s Twitter
  • WeAreNotWaiting: A movement centered around a DIY approach to diabetes management instead of waiting for big companies to commercialize already tweaked – useful tools. It is a community led by diabetic patients and hackers aiming to make diabetes data and technology more accessible and actionable.

Biohacking CGM Devices

Tools & Tactics

Interventions

  • Insulin Therapy: There are two types of insulin injections most diabetic patients use. First, the body requires a background amount of insulin over a 24 h day. Thus patients take a slow-release form of insulin once or twice per day. Second, they use rapid acting insulin with meals such that it can accommodate for food coming into the system.

Tech

  • Insulin Pump: Insulin pumps deliver very minute levels of insulin over the course of a day, thus simplifying treatment and offering greater control. Essentially they simplify the background insulin aspect of therapy.
  • Bionic Pancreas: A closed-loop system, or potentially an open-loop system, which can manage insulin release automatically or semi-automatically. It integrates the insulin pump and continue glucose monitor technologies, so that insulin release responds to real-time data. Essentially, it is meant to serve as a real time replacement of the dysfunctional pancreas of diabetics.

Diet & Nutrition

  • Cheat Day: Cheat days are typically implemented as one day taken off from a diet per week to make the diet easier to follow. This style of dieting is also used by bodybuilders in an attempt to optimize metabolism and fat loss, and by Cyclic Ketogenic Dieters. Tim Ferriss’ The 4-Hour Body book recommended this tool within a Slow Carb Diet. Damien’s experience with this led to seeing high blood sugar levels throughout the entire day, ranging between 130-140 mg/dL. In his personal experience, these days were accompanied with headaches and attention deficit symptoms, adding up to reduced work productivity.
  • Paleo Diet: A diet that advocates eating whole-foods and restricts certain food types including high glycemic foods, grains, and dairy. The diet is low to moderate carbohydrate. Tim found that his insulin sensitivity doubled when he switched to a Paleo-based diet. This has helped him remain in optimal glucose level ranges for more prolonged periods.
  • Ketogenic Diet: A high fat, moderate protein and low carbohydrate diet. This diet is particular in that it changes the metabolism so that it burns ketones instead of glucose for fuel. See episode 7 with Jimmy More for detailed discussion of the benefits of this dietary approach. This should not be confused with diabetic ketoacidosis (DKA) – a serious medical condition suffered only by diabetics when their insulin drops to near zero, and as a result ketones spike to abnormal levels (20 Mm plus). This situation does not occur for non-diabetics following a ketogenic diet.

Supplementation

  • Exogenous Ketones: A new range of supplements that increase blood ketones directly by providing beta-hydroxybutyrate (a ketone body). These supplements are being studied for and used to increase energy, performance and provide other health benefits. Damien remarked on their use. Read this article for a comprehensive explanation of exogenous ketones and their applications and see here for the list of currently available exogenous ketone products.

Tracking

Biomarkers

  • Blood Glucose: This is a simple measurement of the glucose (blood sugar) concentration in your system. It reflects the body’s ability to properly metabolize food and feed cells with essential energy – glucose molecules. Blood glucose levels usually range around 81 mg/dL (4.5 mmol – UK units). On the upper scale, you should aim to stay below 126 mg/dL (7 mmol), but this level is jumped several times every day. Damien notes that 120 mg/dL can often by hit post-meals, depending on what is eaten. As a diabetic patient, Tim aims to keep his blood glucose around the 100 mg/dL (that’s his target to aim for). Previously, we have covered measuring glucose, including fasting glucose as a biomarker, in Episode 22 with Bob Troia.
  • Blood Ketones: As a diabetic patient, testing for blood ketone levels is useful in determining whether your body is likely going into DKA state. For a diabetic, they monitor to ensure their Ketone levels stay below 11 mmol (which would indicate they are approaching Ketoacidosis). This is not the same as with a non-diabetic. For instance, Damien regularly see 8 mmol or higher during water fasts experiments, and specifically this was noted in his 10 day water fast. This is perfectly normal in that different context. Context matters. To understand the ketones values better, see Episode 7 with Jimmy Moore where we discussed measuring ketones in depth. 

Lab Tests, Devices and Apps

  • Pin-Prick Glucose Tracking Devices: The most popular and easily accessible devices for checking blood glucose (and ketones). While we’ve mostly covered these for use in tracking ketogenic diets, blood sugar optimization and fasting therapy these were originally developed for Diabetic patients. The majority of diabetic patients rely on these devices. The most popular devices, and ones we’ve discussed before, are the Precision Xtra Blood Glucose and Ketone Monitoring System in the U.S. and the Freestyle Optium Neo Glucose & Ketone meter in the UK
  • Dexcom Seven Plus: This CGM device has been retired and newer Dexcom devices are available on the market. It cost Tim around 400-500 pounds at the time when he bought it on eBay.
  • Dexcom G4: The CGM which Tim currently uses and one of the most popular on the market. A continuous glucose monitor containing a small sensor that measures glucose levels just underneath the skin. A transmitter then sends wireless data to a receiver which displays glucose trends. Tim has done extensive work on biohacking this device making it more user-friendly and actionable in managing diabetes.
  • xDrip Device & App: This system combines a small transistor device which allows for CGM data to be directly transferred to a phone or a smartwatch. Developed by Stephen Black and widely used in DIY biohacking circles.
  • Sony Smartwatch: Can be wirelessly linked for real-time access to information coming from a xDrip adapted with a Dexicom 4G device.
  • Medtronic 530G Insulin PumpA CGM device which is popular on the market and offers several unique tools, for example the Bolus Wizard calculator makes it easier to calculate mealtime insulin requirements.
  • Nightscout: This app allows parents to remotely monitor a child’s blood glucose levels. It links the Dexcom receiver, a little pager device, to a mobile phone and downloads CGM data readings every few minutes.

Other People, Books & Resources

Organizations

  • UK National Health Service (NHS): Tim discusses the difficulty of obtaining NHS – funded insulin pump devices, despite many more diabetic patients meeting recommended criteria. About 6% of diabetic persons have pumps in the UK.
  • National Institute for Care Excellence: This public organization provides guidelines for insulin pump therapy in the UK  – and on eligibility for getting a CGM device under the NHS healthcare system.
  • US Food and Drug Administration (FDA): Tim explains the complications of developing DIY diabetes management devices due to their sale being illegal under FDA guidelines.
  • Tidepool: A research company which has built a platform for diabetes data and apps that utilize data. Aiming to encourage others to build on this platform, the company uses a freely available open-source code.
  • Theranos: A company that has patented automated delivery of medicine, using sensing and delivering systems similar to the combination of a CGM and an insulin pump.

Full Interview Transcript

Click Here to Read Transcript

[00:05:57][Damien Blenkinsopp]: Tim, welcome to the show. Thank you so much for joining us.

[Tim Omer]: That’s okay. It’s a pleasure. Thank you for having me on.

[Damien Blenkinsopp]: Okay, so I want to dive straight into it. Why are you interested in monitoring your blood sugar? What is it about you personally that has motivated you to do this and is important to you?

[Tim Omer]: Well, obviously for me being a type 1 diabetic and knowing my blood sugar is very useful. I’m sure we’ll talk a bit more about diabetes itself in a moment, but the main reason why I went and got a CGM was the fact that I managed to acquire an insulin pump by the HS.

That insulin pump, I got that because I was going to go traveling, and it allowed me to have one type of insulin with me, but the insulin pump has a lot of configuration. Other people they choose own [unclear 00:06:41] as a diabetic insulin pump, therefore they must be cured.

It behaves like the pancreas. We couldn’t be further from the truth. You get an insulin pump, it’s just making your condition that much more complicated. But gives you that much more flexibility to manage your diabetes.

[00:06:56][Damien Blenkinsopp]: Okay, so what’s the difference between an insulin pump, we’ll have to dive into diabetes now so people can understand the importance of all of this stuff, but let’s just talk about the insulin mechanism for a second here. So when you’re a diabetic, whether it is diabetes 1 or 2, you’re using insulin at times to help you stay in the right blood sugar zone. Is that correct?

[Tim Omer]: The basic summary, everyone has a pancreas. The pancreas produces insulin and in very simple terms insulin converts food you consume into energy. That is a very simple explanation of that. You have two types of diabetes, type 2 that you hear in the press and is generally in all the newspapers about the high costs of HS management, etc. It’s a real issue in the western world right now.

Type 2 is where you have a pancreas that is just not performing as well it could be. So generally you are still producing insulin, but not enough to sustain your lifestyle, and that’s mostly managed by diet and exercise and typically caused by a lack of decent diet and exercise. So that’s the majority of the diabetic world is type 2.

Now type 1 is where your pancreas basically packs in completely. You do not produce any insulin and to replace your pancreas, most diabetics go on to injections. There are two types of injections. There is rapid acting insulin so when I consume food I need to take the right amount of insulin for that food to accommodate the food coming in.

Also my body requires a background amount of insulin, a basal, so over 24 hours of slow releasing insulin, and that’s another injection that diabetics take once or twice a day. It gives a slow release of insulin.

[Damien Blenkinsopp]: Okay, so it’s two different types.

[Tim Omer]: That’s the two different types, correct. Again, for a diabetic type 1 it is a balancing act. How do I give myself enough insulin to cover what my body requires for the food I consume, but how do I avoid giving myself too much or I end up with a very low blood sugar levels if I give myself too much insulin which can result in you passing out, going into a coma, potentially death, or if you don’t take enough insulin, very high blood sugar levels, long-term complications associated with blindness, losing limbs, etc.

[00:09:12] [Damien Blenkinsopp]: Do you know what the rough values you are supposed to [be at], where are the extremes you are supposed to stay out of?

[Tim Omer]: So basically as a non diabetic you’re usually sitting around 4.5, I believe, I may be wrong here, a minimum of blood sugars or something, anyway, the number is 4.5. The 4.5 score. What it’s actually measuring is . . .

[Damien Blenkinsopp]: That is correct, it’s millimolar. These are actually UK measurements though, because a lot of people at home are used to the mg/dL so while you’re explaining that I’m going to look up an old calculator so we can translate this.

[Tim Omer]: Please do. That would be great to assist me on that. I say 4.5. Beyond that, I don’t really care much more. It’s just a number. So 4.5 is like the holy number, the holy grail I’m going after.

I don’t really want to go much below 4 for me as a person, so this does slightly change on every diabetic as well, but for me personally if I get below of 3.5, I start to suffer, my performance degrades, basically other people would associate it with being drunk. So as you go below 3.5 I suffer.

Anything I’d say below 2 or 1.5 we are entering real danger territory. Personally, I’ve been quite lucky. My blood sugars have gone quite low, as it does happen to all diabetics, and I’ve been okay, but it can be quite dangerous going that low.

On the upper scale, my aim is to stay below 7. Anything below 11 is acceptable now and then. You don’t really want to go much above 11. But throughout a day, you can jump between those two values multiple times. Type 1 diabetes is very much a real time situation and you feel the impact if you make a mistake pretty quickly.

[Damien Blenkinsopp]: Okay, for lovers of the metric system. I don’t know if we’re all going to move everything to metric one day, maybe. It would be really awesome if the world just used one system. So the values that Tim just gave out there, so the lower value was 1.5 millimolars so that’s what you want to stay out of if you don’t want to go into a coma is 27 mg/dL.

That’s pretty damn low, so for a comparison, when I was doing my fast, I was in a 55 mg/dL and I think I bottomed out around 50 mg/dL with very high ketones which is a different situation, so obviously another energy source supporting me. What you’re aiming for Tim was 4.5 millimolar, correct?

[Tim Omer]: Yes, that’s correct.

[Damien Blenkinsopp]: Yea, so that’s 81 mg/dL and I think we all know that’s a pretty good range. People talk about 75 to 80 as an ideal range there with diabetes 2 and just people in general. Then 7 was your upper range where you go to sometimes and you try and stay below. Is that right?

[Tim Omer]: Um-hum.

[Damien Blenkinsopp]: Yea. So that’s 126 mg/dL so it fits as well. After you’ve had a meal and so on, you expect it to go up to around that and then drive back down. So even when you’ve had a meal you’re still trying to stay roughly below that or just have that as a top upper limit of where you bounce up to.

[Tim Omer]: Well, in an ideal world you’ll always hitting your ideal number, but the reality is it’s just not possible. Even as a non diabetic you’re blood sugars going to spike, especially on the western diet what we are fed upon and believe to be good for us is generally quite bad for your blood sugar levels, hence increased type 2 diabetes.

[Damien Blenkinsopp]: Which we’re going to discuss soon.

[Tim Omer]: Oh yes, we can discuss more. As an example, I know we’re going to touch on this more, but my artificial pancreas app I’m using right now, so in the best, was it mg/dL?

[Damien Blenkinsopp]: Yes.

[Tim Omer]: That’s the first time I’ve ever had a break out of what that actually means. So high value, the system kicks in as at 125, the very low value that it kicks in to correct is 80 and in my target I’m trying around 100.

So that’s how my system is set up, so those are trigger points where it tries to do something. The other numbers, obviously those were extremes. You don’t want to get that high or that low.

[00:12:57] [Damien Blenkinsopp]: Right, right. So you’re aiming for a 100 because that’s a little bit different to some of the public knowledge out there.

[Tim Omer]: That is correct. It’s a realistic aim, should I say. In the UK formats, about 4.5, that is more non diabetic. If a diabetic can stay like that, that is a good day. Right now, I can tell you, I’m sitting at 106.

[Damien Blenkinsopp]: Okay.

[Tim Omer]: Quite nicely in my safety lines.

[00:13:19] [Damien Blenkinsopp]: Right, right. You feel pretty comfortable and you feel pretty good at that kind of blood sugar level?

[Tim Omer]: Yea. That’s something. The funny thing with diabetes, it’s not the number you’re sitting at, it’s how long you can sit at it.

So for example, if I look at my CGM now. Here’s a great example where the CGM is so useful. For the last 3-1/2 hours I’ve been quite close to around the 100 mark, so I feel quite stable. It’s when it starts jumping up and down is when you have a real problem.

Also, the danger associated with that, is you could get comfortable when your blood sugar is at 200. People do that. They get comfortable with higher and higher blood sugar levels. Therefore, they have to really struggle to bring them down.

[Damien Blenkinsopp]: If they go by feeling? Is that when they’re going by feeling more?

[Tim Omer]: That is correct, yea, and all diabetics do go by feeling. Unless you start losing that, it’s quite a danger. Even though it sounds like for a diabetic they feel comfortable with aiming for around 100, if they manage their blood sugars badly over a long period of time they will get used to it being higher than that, and therefore they’re comfortable at that level.

This is where you’re in real danger because diabetics themselves are very reluctant to lower it because they feel so rubbish by doing so. The explanation would be very easy, aim for 100, but the complications and the reality behind it is immensely complicated for the patient to manage.

[00:14:31] [Damien Blenkinsopp]: That’s really interesting because, I can tell you when I used to do cheat day dieting, so that would be basically eating clean six days a week and then one day a week I would eat crap, so I would eat coffees with sugar in them and donuts and whatever I felt like that day.

I would feel amazing that day. I would be so happy because obviously I am sure my blood sugar was up at 130 or 140 the whole day, and by the end of the day I would get horrible headaches and I would be ADD the whole day as well. That was the negative side effect. It wasn’t very good for performance or work.

I found it really hard to actually get anything done, but for hanging out with friends and just messing around and stuff like that, it would be great, or even go to the gym for that matter. That’s a good example to reflect on. Yes, people could get comfortable with being on a high blood sugar high all the time and then feel bad if they’re not in that zone.

[Tim Omer]: Everyone loves a sugar rush. That’s for sure. I’d say a positive side of diabetes, especially type 1, known as juvenile diabetes because just before puberty when they catch it, that’s quite common, though not always, but it does bring you up with a lifestyle of not being so used to sweet substances if you manage it correctly. That’s not always the case.

So that gave me the benefit to notice how high in sugar a lot of the western diet is and how to avoid it because my body’s never gotten used to having that high amount of sugar. We always have to try and keep that target area.

One that always makes me laugh actually is parents who give their children a bowl of sweets and fruit juice and then wonder why the kids go mental and start running up the walls. It’s because you just shoved them full of sugar and they going nuts. Is that not just the natural reaction?

[Damien Blenkinsopp]: Yea, I’ve seen crazy kids like that who were a real handful, and you’re putting them there in that biology zone. It’s your own fault for letting them have all that stuff.

And then they probably become even more naughty and such, so you sedate them. You say, “Oh, have some more sweets,” thinking it’s going to help.

[Tim Omer]: Yeah, exactly. So, sort of natural sugar and processed sugar, that’s the combination for an explosion, isn’t it? But again that’s the lack of education we generally have on our diets. As a diabetic, I can notice that a lot more. And it’s a lot more in my interest to watch those high-sugary food. Because I went to [16:44 unclear] I felt sick and horrible.

[Damien Blenkinsopp]: Right, yeah, because when you come down afterward. So the upper range there was 200 mg/dL, which is pretty crazy. I’ve never seen anything like that before. So when you were over that, what happens? Is it just causing damage over the longer term, or…

[Tim Omer]: Definitely, yeah. So from a long term perspective, anything above — for example, my sugar level is at 125 right now. That’s when you start saying, okay it’s starting to get a little bit too high let’s do something to correct it. At 200, obviously we’re entering danger territory there, areas you don’t want to be. You just feel sick, is the best way I can describe it. You just feel really sick. And the problem is not just that.

A lot of people don’t realize diabetes isn’t just the physical issues, it’s also mental. So if your blood sugar is running high, for example, [like that], you also have a frustration and stress associated with your body. Your body is letting you down, or you’ve made a mistake. There’s only one person to blame in these situations. Or, sometimes you just can’t find the cause.

Before I had a CGM, another good selling point for a CGM is you have those situations where you feel fine. Everything feels great, you go to check your blood sugars, and you find out you’re around the 200 block. And the level of frustration that you get hitting that is immense. So its all about how to process those situations or how do we get away. I don’t want to be told when there’s a problem, I want to be told when I’m approaching a potential issue. I need to be more reactive rather than…

[Damien Blenkinsopp]: You need to be more proactive than reactive. Like, oh I’m already in the 200 zone, and I want to get out of there.

[Tim Omer]: Exactly, and this escalates. So what happens then is you’re stressed, therefore insulin is one of the causes for you losing sensitivity. You’re stressed and that doesn’t help. You then start taking injections to try and lower it but your insulin sensitivity has gone. So therefore you start overdosing on insulin to try and fix it. Also there’s a delay between the insulin becoming active and taking effect in the body.

So you end up in a situation, as we’re humans we want to fix our situation now. So the reality is, you overdose on insulin, an hour later all the sudden your blood sugar goes crashing down, and that’s what makes you feel really bad, because you did a sudden change.

And then you have a thing called the rebound effect, where you go from being 200 all the way down to 20 within the space of 30 minutes. And then you end up doing the opposite: stuffing your face full of food, feeling really shit, feeling really rubbish. And then you rebound back up.

And this process, as I said it’s called the rebound effect, can take up to two days sometimes, of this constantly bouncing up and down, because you’re struggling to get control of your actual body’s blood sugars. I speak on behalf of other diabetics [but] I know for me, that can easily take two days where [I’m] trying to really gain control.

[Damien Blenkinsopp]: Yes. So really the situation you’re in is an extreme compared to most of the listeners today. It’s fair to say diabetes 1 is more extreme than diabetes 2, in terms of trying to manage it and control it and the importance of that.

[Tim Omer]: Yes.

[Damien Blenkinsopp]: You have to micromanage it more?

[Tim Omer]: You do. And type 2, you can only take tablets, it’s more lifestyle based. So if you adapt your lifestyle and get used to that lifestyle, then it’s easier. With type 1, it’s really [hard] because it can swing either way very quickly. Right now I’ve got very good blood sugars. In an hour, ask me again [and] it could be completely different. And that’s kind of the mental stress with diabetes; it’s not just physical, it’s very mental. It’s always constantly on your mind. And if you try to ignore it you’re not going to do yourself any favors in the long run.

[Damien Blenkinsopp]: Yeah, great.

[20:13] Okay let’s quickly cover our bases with diabetes. There’s two types of diabetes, and one of them, let’s talk about your situation first. Some people are born with this, and some people get it early in life. How do you get diabetes 1?

[Tim Omer]: There’s no real answer for getting Type 1 diabetes. They think it may be inherited, but again, look at a lot of families and that’s not been the case. But then again, if you look at more generations, a few generations before me, anyone with it would have died. It’s only been a kind of recent discovery, insulin.

So it’s typical around [or] just before puberty. You generally [do find] as a diabetic, more diabetics you meet, the more you realize you were diagnosed at a young age. Juvenile diabetes is the name for that is quite commonly named that. But we are seeing more and more older diabetics.

Now, whether that’s a result of lifestyle and therefore more people are getting affected by this at later an age, where it’s just circumstances, it just so happens to happen; there’s no real explanation there. But the percentage of Type 1 diabetics to Type 2, I wish I could give you a percentage, but it is minute. A minority of diabetics, as in something of like seven percent of all diabetics or something crazy like that.

[Damien Blenkinsopp]: Right, so it’s a lot rarer than diabetes 2, which has been growing over time. I don’t know if you know this, but has Type 1 kind of stayed stable while diabetes 2, which we say is due to lifestyle factors that you get this, has been growing over time?

[Tim Omer]: I’d hate to be quoted on that, but I’d generally say yes. As far as I’m aware, Type 1 diabetes I would say has been increasing. I think there is an effect, to a certain degree, of lifestyle. Maybe it’s a minute number, but Type 2 is the one that’s really on the increase. And it’s because our bodies are so good at processing the rubbish we give it, it’s only now later in life where people have been having a lifestyle of eating bad stuff does the body start to get to that point where it goes, right I’ve had enough. And the pancreas packs in — that’s my non-medical description. Let’s just be clear on that.

So for example, I had a good friend of mine, rings me up one day and he’s always been quite bad with his health — always eating pizzas, generally high processed carbohydrates, doesn’t exercise — and says to me, “Tim I’ve become Type 2.” And it’s like, congratulations you just decided to become a diabetic. I had no choice but to have this condition, stuck with it. You’ve actually chosen to become it. So you don’t have any sympathy.

And good for him, he [22:31 unclear], got into exercise, improved his diet, and now he’s not Type 2 diabetic anymore. So the difference between Type 1 and Type 2 is almost two different conditions. You know some people get insulted actually by the two conditions having the same name, because they can be so different.

[Damien Blenkinsopp]: Yeah, you just mentioned he reversed that situation.

[22:49]A lot of this is due to the pancreas not working so well, and in diabetes 1 is it an autoimmune issue, where actually the cells of the pancreas have got destroyed?

[Tim Omer]: That is correct, yeah. I believe that’s the case. It’s an autoimmune issue. So your body itself destroys the beta cells in your pancreas that actually produce the insulin. I would guess that’s the same for all Type 1s.

[Damien Blenkinsopp]: I’m mostly not sure what the Type 2 is. Because a lot of people can reverse it if they actively manage their lifestyle, get off…

[Tim Omer]: I believe Type 2 is generally the fact that your body is not accepting that insulin. So it could be that the pancreas is producing enough insulin, but your sensitivity — I have read a lot of things again I won’t be quoted — but it’s the sensitivity to insulin that can go.

So for example, I’ve generally had a healthy diet for most of my life [23:30 unclear]. But only in the last few years did I start looking into the right Paleo diets. And funnily enough, that’s actually more associated with gym than it was with Diabetes, because that’s not really taught with my condition. But when I moved to the Paleo diet, I found my insulin sensitivity doubled.

So it wasn’t the fact that, because I had less carbohydrates therefore I needed less insulin, correct. That does happen. But the insulin that I tookI was twice as sensitive to it.

[Damien Blenkinsopp]: Right. So before your diet was what, specifically, and what’s the time range we’re talking about here? So for most of your life your diet has been…

[Tim Omer]: So the majority of my life — I reckon less the last three years — so the majority of my life, for example, I had bowls of cereal in the morning, I would have a sandwich for lunch and typically boiled potatoes or rice or pasta, a main carbohydrate with dinner. I’d also have quite significant portions as well. I used to eat quite a lot.

And once I educated myself about the Paleo diet and the effects of those processed carbohydrates: one, I discovered I wasn’t hungry all the time by cutting back on those processed carbs I was more satisfied with less portions; and two, the amount of insulin I required dropped, clearly, so I had less carbs, but also the insulin I took I was twice as sensitive. So my body’s reaction to that insulin actually changed.

[Damien Blenkinsopp]: Yeah. You’d have to lower your doses over time, and you’d take them less frequently.

[Tim Omer]: Yeah. And, again I won’t be quoted, but there’s a lot of research right now going on about the effects of high insulin in the body and what it actually causes. So there’s a lot of things going on right now, discovering the effects of high insulin. And obviously all the non-diabetics out there do have unnatural high levels of insulin because of the diets that they’re eating. So the effect of this high amount of insulin in their system is now starting to be connected to other things.

[Damien Blenkinsopp]: You’re saying, I guess, health risks?

[Tim Omer]: That is correct.

[Damien Blenkinsopp]: So high insulin is probably not a good thing. Okay.

[25:15] We touched on the long term risks of this. We talked more about the acute risks, but the long term risks for a diabetic if you’re not managing your blood sugar within the zone as much, what kind of things [happen]? So we just say like high insulin, which obviously you’d be doing if you’ve got more variation. You’re bouncing around, you’re going to have to use high doses of insulin, and if you’re not on a Paleo diet, as you pointed out.

What kind of long term risks are there for higher blood sugar in general? So if you’re constantly around 120-140, does that do some kind of damage over the longer term? Does it affect your longevity?

[Tim Omer]: In a way it definitely does. The overall effect is that it damages the capillaries, and one of the first effects you notice of that is your sight. So you’ll start to lose your sight, basically. And I’ve known one or two people who’ve had the high blood sugar levels. Funny enough actually, these people were both females because high blood sugar levels help you lose weight and the result of that you actually end up partially sighted.

In the last few years, they’ve now started taking photographs of Type 1 diabetics eyes, the retina at the back, to see that damage. And even me, as a 20 year diabetic with reasonable control, not perfect, I’ve got the signs of a slight bit of damage. But that’s expected.

So basically it’s one of the first things to hit will be your eyesight, and then, god, I don’t really have a list of complications in front of me but all sorts of nasty things happen with blood sugar levels, you really do not want to encounter. Let alone just the day to day effect that it must be having on you system.

You also, in high blood sugar [levels], your body will produce ketones, so it’s kind of like a poison. You’re literally poisoning yourself if you have very high blood sugar levels over time.

[Damien Blenkinsopp]: Right.

[26:51] Just to jump in on that note, because there is a lot of talk on the internet on ketoacidosis, which is extremely high ketones. Do you know what range that is?

[Tim Omer]: Again, it would adjust slightly based on the diabetic, but it’s generally taught that anything above around the range of 11, in UK numbers. Above that, you should be checking for ketones.

[Damien Blenkinsopp]: Right. So that’s millimolar, and easy one this time since the US actually uses millimolar as well. And that’s the same as the numbers I’ve given out in previous podcasts. So we all get that one. Eleven, so that’s pretty damn high.

And so is that what happens when you have very low blood sugar? What kind of mechanism is driving high ketones for a diabetic?

[Tim Omer]: High blood sugar levels.

[Damien Blenkinsopp]: Oh high blood sugar gives you high ketones. That’s interesting.

[Tim Omer]: Yeah. So it’s generally taught that if your blood sugars are above 11, then you should be checking for ketones in your urine. Reality is that doesn’t really happen quite often. But the advice is if you do discover ketones in your urine is immediately go to Accident and Emergency. And it’s that critical that your body is poisoning itself.

[Damien Blenkinsopp]: What actually is happening there? Is it the pH of your blood changes? Do you know what the ketoacidosis refers to?

I don’t know myself. I do know that there’s a difference between, because there’s a lot of discussion on the internet, so I just want to make it very clear. I’ll have ketones when fasting at seven, or eight, it goes about as high as that. I could bump it up a little bit more if I took some exogenous ketones, like beta-hydroxybutyrate or some other products that are out now. But these are not dangerous conditions, basically. We don’t get the same impact on our blood and the same negative mechanism.

So I’m completely safe within those. Because a lot of people on the internet start talking about this. You go into ketosis, and they say, “Oh my god, that’s really dangerous, that’s what happens to diabetes.” It’s not at all the same thing, and it really comes down to the difference in these ranges again. Right? So seven, eight millimolar is fine, and when you’re pushing up there to 11 that’s when it becomes problematic.

[Tim Omer]: Yeah. So the Diabetes UK website ketoacidosis DKA diabetic is basically a severe lack of insulin, and the body cannot use glucose for energy, and the body starts breaking down other body tissues as an alternative energy source. So I don’t really want to read that [29:03 unclear].

[Damien Blenkinsopp]: So there’s actually a very different mechanism there. There’s something going on where your body is breaking you down and it’s creating this situation where you can’t absorb glucose anymore. So that’s not like when we fast or something like that. Just to make it clear. Or when we go on a ketogenic diet, a high fat diet, that’s not at all the same mechanism.

[29:21]So you’ve done a Paleo diet for a while, for three years now, did you say?

[Tim Omer]: Kind of, yes. I was traveling for a year so it was a struggle to do it then, but I do my best to have kind of a low processed carbohydrate diet. So, should we say 60% Paleo 40% normal would be realistic percentages.

[Damien Blenkinsopp]: Right. Do you have a lot of protein? Because I know Paleo these days, there’s a lot of differences in what people are doing. So when you say Paleo, it’s mostly you’re eliminating the grains and…

[Tim Omer]: Yeah, the majority I’m eliminating [is] grains and also eliminating white potatoes; I’ve switched now to sweet potatoes. Those sort of things. I’m not so much into dairy, to be fair. But without eating cereal, the main source of dairy kind of disappeared with that as well. So again, I don’t eat Paleo to the point where I walk into a restaurant and freak out, but I eat it to the point where I try and keep my diet as healthy as possible. The difference in cereal especially really makes a difference in blood sugar once you get rid of cereals in your diet.

[Damien Blenkinsopp]: So when you say cereals, is that oats or what types of cereals?

[Tim Omer]: Any breakfast cereal basically. Anything that is breakfast cereal is general a kind of grain based. So Weetabix used to be mine, [they] always raved on about how it has a slow release. And the reality as a diabetic, especially with a CGM, you look at CGM, it’s not slow release.

[30:39][Damien Blenkinsopp]: Great. So let’s dive into continuous glucose monitoring. What motivated you to start that? Because I assume it one point you were using pin-prick devices, and when did you make the switch?

[Tim Omer]: So yeah, as we were saying earlier I had acquired an insulin pump before I went traveling. One because I wanted that tech and two because it meant I only had to travel with one type of insulin so it made my life easier. With an insulin pump there’s a lot of functionality there so you can really tailor the background basal release of insulin over 24 hours. But how can you guess how much insulin you’ll need over that period if you don’t have a way to see what your blood sugars are over a period like that?

So the kind of NHS taught way, I believe, is kind of like, you have these days where you try your best to be as normal as possible, or miss breakfast and see what your blood sugar is [31:28 unclear]. It’s really difficult to try and get a life that boring. I actually did those tests and they suggest taking a blood sugar every two hours. But again, a lot can happen in two hours. So I can go high to low in minutes, let alone two hours.

So to have a real time reading of your blood sugar to help you calibrate your insulin pump, well I would dare say it’s almost impossible without the CGM. And that’s what drove me to get the CGM device.

[Damien Blenkinsopp]: Yeah, so a normal diabetic would do this every two hours, so say eight times a day or something like that. And obviously it’s not getting as fine a picture. So you mentioned a lifestyle impact there. You said you kind of have to have a boring lifestyle, you’re not able to do things because you’re not aware of where your blood sugar is going to be.

[Tim Omer]: You have to discover what your background insulin has to be. You have to, obviously, not disturbing your body in any amount, so one not consuming food, two not being too active, three not being very stressed. And then you try and have those periods of time, generally over a morning, lunch, or evening, overnight, have those periods of time where you can see what is your body doing? Is your blood sugar slowly creeping up, slowly creeping down? It gives you an indication of how much insulin you need per hour of that period.

Now, the reality of life, when do you get those quiet periods? I’ve been trying to do that calibration for the last three or four years, and have not been able to get those quiet periods in my life. So to do it via that mechanism of checking every few hours over that quiet period is really, really difficult.

So a CGM, it can give you that more real time information. So yes, it’s still beneficial to fast, yes it’s still beneficial to have those quiet days, but at least I know what’s happening in every five minute intervals.

So in those two hours if I’m finger pricking, I have no idea if I suddenly crashed and rebounded; I don’t know. It’s only two data points, I have no idea what’s happened. Also, if I do that test every few hours and I’m a five, what does that mean? Does that mean I’m going up, does it mean I’m going down? It’s a point in time value, it’s not really an indication of what the trend is. You know, where is your body kind of directing itself?

[33:28][Damien Blenkinsopp]: You mentioned there’s a number of things that you’re kind of looking at there, which I guess are things that you’ve learned; you said stress, activity, and food are the main inputs, what you’re thinking about when you’re thinking whether it’s going up or down.

Are these the main inputs? What have you kind of discovered from using a CGM over time? What things maybe are you surprised about? What kind of things is your blood sugar going up and down with that you’ve learned over time?

[Tim Omer]: It’s allowed me to understand what’s happening, and that in itself, even if there’s a problem, is incredibly valuable. It’s allowed me to notice when issues are potentially going to happen. So the general CGM, if you start going up high quickly or if you hit a threshold, while you still have hit that threshold at least the system can alarm you.

So you can deal with the issue. So in some ways it’s empowering the patient. As we described earlier, having a day where I feel fine, check my blood sugar and suddenly discover I’m 15 or 200, and oh no. I want a system that can at least assist me and take away some of that mental stress of constantly having to guess what’s actually happening.

[Damien Blenkinsopp]: Right. And that decision making, is it like taking away some of that having to think about it, so you can get on with other stuff in your life?

[Tim Omer]: Well not from a CGM perspective. In the artificial pancreas, yes. And we can come to that more in a second, but from the CGM, all the CGM does is give me more information.

So again, it’s like actually with a pump. Great, you have a pump, your Diabetes is cured. No, I have a pump my Diabetes is now that much more complicated, but I am now more empowered to deal with it. The same with CGM. It doesn’t cure my diabetes, it gives me more information. And what is more stressful, and for some people it’s too stressful; they get rid of the CGM. So it doesn’t help me manage my Diabetes, it gives me the information to help me make better judgment calls.

[35:13][Damien Blenkinsopp]: So, we’ve spoken about the insulin pump. Is that something you attach on you and it automatically injects you, versus having to do injections? You just kind of pump it and it injects you? How does that work? What’s the difference there?

[Tim Omer]: So what we described earlier, there are two types of insulin: one that happens over a long period of 24 hours, and the instant action one when you eat. So what the insulin pump does is it has one type of insulin inside it, and that’s the rapid action insulin. It has a profile on the pump, so ideally it can deliver very minute levels of insulin over the course of a day. And that level of insulin I can tailor the pump how much it gives me over that period.

So for example, a lot of diabetics have a thing called the dawn phenomenon, which basically means in the morning they have very high blood sugar levels. Unless somehow you can wake yourself up when that happens and inject yourself, you can’t manage it. With an insulin pump, you can at least tailor your profile to say deliver more insulin in this morning period to accommodate for the fact I know I have naturally high blood sugar levels. So that’s kind of one of the real powerful things with the insulin pump.

Second, obviously as we said as well, it gives boluses, so shots of insulin at any point in time. Just the same as taking an injection, just take a lump of insulin with the food you are eating. That in itself doesn’t sound like much, but let’s say for example you for a barbecue. What happens in a barbecue? You normally eat over a period of two or three hours. As a diabetic I’d have to be injecting myself constantly over that period.

With the insulin pump I can control it through the pump or the remote I have for it, and basically set it to give me an insulin injection now, another injection later. So I can kind of give myself the insulin as I might require it, and my lifestyle doesn’t have to be so controlled. I can be a bit more relaxed.

[Damien Blenkinsopp]: A bit more flexible.

[Tim Omer]: Exactly.

[Damien Blenkinsopp]: First of all, this sounds like it’s an implant, the insulin pump is an implant.

[Tim Omer]: Yeah you are correct. The insulin pump is a small pager device that has the insulin. It has a tube that comes out of that and goes to a cannula, like a little device that just sort of sits in my stomach. It sounds worse than it actually is.

[Damien Blenkinsopp]: That did sound quite bad the way you said it.

[Tim Omer]: But a cannula is kind of like a little plastic tube that goes into your stomach and you fire that in by a little device that just sort of smacks the skin and puts it in for me. And that stays on for about three days until I rotate to another site.

[Damien Blenkinsopp]: Okay, so you actually push it in yourself into a different area; so it doesn’t go in very deep?

[Tim Omer]: Yeah, correct. So I rotate the area myself. I have a special device; most insulin pumps will have this, it’s like an insertative device. What typically happens is it kind of fires it in, and the reason for that is the actual impact of it hitting your skin is kind of more distracting than the effect of the needle going inside you.

[Damien Blenkinsopp]: Right.

[Tim Omer]: But once you take the needle out, the only thing that’s left is a hollow tube. That’s, I think the ones I use are about 8mm long that go into the skin.

[Damien Blenkinsopp]: And then you can remove those tubes afterward when you go to a new site?

[Tim Omer]: You literally just peel it off. It’s like one of those things, the first few weeks you freak out…

[Damien Blenkinsopp]: As with everything.

[Tim Omer]: You almost go mad, and then suddenly you just get used to it.

[Damien Blenkinsopp]: Yeah, that’s the same with most stuff. Okay cool.

[38:02] So in terms of changes you’ve actually made, how long have you been using a continuous glucose monitor now?

[Tim Omer]: Permanently, actually only for the last six months, really. So the way I sourced my original CGM, I bought it secondhand off eBay in the US. Because I used one the NHS lent me for a week. They got all my data; I went and showed it to them, and they said, “Oh, we can’t really make much information from this, we need you to use it for longer.” So I said great let me have it for longer. “No, we can’t afford it.”

[Damien Blenkinsopp]: So why did they give it — I guess it’s just politics, I assume — but why give it to you for a week if they can’t use it?

[Tim Omer]: It’s generally down to costs. Diabetics on insulin pumps — I actually do have these numbers — from March 2013 there’s a survey, and I believe it’s about 6% of diabetics have pumps.

Getting an insulin pump is very difficult, you really have to hit a decent criteria. And even if you hit that criteria and NICE guidelines in your favor, if they don’t have funding you don’t get one. So to get a insulin pump itself is a challenge. The number of patients on CGMs, again the criteria for that is even tighter. It’s so tight I actually don’t know anyone who is on an NHS funded CGM.

[Damien Blenkinsopp]: Okay, so it’s very rare to be on a CGM.

[Tim Omer]: Very, very rare to be on one funded by the NHS. So the majority of people self-fund it in the UK — it’s different in the US with health insurance. So, with the frustration of only having the CGM for one week, and it being useless, in the US a new model came out and everyone started trying to flog their old models on eBay. eBay [couldn’t] quite take listings down quickly enough, because they weren’t allowed to sell medical devices. So I managed to nab one of these CGM devices, called the Dexcom Seven Plus.

A few weeks later it was in the post, and this device turned up in front of me with these two horrible looking needles that looked like something out of hell raiser. Out of date but still sterile. And I had to stick them in my stomach. So the whole process to do that, I have to say, was traumatic beyond belief, having to stick something inside you that you have no real medical guidance on. But that just goes to show the power and how useful day-to-day data is that I’m willing to take that risk.

[Damien Blenkinsopp]: So to cover the horror story part; if we think about the current technology that’s available in the market, Dexcom and others, currently is it the same situation where you have something quite horrific you have to plug into you? Or is it a little bit getting more friendly than that?

[Tim Omer]: Now I’m using the Dexcom G4 system. The process to stick the sensor in you is the same. It looks, honestly, more scary than it is. The process of actually sticking it in you is more scary than it generally is. But I’m guessing the process just isn’t natural. You don’t really want to be sticking needles in you. And and also you have to push to plunge it down, so you feel the sensation of it hitting your skin and going inside you.

So it’s all kind of, one of those things your gear yourself up for, you do it, and then say, “I don’t understand what the fuss was.”

[Damien Blenkinsopp]: Right, it’s more psychological.

[Tim Omer]: It definitely is, it’s definitely psychological for sure.

[Damien Blenkinsopp]: How deep does it go?

[Tim Omer]: Oh, good question. I’d say about, it goes in at an angle unlike the insulin pump cannula. There’s a bit of metal that’s left in there, and it goes in about a centimeter and a half I’d say. I think.

[Damien Blenkinsopp]: Okay at an angle, so it’s not going all…

[Tim Omer]: That’s true, but the problem I have is that I don’t have enough fat on my body; I’m quite lean, that’s annoying. So I can notice it a bit more, and sometimes it comes a bit too close to my muscle fibers.

The system is generally designed to go into your stomach, where it is more fatty, but the reality is you move your stomach a lot, and it therefore lasts a less amount of times. So I actually stick it in my upper arm.

[Damien Blenkinsopp]: Okay. So you have a choice where you [can put it]; it’s not specifically built and will only work on one part of the body. You can plug it on your upper arm and it will [work].

[Tim Omer]: It’s medically signed off to be in your stomach, for children I believe it can go on a thumb cheek. But it does definitely work elsewhere, yes.

[Damien Blenkinsopp]: Alright, excellent. Good, we’re past the horror story.

[41:48] Are there other makers? How many of these are on the market right now? What’s the cost of this? How much did you buy it for and how much would you buy these things for, brand new?

[Tim Omer]: So the main two players are the Medtronic and Dexcom in the UK market. There is another company who produces something similar called the FreeStyle system I think. I can’t remember what it’s called, but it’s very popular right now in the Diabetes circle. It actually works by NFC, near field communication. So it doesn’t give real time readings, but you can tap it for readings. And that’s an implant as well.

[Damien Blenkinsopp]: Yeah, I was actually looking at that one recently. It seemed like there were a lot of complaints. This is just from my reading around. There were a lot of complaints about it, and I was wondering if they put it off the market. Because I was looking at buying one and it seemed like it wasn’t available currently. So I was wondering if they were figuring of looking at it, because it seemed like a lot of people were having problems with it getting broken, basically, and having to return it.

[Tim Omer]: Well I have a lot of suspicions about the system, because it doesn’t quite calibrate as well. I don’t really quite understand how you do not have to calibrate it to a patient, I don’t get that. Also, that system only works by being tapped; it’s not in real time. So, I have a lot of questions in my head why. Do they know something’s not as accurate, or I don’t know.

[Damien Blenkinsopp]: So when you say it’s not in real time, you have to tap it every time you want to take a reading.

[Tim Omer]: Right. Like an Oyster card that you tap in on the Tube. You have to tap that with the reader and it gives you a reading. So it’s not as if like the Dexcom and Medtronic devices I have a pager in my bag and every five minutes it gets a reading. With the Libre system you have to tap it. Now I did speak to someone actually the other day and they did tell me they had done a recall because there had been some issues. So I would say your thoughts are correct there.

So I use the Dexcom G4 system, and it’s shall I dare say renown, it’s been one of the best on the market. The downside, as with all of these things, is obviously the cost. And a CGM it’s damn expensive. I have numbers on my blog, but the cost of the G4 at the time I did the blog page for the first year it’s just under 5000 pounds, and then after that it’s just under 4000 pounds. This is a really expensive system to maintain.

[Damien Blenkinsopp]: And are they consumables? What’s the base cost versus…

[Tim Omer]: Definitely is consumable, that’s how these things works. So you have the sensor that actually goes in your arm, that’s in theory only supposed to last a week, and then you rip it off and put up another one. That sensor costs about 60 pounds.

You then have a transmitter, which is a plastic thing that clips on top of the sensor and that broadcasts the actual reading every five minutes. And that’s a consumable that lasts approximately six months, maybe up to a year if you’re lucky. And then finally you actually have the receiver itself, it looks like a mini smart phone, that actually gets the readings.

So when I came back from traveling I wanted to start using my old Seven Plus CGM and I discovered that the transmitter, the little device that sits on top, the batteries had died. And when I researched the cost, it was — again, I can’t give exact numbers here but it isn’t cheap — something like 600 to 500 pounds for this transmitter. Where the cost of the batteries inside are no more than a couple of pounds.

So, personally I felt quite insulted by that. I wanted to use a medical device that’s helped me use my readings and clearly the markup on this was ridiculous. So the first thing I did was research the process actually how to access those batteries, and found other people who had done similar. I managed to cut the transmitter open by slicing the top off and popping the batteries out myself. So approximately five pounds later I had a device that would have cost me around 600. So the potential for savings were massive.

So this year when I wanted to move onto the G4 system, I can’t afford 5000 for the first year. I do not have this cash knocking around. But the actual community of diabetics, a lot had happened since I’d been traveling in 2014 and they all started to develop a lot of different ideas of how to access that data. And there’s an offshoot for this, a guy called Stephen Black developed a device called xDrip, which is like a little Tic-Tac box. And in it it basically has two circuit boards; one is a radio device that picks up RF frequency from the transmitter, and the second circuit board is a Bluetooth device that then relays it to your mobile. So you can actually get rid of the receiver for the system by using this device on your mobile phone.

[Damien Blenkinsopp]: So you’re using your mobile phone and this device.

[Tim Omer]: Yeah so you’re using this xDrip device, which looks like a little Tic-Tac box, and the xDrip mobile app. So by using those I don’t need to get the receiver, which itself is I think about 800 pounds to a 1000, something like that. So that was one cost down.

So the final tackle was the new G4 transmitter. There are people everywhere binning these every other day that are perfectly good devices, just the battery needed [to be] changed. So a few kind people donated their transmitters to me and I managed to, again following some other people’s guidance, managed to hack open and replace the batteries.

So for a really low cost I managed to get a G4 system where the impact was only me buying the sensors. So my consumables had gone down to just the sensors I wear. And if you’re tactical with the sensors, you can actually get up to three weeks to four weeks out of them, not just one week.

[Damien Blenkinsopp]: Yeah, and that’s because one part of that was you were lucky that there were a lot of people selling these on eBay at the time, the original Dexcom.

[Tim Omer]: Yeah the original one I bought on eBay that has end of life, so I was lucky to get that. And I paid about 400 or 500 pounds for that. And then moving to G4 system — I had to move to that system because the old one was being retired — I managed to get it working by a donated transmitter that I replaced the battery, building my own receiver with the xDrip stuff, and then still buying the retail sensors but making them last up to four weeks rather than one week.

[Damien Blenkinsopp]: Wow. That’s a hell of a cost reduction there.

[Tim Omer]: Massive. So, as we said earlier, the cost of the first year is roughly 5000. I brought that down to just over 1000 in the first year. So the saving was 3,500. So that’s massive.

[Damien Blenkinsopp]: And so other people could repeat this.

[Tim Omer]: Yes, definitely. Other people are doing similar, so I wasn’t the first person to discover any of this, really. I was the first to, or one of the first, shall we say, to actually go into the CGM world with the attitude, I do not want to buy a manufactured system. I need to get this to a point where it’s affordable. Or what’s the point I’m not able to use it.

[47:59][Damien Blenkinsopp]: Right. Is this called the DIY community?

[Tim Omer]: Yeah. In a very small nutshell, and I’m not going to do it justice, but the community We’re Not Waiting is a collection of basically diabetics or diabetic assistance — family members or hackers — all helping to make better use of the technology. And there’s two core projects that have come out of that, and they all revolve around individuals who wanted to better access their data. And therefore things came out of that.

One of them is called Nightscout, and that basically was originated from some parents who wanted to monitor their children remotely. So for example, say you’ve got your child on the Dexcom, they carry a little device in their bag and they wish to stay over a friends house for the first time. As a parent, you’re freaking out. You’ve constantly monitored this child from a young age, you have no way of knowing how they are.

So what they found was a process to link the Dexcom receiver, the little pager device, to a mobile phone [and] download the reading every few minutes. And once the patient had control of those readings on their phone they could do what they wanted with them. So what they did is develop a system called Nightscout and basically published it to a webpage. So this then blossomed into a community, where a lot of people are contributing towards it, and benefiting.

Then later on to Stephen Black who developed the xDrip app, the little Tic-Tac box I said that picks up a signal and pops on your mobile phone. So this was a wider solution. And what that allowed was first to not have things cabled together that’s just unreliable. They allowed you to take control of data on your mobile phone. And again, what would you want to do with that? Some people then published it to their website.

Stephen then developed an application that actually sends it to a smartwatch. So right now I’m sitting here with my smartwatch on, a Sony smartwatch that cost about 80 pounds, and I have my real time blood sugars on there. So rather than having a device in my bag or my back pocket that’s a pain in the ass to get out and check, something that I should be checking pretty much every 10-15 minutes to see what’s going on I now have on my wrist.

Now the quality of life improvement by just taking the data already produced and putting it somewhere more accessible for me is massive. I can’t even begin to describe the quality of life you get from that. Just having better access to your data. And that’s what the community discovered was if they could free that CGM data, then the patients can be creative in how they wish to visualize and view it.

[Damien Blenkinsopp]: Yeah. And it really has a big impact on their flexibility, and just their quality of life.

[50:32] So you mentioned that these things have to be calibrated. I understand that they’re not as accurate as a pinprick device, if you take the standard pinprick and then the strip that you use to assess your blood sugar. Are these not as accurate, or they can be as accurate? What are you dealing with there?

[Tim Omer]: The official term is they’re not. They definitely can be if calibrated correctly. And what I mean by calibration is every 12 hours you do have to prick your finger and draw blood and basically tell the CGM system what the reading is. And then it understands approximately whereabouts the reading it’s receiving, I believe it’s like your intravenous fluids, it reads it from there.

[Damien Blenkinsopp]: Yeah, rather than directly blood, yeah.

[Tim Omer]: Rather than direct blood, correct. So it calibrates it to that.

[Damien Blenkinsopp]: What have you found when you were doing it? Are you pricking yourself once per day or twice, morning and evening?

[Tim Omer]: So generally I’m pricking myself, if the system is functioning and I’m comfortable with it, then it will be once every 12 hours. Sometimes it’s up to three or four times every 12 hours because it’s very easy to miscalibrate. So for example, if my blood sugars are suddenly moving very quickly and I calibrate then, then the system becomes quite unreliable. It still has a decent trend; I can still see if I’m going up and down, but the reading it gives me will be off by a fair amount.

[Damien Blenkinsopp]: Well how much would that be? Is that…

[Tim Omer]: It really could be anything. So in a good day it would be, say, out by 1 unit, and this is the UK measurements I’m going here, by one unit roughly. And if it’s within one unit that’s generally classified as pretty damn good. I’d be quite happy. But it can be up to four if it’s been miscalibrated.

[Damien Blenkinsopp]: So we’re talking about eight milligrams per deciliter, or something like that, could be. Yeah, your one unit.

[Tim Omer]: So for a lot of people that freaks them out, but the power of the CGM is not necessarily giving the most accurate reading, it’s more the power of seeing the trend. So I know if I’m going up or down, or something is changing.

[Damien Blenkinsopp]: Or if you’re going up really quickly.

[Tim Omer]: Exactly, yeah. So don’t get me wrong, having a well calibrated device is amazing, but having one that’s not as good calibrated but still a lot of value in the system even though the numbers are slightly out. Now I know with a G4 system, I believe I’m correct in saying that, even if the system tells you something and you wish to act on it, the strict medical guidance is you still have to prick your finger. Because the system is not really designed to be a complete replacement.

[Damien Blenkinsopp]: I get you. So how do you use it? You personally. You make changes based on the trend you’re seeing?

[Tim Omer]: You have to be careful as well because there’s such a thing as over calibrating. As I said, with all these things there’s no right or wrong way, really it’s kind of a fine line balance.

So I personally, before the artificial pancreas stuff that I’ve worked on, I used the CGM more as information gathering. So are my blood sugars good when I think they are? Are they going down or up quickly? Is there something not right here? Is my carbohydrate to insulin ratio for my meal correct? Am I spiking too much after a meal?

The CGM is just like this constant feed of data and the limitation here is not the system — the system is very good — it’s the patient, because I’m just human. I can’t process that much data and understand what’s going on and benefit from it, and then configure my insulin pump to react, if need be to changes.

I’ve now gone from a point where I’ve had very little data and a lot of guessing to now where I am overloaded with data. I’m overloaded with CGM readings, I’m overloaded with the insulin pump that has more features than I could possible use. I’m overloaded by logging all my carbohydrates, my boluses, my exercise. I’m constantly producing all this data, but as an individual it’s mostly wasted.

[Damien Blenkinsopp]: I think it’s always important to come back, what do you actually look at now? If you kind of take a step back, what are the things you actually do look at now in terms of when you’re looking at it?

Is it you’re just looking for when it starts to rise quickly or drop quickly? Are those the main things that you’re taking into account? If you pull out a week’s data, what are the things that you notice and you think are interesting?

[Tim Omer]: So to be honest the only stuff I generally use it for is real time information. So what am I like now, where am I going, am I headed up or down? I’ve recently eaten and I feel pretty misjudged so I need to take more insulin. So it’s all real time that I benefit.

Now, this, again we can go on a whole long conversation here on historical data, but typically we’re lazy. I’m lazy; I can’t be bothered to look at my historical data. I struggle with dealing with the real time stuff rather than historical. But this is again, this is not an issue myself, this is an issue with the lack of usability of the technology around me. There should be ways to analyze that data for me and give me suggestions. And there are things in the community being worked on to benefit from that.

[55:05][Damien Blenkinsopp]: Right, so I guess that would be like looking at your diet and stuff. So I know that we spoke before about some things that you’ve noticed over time with respect to time to glucose change, and things like that we were speaking about. So one of the things we discussed last time was that nuts, one of the things you learned is when you eat nuts.

[Tim Omer]: Yeah, so that’s an interesting one and another great example, actually, of the benefits of CGM. For a few weeks I was noticing I was having very high blood sugar levels over night, and I couldn’t quite understand why. And over time I slowly realized I was consuming nuts before going to bed on those days. And nuts are high in protein and have a very slow release; they’re generally quite good. But, for me anyway, apparently they cause a spike in my blood sugars.

[Damien Blenkinsopp]: How long did that take? Was it over a few hours, or more?

[Tim Omer]: I think it was about two hours, actually. Or maybe less, maybe about an hour and a half. But it was very noticeable. And once you found the pattern it was easy to produce and easy to fix, because I could give myself insulin, but with my pump with insulin being delivered over an extended amount of time. So it was ready to kind of cope with that spike later.

And again, that’s another benefit of the CGM, the fact that you are now aware of these things. If not, I’d have just been asleep. Or maybe those blood sugars would have fixed themselves, maybe they would’ve rebounded, and I’ve been woken up with a severe low. You just don’t know. But now I have access to that information and can see what’s going on.

[Damien Blenkinsopp]: Yeah, and you can decide not to eat nuts before you go to bed as well.

[Tim Omer]: Well yeah, that’s been a challenge, that one.

[Damien Blenkinsopp]: Oh yeah? It’s just a thing you like to do. Cool.

[56:30] Are there other types of proteins or other things you’ve discovered which you’ve actually changed or you’ve had to think about managing more that you’ve learned from the CGM?

[Tim Omer]: Definitely cutting out breakfast. Cereals for breakfast, that’s definitely quite an easy one. Noticing the spike with coffee; I do like to drink a coffee a day.

[Damien Blenkinsopp]: That’s interesting. Could that just be black coffee, or is it…

[Tim Omer]: I generally have mine quite milky, because I’m quite a wuss. So obviously it’s kind of carb based as well as caffeine. The best way I can describe it is like wearing glasses for the first time. So you’re partially sighted, you know the world’s around you, you know things are going on around you, but you can’t see. You put glasses on and suddenly it’s all clear. Now the negative side of that is you are suddenly overwhelmed by everything.

So there’s a lot more stuff that CGM can help me with that I can’t possibly process. And that kind of comes on to the artificial pancreas stuff that I’ve been working on, which actually uses this day to day to help manage my medication.

So, earlier we spoke about Nightscout, and that’s one project in the community. There’s another one called OpenAPS, an open artificial pancreas system. Again, a bit of story behind that. A couple met, Diana and — oh dear, my mind’s gone blank. I apologize, I should know this. I was only talking to them last night.

[Damien Blenkinsopp]: Don’t worry, we’ll look this up afterward and everything will go into the show notes. So for everyone at home, the post Tim mentioned on his website and all the links to that kind of stuff and everything else will be at thequantifiedbody.net/CGM and you’ll have the links to everything we mentioned. We’ll look them up afterward if we need to.

[Tim Omer]: Thank you. I can definitely say now I’m not doing the community justice or I’ll be talking here for a lot more than an hour. So anyway, this couple built a system. They captured CGM data and used it to give themselves a louder alarm, because their alarms weren’t loud enough. So at times Diana would sleep through the night and not hear the alarm. And then they captured more data and they suddenly realized, actually with all of this data we can do a simple algorithm.

In extremely simple terms, it basically says I can see my blood sugars are starting to go up [from] CGM data. I know how much insulin I’ve given myself by capturing treatments as you do as a diabetic. Therefore, I clearly don’t have enough insulin in my system. Therefore, let’s increase the background insulin on the pump.

So that’s system basically, it’s called a closed-loop system. So it takes the readings in real time, it processes the information that it already knows about the patient — the stuff I have to log as a diabetic — and it does slight adjustments to my insulin pump. The algorithm is very simple and that’s an extremely simple description I’ve just given you.

But when I started working with the xDrip stuff and getting the CGM on my phone, I suddenly realized how now I own this data, what do I want to do with it? Well, I want to integrate this OpenAPS code and import it onto a mobile phone. And right now it just runs on [59:10 unclear]. So there’s a bit of a cable system, where it’s all cabled together.

So what I have done is basically got a mobile app that now takes my carbohydrate consumption I have to log anyway, it takes my boluses, insulin I take, that’s being logged. It has a wizard in there that helps me calculate how much insulin I need based on my sensitivity and what I’ve calibrated for it. The app still requires a lot of calibration. The app knows how my insulin pump is configured.

So what it can do, it can see the real time readings of blood sugars, and go hang on. I know what Tim’s consumed, I know how much insulin his pump is delivering, I can see his blood sugars are going high, for example. Let’s give himself a little more insulin to prevent that. And that’s a closed-loop system.

So now I’m not just sitting here producing data that I struggle to analyze, I’m now putting that data to work. My insulin pump itself is Bluetooth. So technically there’s no reason why my mobile phone and my insulin pump cannot talk to each other. It’s just the manufactures and regulation bodies that don’t want it to happen.

Technically it can. So, right now I have a system called an open-loop. So what happens every 15 minutes it takes all this information. If it thinks I should adjust my insulin pump, on my Android wear watch it pops up with a message and says, “Tim make this adjustment to your pump, based on the prediction I’ve given.”

[Damien Blenkinsopp]: Giving you information for you to decide.

[Tim Omer]: So open-loop is it notify me to action. So I’ve been notified on my phone, I acknowledge it, and I manually adjust my pump. That’s open-loop.

[Damien Blenkinsopp]: That still looks great, because it takes a lot of your decision making out of it.

[Tim Omer]: It’s surprisingly, actually, quite powerful. And again, like we said, it’s that mental stress. Now I’m not constantly looking at my CGM and panicking on what to do to prevent something.

And again, I’m human; I’m going to overreact. I constantly do things wrong. I don’t know how well educated I am. Now, the system suggests — so I just wait for the system to give me a suggestion and I act on that. I’m now working with someone to help me hack the Bluetooth interface on the pump. Once that’s done, I’ll have a thing called a closed-loop system.

So not only will it do these calculations every five minutes, because that’s how frequent the data can be, it will action at every five minutes. And always doing these very slight adjustments every five minutes. It’s not going to give me a load of medication at once, or removing medication. With the insulin pump, I could turn it off potentially, so naturally let my blood sugars come high. I’m just doing very tiny adjustments every five minutes.

[Damien Blenkinsopp]: Right. And that way you reduce a lot of the risk as well. Because you’re making such minor adjustments even if it’s wrong, it’s not going to be really out of line.

[Tim Omer]: Absolutely correct.

[Damien Blenkinsopp]: Yeah. It’s better than your judgment. Will you feel more confident about this, or as confident as your own judgment?

[Tim Omer]: Well I’ve already discovered that I have less rebounds. If I don’t fight with the system and I let it [be], one it kind of triggers itself before I realize a problem, because it’s obviously checking my data constantly. So I get an early opportunity now to give myself more insulin or less insulin, depending where I’m going. Also the system will say, hang on, I’ve delivered quite a lot of insulin for you now, I’m actually going to stop. And if I acknowledge that and accept it, I am less likely to overdose myself.

So I find that I still go high and low, this will never go away. That’s a fact of life with Diabetes. But I find that the system can better manage and make decisions rather than me being emotional and overreact. And even though, as I said, the system’s not completely automated, even now if my sensor dies on me and I have a gap without, I’m a bit lost. I’ve gotten used to this system taking this worry away from me.

Now the interesting thing is there are 16 people, I believe, to date who are actually using this system fully closed. They’re using slightly different equipment than me. So they have a slightly more technical set-up, shall we say. They’re using Raspberry Pi, it’s using some older hardware. My device is more of a plug-and-play kind of install and it works. With a lot of calibration, that is.

[Damien Blenkinsopp]: So they’re doing closed already.

[Tim Omer]: They’re doing closed, yeah.

[Damien Blenkinsopp]: So it’s hands-off completely. They can monitor it, they can check it, but it’s just actually pumping itself. It’s taking care of it.

[Tim Omer]: Right. So they walk around with a little bum bag on, basically, with all the Raspberry Pi with bits in there. So it’s not an elegant solution, shall we say, but it’s very useable. And even parents are using this on their children. So this is kind of, you can see the power behind such a thing. People are very enthusiastic.

[1:03:23] The interesting risks my device brings, is mine is an Android app. So once you install the app and set all the settings — again, most of the settings as a diabetic you should know because it’s all typical stuff you have to understand. And if you have the right equipment, insulin pump and the CGM data, it’s a very easy system to set up.

And that introduces a lot of potential dangers as well. Because now you’re not forcing the system to be only, you have to be highly technical to implement it. I’m kind of bringing that barrier down. What does that mean? It can potentially be a high risk situation. So I’ve got to be very aware of what code I release, and who accesses it, and how we manage that barrier.

You know, the typical situation, you get a parent whose child is diagnosed: “Oh no, this is terrible. Oh look, there’s an app out there that will fix it.” And with pure ignorance just install it thinking it will cure the Diabetes. Again, my app makes my life easier, but it does make it that much more complicated still. Because I have to make sure the app is correctly configured.

[Damien Blenkinsopp]: Yeah, because you’re going to rely on the technology. So if the technology has a bug in it, if the app has a bug in it and maybe just turns up in a specific situation, like once every seven days or it doesn’t get spotted, then there’s that kind of risk there for someone who’s, like you say, not technically savvy to not see it. Or it just kind of goes unseen.

[1:04:36] Does this tie in with, I know you have the #wearenotwaiting?

[Tim Omer]: Yeah, and that is the community. So the community I utilize in that #wearenotwaiting, and well the name explains itself. It’s basically the frustration of diabetics in the lack of access to their data, lack of capability between devices, and the lack of progress.

And one real frustrating things as a diabetic is that you constantly have so called experts who are not diabetics making decisions for you on what equipment you get, and how you should look after yourself. And unless you live with the condition, whether you’re a good or bad expert, you’re still the expert. So, the community has kind of taken it upon themselves to kind of produce these better solutions to improve the quality of life for people.

Again, there’s loads more information on that on my blog and where the hashtag came from and the rally cry between people saying we’ve had enough. The technology is already here, and we’re already producing the data. If I can sit on my sofa and control my life from my phone, why the hell can it not talk to my insulin pump. This is not a technology problem.

[Damien Blenkinsopp]: Yes, it seems like it’s more of a regulation and things that are medical to market and managing that risk. That’s kind of the thing, it seems, that’s really holding things back.

[01:05:46] So, just for people at home, this has also been called a bionic pancreas as well as an artificial pancreas. The goal is really to just replace that body part which isn’t working that well in diabetics, right? The insulin pump, and just completely replacing it.

[Tim Omer]: That is correct, in simple terms, yes. As with all of these things to configure and manage it is a bit more complicated, but all it’s doing is monitoring that data and helping me make decisions. And that’s helped me in real time.

There are still a lot of benefits of data mining that data I capture and giving adjustments to my profile and how I treat myself. So that whole world is there to be discovered still. And there’s an open source company called Tidepool who are doing great researching in that area and publishing a platform where [you] can number crunch.

But the artificial pancreas stuff is all about giving me some kind of benefits right now. So for example, I can look at my artificial pancreas app, I can see even though I’m having a late lunch today that my blood sugars haven’t started dropping. And if it did start dropping it would tell me, and therefore allow me the opportunity to adjust my pump. So my blood sugars don’t go too low.

[Damien Blenkinsopp]: So this is pretty cool stuff, because it’s one of the first projects where it’s actually replacing a body part with this closed-loop system, as you call it. So it can just start operating. Kind of like if you took something out of the Terminator and put in your body, if you use a science fiction analogy.

I think it’s also interesting. A lot of people have probably see the press around Theranos, the big blood testing company in the US recently. That company was actually based on a patent for something similar to what you’re talking about, but for drugs. In terms of it would automatically pump drugs into patients of all different types based on readings taken from something like a continuous monitor of their blood.

And so you can see many, many applications with you guys leading the charge, because Diabetes is common and it’s a very specific blood monitoring and insulin pumping situation. But you can see how this could eventually apply to many different areas, whether it be oxidative stress and pumping glutathione into your body. Or other adjustments to optimize your biology. So I think it’s really interesting.

[01:07:47] Just wanted to make sure we do cover the legal regulatory system a bit better.

So currently the FDA and all of this is saying you’re not allowed to do this. So of course you’re not allowed to sell these devices. Is it fine for you to do this at home? Obviously there’s the risks everyone should be aware of, because if you’re not technically savvy this is DIY project at the moment. It’s not like it’s 100% signed off and stuff and it hasn’t gone through compliance testing and trials to make sure it’s 100% safe.

So how would you put it? The kind of situation for people at home if they’re interested in learning more about this, and what they should be aware of in terms of the risks and legal situation.

[Tim Omer]: So one thing to really highlight regarding that is with all the devices you can get right now, every risk here is delivering medication. That’s the real risk. If I misconfigure my insulin pump, I could still kill myself. So the risk always exists; there’s no solution on the market that removes complete risk. So you’ve always got to be aware that whatever you’re utilizing has to be utilized correctly, or there’s the potential for serious harm.

And there’s already commercial products out there that have bugs, and have had issues with them come up. So it comes down to, while the open source stuff is obviously not therefore going through the same regulations doesn’t mean the stuff that has gone through regulations is therefore perfect. You always have to be aware.

Now clearly with a community producing this open source, the main reason for that is to try and get it out there sooner. If I tried to commercialize a product I would basically be looking at X number of years in research and development. And rightly so; I’m not saying that’s wrong, but I want a better quality of life, and I kind of want it now, and I have the data and systems in front of me.

So it’s up to me if I wish to take code that’s available out there, that’s been published, and I wish to utilize it myself in something that gives me a better quality of life, that’s my decision. And that’s what I want to do, and it works for me.

Now, that’s the question everyone else needs to ask. There is a lot of code out there and a lot of information. Whether it works for you, whether you feel comfortable and understand it is a decision and a path you need to follow yourselves.

It’s not that we all hate the regulatory bodies or the actual manufactures themselves; they have a difficult job. But the reality is, the cost of managing long-term conditions has not gone down. The NHS already acknowledges that. There’s a wealth of individuals out there with a lot of knowledge and are now utilizing that in a technical way. How do we embrace that community and somehow introduce it into our kind of care pathways? No one knows.

We’re at the point now where the regulatory processes, they’re designed for a world 100 years ago. They weren’t designed for a world where in two months I can develop an artificial pancreas out of my app on my mobile. That never was possible; it now is.

So what do we do? Do we just ignore it and try to brush it to one side, or do we have to learn and try and discover how we cope with that? So I don’t have answers for that; no one does. And that’s one of the things that makes this so exciting and interesting. How do we utilize this?

And a lot of talks I give are kind of like, this is happening, it’s going to continue to happen. No one knows the answer, but let’s all start talking now and how do we control the risks. And there always will be risks.

So if people out there are interested, there’s a lot of information out there. If you’ve got the enthusiasm you’ll find it. My blog has a lot of details on where to go to get more data. Be aware of what you’re trying to do. It’s very easy to make a mistake, and anything you do if you’re messing around with your health the risks can be quite severe.

[Damien Blenkinsopp]: Great, great. Thank you, that’s great.

I think also just the fact that the movement exists is going to force companies to step up and move along, otherwise they will get left behind. So whatever happens in that situation you’re providing this positive pressure on innovation.

[Tim Omer]: Yeah, definitely. There’s already a believe that has taken effect. Especially Dexcom, they released some equipment recently and it’s believed it was fast-tracked through the FDA process more because of the community advancing the head of Dexcom, so therefore there’s no commercial product. So apparently it has already taken effect out there.

[01:11:51] And also, one other thing I do want to say, is a lot of the closed-loop trials right now, so a lot of the artificial pancreas stuff, is happening behind closed doors. They’re all trying to work on systems that are more 100%. Systems that kind of do a better job, more automated, manage more, and not only deliver insulin but also the glucagon, which can push my blood sugars up if need be. They are very complicated systems. And as a diabetic, if I can have something that can give me just a 10% improvement on my life, I’ll take it now.

[Damien Blenkinsopp]: Right. So you’re kind of saying that they’ve tried to push for the perfect solution. Whereas something that’s half as good is still going to improve everyone’s lives by a measure.

I guess it could be the model because when you’re trying to get FDA stuff, when you’re trying to run trials it’s a bit expense. So I guess they’ve got to think, okay we want to make a big stab at this. We want to make sure it’s a really good product if we’re going to invest all this money and getting it signed off with the FDA. So it could be, basically, the regulatory process that drives that.

[Tim Omer]: It most definitely can be. And it’s interesting, because I speak to some professionals in that area regarding the work, and you can see they kind of fight internally between the medically trained side of them, and then their inquisitive interest side. And one bit is kind of offended that you’re even considering doing stuff, and the other side is respectful of the fact that you’re trying to help yourself as patients. You know, reduce your burden on yourself and the health.

The NHS we have to rely on, and one of the questions I remember getting asked before was, “How do you know this is helping your diabetes if you don’t have the statistics?” And my reply was, “I feel more empowered as a patient.” And that in itself, if that’s what we’re getting from this, feeling more empowered, that’s quite a big achievement.

[Damien Blenkinsopp]: I think it also goes, as you were saying, technology is moving so fast now, and it’s moving faster and faster it’s going to be increasingly difficult for organizations. They’ll have to innovate in their models and decision making models –and governments as well, in terms of their funding and everything — in order to keep with the times as technology is going to be enabling people, enabling these kind of things, which is really cool.

But I think it’s going to challenge these organizations to change the way they work, because I think decisions are made really at a lag; it takes years to make decisions and move things into the market. And I guess that’s where frustration is coming for you guys, wanting to just go with the technology and what’s possible versus waiting for those processes to take place.

[Tim Omer]: Definitely.

According to the NHS I’m statistically a good diabetic, and for the NHS paperwork perspective that’s great. From a quality of life and how long I’m going to live, I’m not as good as I possibly can be. So, to say I’m a good diabetic is fine, but don’t prevent me from making my quality of life better. I want to go beyond this disability and I want to do the best I can. Because at the end of the day, it’s going to be my life that’s going to suffer from this.

So the ability to be empowered so I can help that is a significant mental win.

[Damien Blenkinsopp]: Excellent. I think these are exciting times. With all the health tech that’s coming up, this is going to more the case where we have these options to kind of push forward ourselves if we want to solve things and make our lives better. So there’s going to be a lot of things like this coming up in the future.

[01:14:52] Okay, last question for you. We ask this question of everyone. What would be your number one recommendation, based on your personal experience using these kind of things in terms of using data to make better decisions about your health, and to others if they just want to use data. What would you suggest is the number on recommendation for this?

[Tim Omer]: So it’s all and good my phone telling me something, and then me just reacting on it. If I don’t understand why it’s telling me that, then I’m just going down a dangerous path. Now I need to have an understanding why things are being recommended. Why trends have come up that were not there before.

Having systems like this doesn’t mean your diabetes goes away, it means you get a better understanding of it. So if you don’t try and understand that information, that’s not good.

[Damien Blenkinsopp]: Excellent point. Thank you very much for that.

Thank you so much for your time, I appreciate it. We went over a little bit longer and everything. I think this is relevant to a lot of different areas, and what you guys is doing is kind of at the forefront, just because of your specific situation. So it’s interesting to everyone.

[Tim Omer]: It’s also interesting [01:15:48 unclear] actually. It’s also going into other areas. So I have a guy who’s trying to build a deaf community based on hearing aids, basically: a hearing aid community. And they’re trying to raise the same hashtag now, we’re not waiting, and develop their own open source hearing aid because the costs are so high. So it’s contagious.

[Damien Blenkinsopp]: Yeah. It’s going to be exciting times, I think. The next five, ten years. The technologies are getting simpler, right? In terms of trying to use them. Because as I understand, you’re not even a developer. I think I read that somewhere.

[Tim Omer]: No. I’m an IT professional, but programming is a hobby. And I kind of get the gist of it, but no I’m not a developer. And now I’m producing an app that gives medical suggestions. That’s pretty nuts. The barrier of entry is so low. And the tech, my insulin pump is like seven years old, the technology.

[Damien Blenkinsopp]: Yeah, it’s pretty amazing.

[Tim Omer]: That’s insane. Would you walk around with a seven year old laptop? So the technology isn’t new, it’s not expensive to produce. It’s just the markups.

[Damien Blenkinsopp]: Really appreciate having you on the podcast, it’s been a great episode. You’ve got this hands-on experience and you’re pushing things forward so it’s a really interesting perspective on a DIY approach to making things better for yourself and using the tech out there. So thanks a lot for coming in today.

[Tim Omer]: It’s been a pleasure. To everyone out there, there’s a big community out there and they’re really doing a lot of work. I only touched on very tiny amount of it. So if you’re interested, get out there and have a look around; there’s a lot of really helpful people.

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Part 3 in our series of Fasting Self-Experiments. In this longer 10 day water fast I tracked results with a broad set of biomarkers (ketones, glucose, weight, hormones and cognitive performance panels).

This is a long post – if that scares you, jump directly to what you’re looking for:

  1. Why Do a 10 Day Water Fast? (The health benefits that we’re optimizing for)
  2. 10 Day Water Fast Results (Weight, metabolism, cognitive performance, hormones)
  3. 10 Day Water Fast Experience (Anecdotal thoughts, symptoms, and my post-fast rookie mistake)
  4. The Tracking (Details on all the biomarkers tracked and lab tests used)
  5. Tools & Tactics (Details on the exact fasting protocol I used, and some supplements taken)

Video Recorded on Day 10 of Fast Just Before Refeed

Note: I was yet to realize the post-fast rookie mistake I was making!

I’ve been fasting once per month for 5 days since my first water fast experiment in June 2015. If you are new to fasting, you can get all the why and how basic details in that post.

The results from my 5 day fast cycles have been so positive that I couldn’t help but wonder if More is Better when it comes to fasting.

This led me to ask:

“Will I benefit from a 10 day fast programmed into my life once per quarter or twice per year?”

To get an answer to that I broke that down into the following questions I was going to try to answer with this first 10 day fast:

  1. Can I remain productive during a 10 day fast?
    (10 days is a big chunk of time to strike off from work and life – far too big for my taste! Let’s be sure I’m not throwing away the equivalent of 40 productive days a year with this habit)

    • Would my mental performance suffer? Perhaps leading subtly to worse decisions, or perhaps just slower thinking?
    • Would my energy levels remain the same or decrease? Would there be a change in how many hours I could comfortably work per day?
    • How about concentration, focus and drive?
  2. Is “10 day fasting” every quarter sustainable? Specifically, where I’m doing monthly cycles of 5 day fasts in between?
    • Would I double the weight loss of a 5 day fast? And thus make it difficult to recover the weight within the following month? (The question here: Does weight loss follow a linear path based on number of days fasted?)
    • Would a 10 day water fast be as easy, psychologically and physiologically, as the 5 day water fasts? Or would I hate it? (Nothing we hate is going to get done repeatedly)
    • Is there any downside impact on “adrenal health” or cortisol regulation from fasting? (this is a question I’ve been attempting to answer since I started long duration fasting)

itunes quantified body

To try to answer these questions I tracked cognitive performance, hormones, metabolism and weight throughout the fast.

I also committed to following a normal rhythm of life and work during the fast this time. I would run life as usual, and let the chips fall where they may – I would see if the fast got in the way.

(Note: Please do not take this as advice to do this at home yourself – I’m not a doctor, and would be extremely upset if you hurt yourself – please be cautious with fasting.)

The outcome we’ll get to in the results in a second, but but first “the Why”…

Why Do a 10 Day Fast?

We’ve covered the benefits and whys of fasting well in previous episodes, however, as a quick reminder here’s the list:

  • Anti-Cancer: Leveraging the metabolic theory of cancer and Dr. Thomas Seyfried’s work, fasting may be an effective tactic to reduce our future risk of cancer.
  • Immune System Effectiveness: Cyclic fasting has been shown to regenerate immune system cells which deteriorate ‘naturally’ as we age or via environmental or other insults. Thus, it may reduce or stave off some of this natural deterioration and keep us healthier.
  • A Stronger Body: Lean body mass gains including bone density increase and muscle mass increase have also been tracked in studies and myself.
  • Body Fat Removal: Fasting or cycles of fasting can be a useful tactic for removing unwanted excess body fat.

The 10 Day Water Fast Results

Metabolism on 10 Day Fast Looks Similar to 5 Day Fast

In 5 day fasts I consistently see glucose drop to between 50 and 60 mg/dL and ketones rise to between 5 and 7 mmol/L. In the additional 5 days it seems you shouldn’t expect any big change. My numbers came back largely the same.

My ‘switch time’ from glucose to ketone metabolism continues to edge forward to happen slightly earlier with each fast I do. This time just past the 48 hour mark the switch took place – my blood ketones jumped up and glucose dropped down to their fasting equilibrium levels. My metabolism had switched to ketone burning.

10 day waterfast ketones glucose
A few interesting points:

  • There was a slight glucose upwards blip on days 6 and 7 where it rose back up to between 60 and 70 mg/dL. This was most likely caused by the sleep disruption I experienced from day 5 (see sleep details). Low quality sleep tends to impair glucose regulation – thus higher (but still low) glucose.
  • On day 7 and 9 I got several “HI” errors for my ketone readings, meaning that my ketones were over 8 mmol/L, the upper limit of the ketone meter’s range.
  • For the first 3 days post fast, days 10 to 13, my ketones were still spiking high in the evenings and quite erratic – this was most likely an anomaly this time around due to my Post-Fast Rookie Mistake.

Despite the glucose uptick on day 5, I stayed well within the therapeutic range to provide anti-cancer benefits outlined by Dr Thomas Seyfried (see explanation via my interview with him in Episode 16).

So long as you remain under a Glucose Ketone Index of 1, you are assumed to be within the therapeutic range as per chart below where I’m shown to have had a complete 8 days of therapeutic anti-cancer action.
10 day water fast glucose ketone index

Weight Loss: How Much & How Long to Gain it Back?

Over the 10 days I lost a total of 5kg (ll lbs) of weight. The weight loss was at a consistent daily rate as usual, except for Days 8 and 9 where it stalled at a weight loss plateau, before a further drop on the morning of the last day.

I regained all the lost weight by the 18th day after the end of the fast – and this was despite some digestion re-startup issues for the first 3 days post fast (see the post-fast rookie mistake for the details). So the weight was really recovered via 15 days of normal eating.

Weight Loss 10 Day Water Fast

Testosterone on a Fast: Big Drop & Libido Changes

It makes sense that you shouldn’t expect to be on top of your ‘libido’ game while fasting. When food is scarce we should have evolutionarily had more important things on our mind – like finding food to survive.

This was certainly part of my experience. The longer the fast, the less interest I had in women or sex. By day 5 my testosterone levels (DUTCH Test – see in labs) had dropped below the 20 to 40 year old male reference range.

A couple of studies I found corroborated this with testosterone dropping significantly during fasts (and then rebounding strongly with refeeding)1,2.

The Takeaway: NOT a good idea to fast on honeymoons or dates. The day after ending the fast – great idea.

Testosterone: 10 day fast

Is it OK to Fast with Adrenal Fatigue?

In previous fasting episodes I’ve noted that I’m working on “low free cortisol” levels that I’ve been tracking for a couple of years. A situation that I expect, based on symptoms I now understand dates back to as much as 10 years ago.

One of my concerns with repeated fasting (considered a stressor) was that it may not necessarily help with this situation – when you look at it through the lens of “Adrenal Fatigue”.

Specifically, I was referring to the idea that Low Free Cortisol = “Adrenal Fatigue”. Thus adding more stress could exacerbate the issue, reasoning that the adrenal glands are already overstretched in a normal everyday scenario without that added stressor.

In this fast I learned that there’s less reason for concern than I’d initially considered. You need a bit of background to understand why.

Historically, people from the functional medicine realm have referred to “adrenal fatigue” as a state of fatigue of the adrenal glands, whereby you typically have low energy in the afternoons. This can happen to me at times. It is documented and diagnosed via 4-point free cortisol salivary tests like the one from Biohealth that I’ve done previously (See the results from previous adrenal labs in this episode).

However that name doesn’t have a very accurate definition or explanation. The term is used quite vaguely for the most part. We can’t scan an adrenal gland and see it in a withered state for example. We don’t have a specific test that can show the state of ‘adrenal gland fatigue’ that ties it back to the adrenal gland itself.

So a new term that is surfacing for the situation of low free cortisol is “cortisol dysregulation” as a result. It provides at least a ‘less wrong’ definition. Cortisol isn’t normal, it’s lower than it should be – and thus is driving some fatigue symptoms. It’s dysregulated. Another term you may have heard is HPA Axis dysregulation.

The DUTCH test I used to track my hormones is useful where it comes to investigating and better understanding cortisol metabolism as it looks at both free and metabolized cortisol. Metabolized cortisol is a proxy for total cortisol output. The traditional salivary tests used look only at free cortisol levels. Thus, DUTCH enables you to assess whether your total levels of cortisol are low (the adrenal output is lower, or if it’s just free cortisol that is low, and total cortisol is normal).

As you can see below my total cortisol (metabolized cortisol) is right in the middle of the normal reference range.

Metabolized Cortisol Levels (Baseline and Fasted)

10 Day Fast Total Cortisol (Metabolized Cortisol)

So in my case, it turns out that I have above average metabolized cortisol levels – so in fact total cortisol output is well within the normal range. It’s just my free cortisol levels that continue to come back below the reference range (now cross-checked with two labs, DUTCH test + Biohealth #201).

I don’t have reduced adrenal output, I have normal adrenal output – which would fit the old definition “adrenal fatigue”.

That’s good news.

Nonetheless, the low free cortisol has to be troubleshot. The most likely explanation behind this is that I’ve been subjected to a long term stressor and my body has compensated to lower free cortisol levels. That maps to other information – that underlying stress, is most likely high ongoing inflammation levels that I have documented over several years now.

24 Hour Free Cortisol Levels (Baseline and Fasted)

10 day fast 24hr free cortisol

The Takeaway: Rather than just relying on propping up my adrenals with adaptogens, it’s pretty clear that the end game is to continue to explore and resolve all causes of stress. Inflammation is my obvious first target, although it’s another reminder to keep up my lifestyle stress management practices (adaptogens, meditation, circadian rhythm and sleep).

Note: For those who like to dig into the data – here’s an explanation of the cortisol results from the DUTCH test.

Did Mental Performance Keep Up During the Fast?

Although I’ve always “felt productive” when fasting, I wasn’t as sure that my mental performance was the same. This time round I planned to try to capture this information properly. Unfortunately the results weren’t very clear.

I used Quantified Mind, the tool we covered in Episode 33 to track my cognitive performance in terms of Working Memory and Attention Control.

The main issue I was advised to eliminate by Yoni Donner, founder of Quantified Mind was the practice effect. As we perform any mental test repeatedly we get better – to understand if a fast was impacting me cognitively, I needed to try to eliminate that. To do this I used the same test repeatedly during the few months before the fast, due to travel this wasn’t as consistent as I would have liked. The idea is that eventually you peak out, and any practice based improvements will have dried up or be minimal.

10 Day Fast Mental Performance

As you can see in the data above it looks like there were some pretty strong practice effects taking place throughout and after the fast. The fasting period is shaded out in blue.

As a result, I’ll be continuing to use the same test panel in future fasts, and in between, to see if I can separate these out. With continued repetition I should be able to isolate any fasting effects.

The 10-Day Fast Experience

With repeated cycles of fasting I have become a lot more comfortable with “how it feels” – both body and mind do feel different on the water fast – the first experience I was cautious due to this – not knowing if I had new limitations that I shouldn’t cross.

Now that I have got used to fasting, I basically run life as usual. I don’t restrict my activity level or my schedule, or need to plan for it. In this fast of course I committed to making this a goal in itself to understand if fasting limits me.

As a result, during the 10 day fast, I was out meeting friends, business contacts – and even went on a date to an art exhibition.

Nonetheless there are things to note…

Physical Weakness

I experienced less of the feeling of physical weakness than in previous fasts – a heaviness or lack of refined motor control of the arms and legs.

I tested this a bit further on day 2 with one set of 55 push ups (my current 1 set max). This didn’t feel much different to doing it in a non-fasted state.

During this fast as I was going about my days I had times when I actually felt ‘physically strong’ and was naturally walking around at a rapid pace. This was more so on the last 5 days of the fast, so that difference may simply be related to the fast being longer. In many ways the last 10 days were more physically comfortable than the first 5 days.

Sleep – My Next Challenge

On most of my fasts the biggest downside is sleep disruption. After a few days on the fast I tend to start to have interrupted sleep.

This fast was no exception. From day 5 I began to get night wakings as early as a couple of hours after going to sleep. After some of these I wouldn’t be able to get back to sleep for hours. The exception was the last night – on day 10 – I had perfect sleep, longer duration, and deeper than usual judging by the drowsy feeling combined with how refreshed I felt in the morning.

Sleep disruption and night wakings are shown to impair glucose metabolism. So it’s the likely cause of the slight rise in glucose I experienced on day 5 and 6 also.

For future fasts I’ll be making sleep a priority to investigate, track and optimize.

The Mind Retreat

The mental experience of fasting for 10 days allowed me to appreciate more clearly aspects that I’d noticed in shorter fasts. Fasting promotes a less rushed, more practical and more bigger picture thinking state of mind for me.

The contrast of this with the typical more frenetic ‘getting things done’ focus of life is very attractive. In my mind it presents a great counter balance to keep your decisions in check once a month. It enables you to look at life, work from this other perspective once per month (if you’re doing the cyclic fasting) and that strikes me as a good thing for decision making.

This was far more noticeable on the 10 day fast. Some of this may be related to the drop in testosterone (and libido!) I tracked.

The Post-Fast Rookie Mistake

If you’re thinking of undertaking a 10 day water fast yourself. This is possibly the most important section – pay attention – I made the mistake and paid for it.

For 3 days after the fast I suffered from gut and toilet problems. Severe pain the first night to discomfort and the inability to keep anything actually inside me for the 3 following days.

It was a simple mistake. I assumed that what works post-fast for 5 days, should be okay for 10 days despite having spoken with people having done 10 or more day fasts that advised caution.

The biggest difference between the 5 and 10 day fast is how you start to refeed. I prepare and eat a couple of bowls of bone broth after my 5 day fasts without issue. I’ve found it to be a great high micronutrient way to ease back into eating.

However, with the 10 day fast, this turned out to be a disaster. My body simply was not able to deal with high levels of fat found in bone broth. My appetite didn’t return as a result either, so I was having to push myself to squeeze in small meals. After 3 days of failing to get my digestion back to normality with a variety of food combinations I thought would work (vegetable soup, scrambled eggs, etc) I had to rethink my strategy.

I resorted to drinking exclusively blended green vegetable smoothies.

The turnaround was amazing. All my digestion issues disappeared literally with the first couple of glasses, and my digestion issues were completely resolved within the next 24 hours. I kept that program up for a few more days nonetheless, to make sure I was past the issues.

So my strong recommendation to anyone trying this – and myself for future long duration fasts – will be to start with exclusively vegetable smoothies for the first 24 hours as a minimum (better 48 hours). That should lay the digestive foundation to be able to move back to your usual eating patterns.

Symptoms – The Back Rash

I’ve experienced some slight rashes during fasts before. With this longer fast it was a lot more extreme.

By day 10 my whole back was covered with a rash of spots – just the back. It was quite stunning – it made me think back to the time I caught chicken pox.

This rash disappeared just as quick within a couple of few days of refeeding it was completely gone again.

The Takeaways

So coming back to the questions we want to answer:

  1. Can I remain productive during a 10 day fast?
    • Would my mental performance suffer? Perhaps leading subtly to worse decisions, or perhaps just slower thinking?
      Answer: It’s not clear as yet. It doesn’t look like there was any drastic mental performance impact on working memory or attention control. Future testing will need to be done with future fasts to further validate
    • Would my energy levels remain the same or decrease? Would there be a change in how many hours I could comfortably work per day?
      Answer: There was no noticeable big change in energy levels or hours worked during the fast. If anything I felt a little more wired, and thus had to reduce my intake of caffeine.
    • How about concentration, focus and drive?
      Answer: Testosterone is often associated with these attributes in men. Low testosterone tends to reduce these attributes, however while my testosterone dropped during the fast, that’s not something I experienced. In a future 10 day fast I’ll track testosterone on the last day (day 10) to see if the hormonal impact is greater than the mid fast impact (day 5).
  2. Is “10 day fasting” every quarter sustainable? Specifically, where I’m doing monthly cycles of 5 day fasts in between?
    • Would I double the weight loss of a 5 day fast? And thus make it difficult to recover the weight within the following month?
      Answer: Weight loss wasn’t exactly linear – there was a leveling off at one point so weight loss per day was slightly less than with that I’ve experienced with the 5 day fast. The weight was easily regained within 15 days – so there doesn’t look to be an issue with not being able to maintain my equilibrium weight when I introduce 10 day fasts every quarter in between the monthly cyclic 5 day fasts.
    • Would a 10 day water fast be as easy, psychologically and physiologically, as the 5 day water fasts? Or would I hate it?
      Answer: If anything the 10 day fast was easier and got easier as I got into it. This could be due to my growing experience with fasting – “practice effects”, or that fasts do get easier the longer you’re on them. I think it’s probably a bit of both of these.
    • Is there any downside impact on “adrenal health” or cortisol regulation from fasting? (this is a question I’ve been attempting to answer since I started long duration fasting)
      Answer: My total cortisol and 24hr free cortisol were slightly lower on day 5 of the fast compared with baseline. Despite having done many fasts my 24hr free cortisol levels have not dropped from the original values I tracked a year previously – they’re stable. My total cortisol is also well within normal output ranges. So my inclination is to say no. I’d like to check in a future 10 day fast the cortisol metabolism on day 10 to see if there is a ‘declining slide’ in cortisol output over longer duration fasts.

Episode Question: Are you convinced about the rewards of water fasting to try it yourself yet? If not, what else would you need to know to get you there? Let me know in the comments.

Tracking

Biomarkers

  • Blood Ketones (Beta-Hydroxybutyrate / β-hydroxybutyrate): Blood ketones are the gold standard for measuring your state of ketosis. During the fast, ketones are expected to peak in the range of between 6 and 8 mmol/L. Dominic D’Agostino mentions that metabolic acidosis with values over 5 mmol/L place an additional burden of processing on your body, so in non fasting states keeping values between 1 and 5 mmol/L may be optimum.
  • Blood Glucose (mg/dl): A measure of the level of glucose in the blood at one point in time. Values of between 50mg/dL and 60mg/dL are standard for fasts. Non-fasting values should be below 80mg/dL ideally, and at least 92mg/dL.
  • Glucose-Ketone Index (GKI): The ratio between the concentration of glucose in the blood to ketone bodies in the blood. The calculation is Glucose (mmol)/ Ketone (mmol). Dr. Seyfried created the index as a better way to assess metabolic status. Therapeutic efficacy is considered best with index values approaching 1.0 or below. Patients with chronic disease like cancer have consistent index values of 50 or more.
  • Weight (lbs): Standard scales measurement of weight in morning without clothes (to avoid biases).

Lab Tests, Devices and Apps

  • Blood Ketone/ Glucose Monitors: The Precision Xtra in the U.S. or Freestyle Optium Neo in the UK are the current recommended monitors. You’ll need lancets, ketone strips and glucose strips also.
  • DUTCH (Dried Urine Test for Comprehensive Hormones): This advanced hormone test panel from Precision Analytical is currently the most comprehensive and convenient test looking at cortisol metabolism and sex hormones. I used it to track baseline and fasting hormones. You can download my complete lab test results here: Baseline test results / Day 5 of fast test results.
  • Quantified Mind: The free online tool used to track cognitive performance during the fast – you can learn more about using the tool in this episode with its creator Yoni Donner. I used two short tests Yoni recommended to use for a mental performance check-in requiring a minimum of time (~5 minutes):
    • Color Word Inhibition: A test that measures attention control via the stroop effect.
    • Self-Paced 2-Back: A version of the N-Back game used to assess working memory.
  • Muse Calm: Mentioned as one of the better return on effort items discovered through the Quantified Body’s exploration so far. Interview with the founder, Ariel Garten, in previous episode here.

Tools & Tactics

Fasting Protocols

  • Water Fast: “Water fasts” are the standard fast protocol used in most of the research studies, including those looking at cancer inhibition or therapy for cancer patients. People are more or less extreme with the definition of what a water fast consists of. I personally am looking for the ‘biological effects’ or results. I’m not concerned with sticking to purely water unless that’s what is required to gain those results. So my version in this fast includes some supplement support which should not interfere with the beneficial fasting mechanisms – see below in Supplements for details.
    • 5 Day Water Fast: A minimum of 3 days is required to flip most people’s metabolic switch between glucose and ketone metabolism, and attain the benefits of the fast. For this reason a good place to start with water fasting is 5 days, which incorporates 2 days of therapy time (i.e. after the 3 day lead time to switch the metabolism). You can see this effect taking place in my first 5-day water fast self-experiment. The 5 day fast is also manageable on a cyclic monthly basis: 25 days of normal life, and 5 days of fasting per month.
    • 10 Day Water Fast: To provide a deeper dose of therapy (i.e. 7 days) people are extending their fasting times to 10 days, or beyond. As per my interview with Dr. Thomas Seyfried this may be more effective with respect to the anti-cancer effects. Depending on your risk profile, this may be something you consider doing from time to time.
  • Fast Mimicking Diet (FMD): A diet designed by researcher Valter Longo to maximize activation of the beneficial fasting mechanisms while still allowing you to eat to an extent. The details of this type of fast were covered in my FMD self-experiment in episode 31.

Supplements

My goal with this fast was to support my body without interfering with the beneficial fasting mechanisms, and to stay productive throughout (work wise and socially). So this is actually what I did:

  1. Mineral supports: This was the main supplementation I took covering a broad spectrum of minerals.
    • Real Salt: I sprinkled real salt into the filtered water I was drinking throughout the fast.
    • Quinton Hypertonic: A seawater electrolytes solution with a broad spectrum of minerals.
    • Pure Encapsulations Minerals 650: Capsules containing a broad spectrum of minerals.
    • (Both of the above recommended to me by Chris Shade from this episode)

    • Ancient Minerals Magnesium Spray: Typically I apply this to my skin daily after showers for absorption via that route. However, I’ve also started to spray it into my drinking water along with the Real Salt, and continued this during the fast (Note: Spraying the oil in drinking water was a tip from Andrew Scarborough in an upcoming interview – Episode 44).
  2. Drinks: Besides water I also consumed some other drinks during the fast, primarily for productivity purposes. My usual routine is to have a coffee in the morning, with the obvious caffeine jolt – so I kept to that usual routine, just keeping it to simple no calorie versions.
    • Black Coffee: For the first 5 days I took a black coffee in the morning, however I typically found that I naturally didn’t finish it. As the first continued I increasingly felt the caffeine from this single coffee was too much of a stimulant, the effect seemed to be magnified. So half way through I switched to…
    • Teas: Mostly Green Tea, also some Rooibos and Camomile tea. I found the green tea didn’t over-stimulate as much although I was still maxed out on 1 or 2 cups. More than that and I got the jitters.

Personal Note: Background on Using Minerals in Fast

There was another, more personal, reason I included a good amount of mineral supplementation during the fast. Since the episode with Chris Shade I’ve been following his mercury and heavy metals removal protocol.

Part of that protocol requires that you take a break from time to time to halt the process and remineralize the body since a side effect of the protocol is removing needed minerals along with the heavy metals.

I wasn’t going to be following the Shade protocol during the 10 day water fast (I stop all other experiments and protocols while fasting), so it made sense for efficiency to use that time for remineralization.

Other People, Books & Resources

People

  • Dr. Thomas Seyfried: See episode 16 for a discussion of his theories and work.
  • Dominic D’Agostino: Dominic has led some of the research into the benefits of ketone bodies and metabolic therapies, he is now turning much of his research effort towards cancer similarly to Thomas Seyfried.
  • Chris Kresser: Damien first learned about the benefits of the DUTCH test at Chris’ recent seminar in London.

References:

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What defines human microbiome health? The co-founder of American Gut Project discusses the differences we’ve found in the gut microbiome and how it influences our health. We look at tools and lifestyle choices that have been shown to change the microbiome (for good, and for bad).

Our microbiome plays an important role in our ability to overcome health issues. A healthy biome can make you resilient to these challenges, while a poorly-balanced one can create or worsen health problems. We first talked about the microbiome in Episode 9 with Jessica Richman, and today we are going to dig deeper into what affects it.

In this episode, we look at how the microbiome and our life choices impact each other. This can relate to how we live, our health, and even how many mosquito bites we get. Research shows that many chronic and gut diseases are related to our microbiome. We also talk about how medical interventions like antibiotics, Cesarean sections, and fecal transplants change our biome.

Anything that’s in the literature has got to be based on population averages. And one thing we know about people is that there are tremendous amounts of variability. So what works on average in the clinical trial is not necessarily going to be what works for you individually.
– Rob Knight

Advances in DNA sequencing have made it possible to look at the microbiomes of huge groups of people. Several large-scale projects, which we’ll discuss today, aim to look at microbiomes of groups or whole countries. It is also easier for individuals to learn about their own microbiome. This lets you see how your lifestyle, diet, or medical treatments alter your biome.

Today’s guest is Dr. Rob Knight, professor of Pediatrics and Computer Science & Engineering at the University of California San Diego. Dr. Knight was chosen as one of 50 HHMI Early Career Scientists in 2009. He is also a member of the Steering Committee of the Earth Microbiome Project, and a co-founder of the American Gut Project.

Dr. Knight and the Knight Lab at UC San Diego use state of the art computation and bioinformatics to understand the microbiome and what affects it. Dr. Knight is on the forefront of this exciting research and will walk us through the topic.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!

itunes quantified body

What You’ll Learn

  • What DNA and RNA are (6:52).
  • Initially researchers thought that the human microbiome would be uninteresting (8:20).
  • Advances in DNA sequencing made projects like Human Microbiome Project and American Gut possible (9:53).
  • Novel information on how lifestyle affects the microbiome (13:50).
  • The different biomes of your body, what is known about them, and how the affect the body (16:50).
  • Long-term diet has the largest impact on your gut microbiome (19:40).
  • Individuals show variation in their microbiome from day to day, and this variation could make single samples less useful (20:05).
  • Research shows that only a few activities and dietary changes significantly affect the microbiome (22:50).
  • There are still questions about how variation within an individual’s microbiome relates to health (26:08).
  • Resources like American Gut can be used to assess your own response to medical interventions like antibiotics (27:20).
  • Fecal transplants to replenish your microbiome after medical intervention is an area of promise for those battling C. difficile (28:15).
  • The effect of antibiotics on the microbiome vary among treatments and individuals (31:06).
  • The microbiome is incredibly complex, but research into a few microbes could yield tremendous health benefits (33:16).
  • Although there is anecdotal evidence that probiotics are effective at positively impacting your microbiome post-antibiotics, there are currently no clinical trials on their effectiveness (37:44).
  • The Ancestral Microbiome Project is comparing the microbiomes of people with traditional lifestyles to see if the Western lifestyle or diet has led to a loss of certain microbes (41:05).
  • Living with a group of people or a new partner can change your microbiome (42:54).
  • IBS has been linked to the microbiome, and probiotics have shown promise for treating the condition (44:20).
  • Damien and Dr. Knight discuss places to find additional information on the microbiome (45:22).
  • Dr. Knight suggests tracking travel, medications, and diet if you are interested in how your lifestyle affects your microbiome (47:11).
  • Those interested in learning more could also track their fitness, do an EEG of brain activity, or an MRI of areas of interest (49:44).

Thank Dr. Rob Knight on Twitter for this interview.
Click Here to let him know you enjoyed the show!

Dr. Rob Knight

Tools & Tactics

Interventions

  • Fecal transplant: The purpose of this treatment is to re-balance the microbiome of the transplant recipient by placing fecal matter from the donor is placed in the colon of the recipient. The most common reason for this treatment is a serious illness caused by Clostridium difficile after the healthy gut microbiome is destroyed by antibiotics.

Supplementation

  • Probiotics: Probiotics are live bacteria and yeasts that assist in gut health; this includes antibiotic-related diarrhea, IBS, and IBD. They can be found in a variety of food products (like yogurt with “live cultures”) and in capsule form. Strains of Lactobacillus and Bifidobacterium are the most commonly available.

Diet & Nutrition

  • Plant-based diet: Dietary changes can quickly alter the gut microbiome, and Dr. Knight specifically discussed the choice of animal vs plant-based diets on the rates of Prevotella and Bacteroides. Here is the paper by Gary Wu and others discussed Rob Knight. For more information, here is a paper discussing how people on animal-based diets had higher levels of microorganisms related to inflammatory bowel disease in their microbiome.

Tracking

Biomarkers

  • Microbiome community composition: To determine what is in your microbiome, labs report the percent of each type of bacteria present in your sample. We are still learning about how microbiomes affect health, so there is currently no information on what an “ideal” microbiome looks like.
  • Gut microbiome: This is the microbiome in your colon and is the most commonly assessed of the biomes. Some “good” bacteria like Akkermansia, Lactobacillus, and Faecalibacterium are associated with reduced obesity rates and gut health.
  • Fine grade fitness information: This biomarker includes daily information on caloric intake, steps taken, calories burned, sleep quantity, and sleep quality.
  • Blood and Urine Metabolites: These small molecules include amino acids, sugars, and fats. They provide insights into health, disease risks, and optimal diet. No specific biomarkers were discussed – the biomarker would be a specific metabolite. A common test is the blood metabolite panel (BMP), which looks at calcium, glucose, electrolyte, blood urea nitrogen, and creatinine levels. For urine, proteins, leukocyte esterase, and hemoglobin are all commonly assessed biomarkers.

Lab Tests, Devices and Apps

  • American Gut Project: A not for profit, research-based initiative to understand the American microbiome. Participants are asked to provide details about their diet and lifestyle.
  • Michael_Pollan_Bug_Data

  • uBiome: This test can be ordered and used by anyone in their home. The test allows collection of microbes from your gut, mouth, ears, nose, or genitals.
  • Electroencephalogram (EEG): EEGs record electrical activity in the brain. The frequency of waves can indicate whether brain function is normal or disturbed. Alpha (8-13 waves per second) and beta (more than 13 waves per second) waves are the most common in healthy, awake adults.
  • Magnetic Resonance Imaging (MRI): MRI scans are use pulses of magnetic energy to visualize internal organs and structures. It can be used on almost any area of the body and provides information on tumors, bleeding, injuries, blood vessels, or infection.

Dr. Knight’s Recommended Resources to Learn More About Microbiome

  • Follow Your Gut: The Enormous Impact of Tiny Microbes: Our guest’s book on how the microbiome affects our health. The Appendix includes information on how to interpret the results from American Gut.
  • Missing Microbes: Our guest recommended Martin Blaser’s book as a resource for those interested in learning more about microbiomes and antibiotics.
  • Not Exactly Rocket Science: A science blog written by Ed Yong, our guest suggested the posts on microbiomes as fun reading for those interested in the topic.
  • Some of My Best Friends are Germs: Written by Michael Pollen for NY Times in 2012, the article is a quick read on the relationship between microbiomes and health.
  • Jonathan Eisen’s TED talk: Dr. Eisen’s talk “Meet Your Microbes” focuses on microbes and their co-evolution with their hosts.
  • Jessica Green’s TED talks: Dr. Green is the founder of Biology and the Built Environment (BioBE) Center, and has given two TED talks on microbes.
  • NY Times Matter Column: A weekly science column written by Carl Zimmer.

Other People, Books & Resources

People

  • Jeff Leach: Co-founder of the American Gut Project, and microbiome researcher.
  • Dr Catherine Lozupone: Professor of Biomedical Informatics andPersonalized Medicine at the University of Colorado, Denver. Dr. Lozupone researchers the impact of the gut microbiome on human health.
  • Dr. Jeffery I. Gordon: A research scientist studying the link between gut microbiota and obesity. Our guest collaborated with Dr. Gordon on this topic.
  • Dr. Pieter Dorrestein: A professor working at UC San Diego, Dr. Dorrenstein and our guest have collaborated on research. A recent paper of Dr. Dorrestein’s in PNAS looks at the chemical makeup of skin surface and relates it to the microbes that live in the skin.
  • Dr. Dan Littman: Professor of Molecular Immunology at NYU School of Medicine, Dr. Littman studies the human immune system.
  • Hans Herfarth, MD, PhD: Dr. Herfarth is a member of the UNC Multidisciplinary Center for IBD Research and Treatment and the author for the UNC Patient Guide to Inflammatory Bowel Disease (IBD).
  • Balfour Sartor, MD: Dr. Sartor is the co-chair of the UNC Multidisciplinary Center for IBD Research and Treatment.
  • Dr. Peter Turnbaugh: A professor in the UCSF department of Microbiology and Immunology.
  • Dr. Dave Relman: Dr. Relman’s research focuses on the human microbiome.
  • Dr. Cecil Lewis: Dr. Lewis studies anthropological genetics, including the evolution and ecology of the human microbiome.

Organizations

Other


Full Interview Transcript

Click Here to Read Transcript

[05:22][Damien Blenkinsopp]: Hi Rob, thank you so much for joining us on the show.

[Rob Knight]: Sure, thanks Damien, and thanks to your interest on this topic.

[Damien Blenkinsopp]: It’s great. So we’ve already looked at the microbiome, but I wanted to know, why is it that you got interested in this specific area? What is it that first caught your interest, or you first got involved in this area?

[Rob Knight]: Yeah, well it was a very indirect pathway from my graduate work at Predison’s Lab in studying the evolution of the genetic codes and a large part of that was looking at RNA molecules down to particular molecules that are useful in metabolism. So from there I went to the University of Colorado working on RNA sequence states and trying to figure out how many random RNA sequences you need to look at before you find one that does something interesting.

So there were a lot of one particular kind of sequence, the ribosomal RNA molecules in the database. I really wondered why were there so many of that particular sequence that had been studied. And so I started talking to Norm Pace, who was one of the other faculty members at Boulder. And I realized they were using the ribosome’s RNA not as an object of study in and of itself, but as a tool to understand the relationships between different organisms, and to read the mass in the communities that they were looking at. Everything from rocks to shower curtains to caves.

And so it really is just going from basic studies of RNA to understanding that you could use a particular kind of RNA as a tool to find out something about microbes, and then from there realizing that the microbial communities themselves could be used as a tool to find out about different environmental conditions, including the conditions within our own bodies.

[Damien Blenkinsopp]: Great, great, thank you.

[06:52] For some of the people at home, they might not understand what RNA is in reference to DNA, and how that works. Could you give a quick overview of what the mechanism for RNA is, and what role it plays in our bodies and the other things that you’ve been talking about.

[Rob Knight]: Sure, absolutely. So I think everyone’s familiar with the idea that DNA is the genetic material we use that passes down from one generation to the next. So, the proteins are most of the catalysts that do reactions in our bodies, most of the structural elements. So what happens is the DNA gets transcribed into RNA, ribonucleic acid, which is chemically relatively similar to DNA. And then the RNA gets translated into proteins.

But there are some kinds of RNA that don’t get translated, and have a function that is of themselves. One really important kind of RNA is ribosomal RNA that actually makes up the factory in the cell, the ribosome, that makes the proteins. And so because it plays such an important role in life, you can detect similarities in those even between very distantly related organisms.

So similarities even between us and bacteria. And so you can use that molecule to reconstruct the evolutionary tree that relates all of those organisms together, based on the similarities and differences in the sequence.

[08:04][Damien Blenkinsopp]: Great. So then you, from those studies, you started working to look at the bacteria, because you saw that they had a pretty important role, and that there was a lot of similarities between the things you were studying. On a human level and in the animal level, could you tell us a little bit about what it was that kind of pushed you to look more at the microbiome?

[Rob Knight]: Yeah, sure.

Originally the tools that I was developing together with Cathy Lozupone, then a very talented graduate student from my lab but now a faculty member of the University of Colorado Health Science in Denver. Initially we were just looking at tools to compare microbial communities out there in the environment.

So looking at the effects of things like salinity and pH as the chemical factors, of drivers, for how microbes are different in different places, like different samples of soil, sea water, or other communities like that. And so at the time we thought that maybe the microbes associated with the body wouldn’t be that interesting, because at the time there was fairly heavy bias towards the idea that most people probably have the same microbes, because if you grow them on a Petri dish, you get more or less the same thing from everybody.

But it turns out there’s a huge number of microbes in there, even in our own bodies, that we don’t yet know how to culture. And as a result, when you look at them with these culture independent, they are directly sequencing the DNA that codes these ribosomal RNA genes. And figuring out what’s in the communities directly you see all this diversity in the human microbiome that no one ever suspected was there.

So, we started doing this in mice, actually, in collaboration with Dr. Jeffery I. Gordon, he’s a physician at Washington University, a gastroenterologist. He was really interested in looking at links between microbes in obesity. So we started with mice, then moved up to humans. And then increasingly we’ve been interested in looking at the microbiome not as a static system, but as a dynamic system. So looking at how it changes over time, both in health and in disease.

[09:53][Damien Blenkinsopp]: Great, great. Thank you very much. And of course you are a co-founder of a project, which is being designed to explore the microbiome in America, of the population in America. What kind of latest update of American Gut, and what you’ve been doing there?

[Rob Knight]: Let me give you just a little back-story to that project. So, before American Gut, we were involved in the Human Microbiome Project, which was a very large scale NIH funded initiative, 173 million dollars to characterize what the microbes look like in healthy people. And with their whole microbiome, is there a lot of variation person to person, and how does it vary in different parts of the body.

So during that process, and in part because of technology that was developed, during the Human Microbiome Project DNA sequencing and tools to analyze the DNA sequences made the whole process dramatically cheaper. So essentially we wondered can we bring this technology to members of the general public, using the tools that we were able to develop during the Human Microbiome Project, to essentially allow anyone who was interested in finding out about their own microbiomes to be able to do that at a reasonable cost.

Jeff Leach and I launched as a collaboration between the Earth Microbiome Project and the Human Food Project. The crowd funded initiative where basically it’s donation supporters. And people can find out directly about swabs from their gut, and how it compares to the gut microbes of other people around America, or around the world, especially including the people who were analyzed in the Human Microbiome Project.

And also including people in Africa and South America, and soon people in Asia, to try to compare what the microbes look like, and how do they relate to health and disease.

So, unlike the Human Microbiome Project, where there were very rigorous exclusion criteria, so you could only participate if you were certified by a physician as being extremely healthy, in American Gut, we are interested in anyone, essentially to see what kinds of microbiome configurations are out there in the wild when you give everybody the opportunity to participate.

[Damien Blenkinsopp]: Great, great. That’s a great back-story.

[11:54] What’s the number of samples that you’ve collected to date? You said it’s called American Gut, but it sounds like it’s not just focused on America now, that it’s spread out and it’s available to more widely internationally. Is that correct?

[Rob Knight]: Yeah, that’s correct. So it’s relatively expensive to pass inspection internationally because the shipping regulations are fairly burdensome. So what we’ve been doing is we’ve been launching spin-offs in other countries. And so we started with Australian Gut, and with British Gut essentially because it’s a lot easier to translate all the instructions from English into English, rather than to tackle those translation issues.

But we’re hoping to expand to a lot of other countries. And at the moment with the transition from the University of Colorado to the University of California, we’re essentially in a holding path, and at the moment waiting for AMX approval. But we’re hoping to scale up the project dramatically, and greatly facilitate the ability for people all over the world to participate.

[Damien Blenkinsopp]: Which approval did you say you were waiting for? Was it an academic program approval?

[Rob Knight]: Institutional Review Board Approval. So in order to ensure that the project was conducted ethically and that the results that we get are going to be meaningful, everything we do in American Gut has been approved by Institutional Review Boards from the beginning.

I moved from the University of Colorado to the University of California right at the beginning of this year. What’s happening right at the moment is we’re waiting for the ethics approvals to be transferred from one institution to another, which can take a lot of time.

[Damien Blenkinsopp]: Right, right. Got it.

[13:19] How many samples have you collected to date for the project?

[Rob Knight]: We’ve released data from about 4500 samples. We’ve sent out about 9,000 kits. We have about another 1500 samples in hand that we’re just waiting for that ethics approval to be able to move forward on sequencing.

So, for anyone who’s listening, if you’re wondering where your results are, we’ll be able to get them out pretty soon. We just need to make sure that everything is completely compliant with all the regulations that apply to the Human Subject Research in the United States. Just to make sure that everything is completely above board.

[Damien Blenkinsopp]: Excellent. So, has any analysis come out of it, or insights yet that you’ve been able to do?

[Rob Knight]: Yeah, absolutely. So one thing that was exciting about it, or already, in the Human Microbiome Project, this paper, which came out in Nature in 2012, we looked at about 250 healthy subjects. So I think we reported data for 242 where there was information from all body sites.

So you have about 250 people involved in that project. Versus American Gut, where you have thousands of people involved. As a result, with a much larger population size we have much more statistical power to look at subtle effects.

And we also put on the questionnaire all sorts of things that were considered too crazy to ask in the HMP. But in the intervening time we’ve discovered so much more about what the microbiome does, especially in a range of different animal models. And it seemed a lot less crazy to ask those questions in 2012 than it did in 2008.

As a result, we’ve been able to see associations between the microbiome, and all kinds of things you might not have expected. So you might have expected that how old you are affects the microbiome, which it does, but you might not have expected that, for example, how much sleep you say you get a night is also linked to the microbiome. And we see a statistically significant effect of that.

Similarly, you might have expected that how much alcohol you drink affects the microbiome, but you might not have expected that we can also pick up a difference based on how much you exercise. Or I should say how much you say you exercise, because all of this is reported data. But how much you say you exercise, even whether you say you do it indoors or outdoors, has an effect.

So we’re really picking up a lot of interesting associations. And what we’re hoping to do in the next stage of the project is to take a bunch of these associations and turn them into something where we can start to get causality. So what we’d love to know, if we see in association with alcohol and an association with exercise, or with sleep or with any of these other things, is to actually encourage people to change what they’re doing in those respects, or you know more obvious things like diet, or antibiotics.

Where the idea is that if you take a sample before you have a change in any of those things, and then you have the change and then you take another sample again after. Can we start figuring out which of those changes are actually caused by those different lifestyle things that you could be doing. This is watching simply effect.

[Damien Blenkinsopp]: Right, because a lot of when we’re thinking about the microbiome, and –just to make sure I’m correct here — you’re just looking at the gut, right? The microbiome of the gut?

[Rob Knight]: Well, actually with American Gut you can look at the microbiome. So most people are looking at their gut biome, but it’s also interesting to look at other body sites. We have been sending out a number of batches of kits that allow you to sample multiple sites simultaneously.

So another project we’re doing, we’ve been looking at skin. So for example, we had a very interesting paper that came out in PNE of last week with Pieter Dorrestein doing very high resolution maps of the skin in relation to the microbes, to the metabolites. And then there’s also a lot of interest in the oral microbiome, the vaginal microbiome, and so on.

So, although the gut microbiome is where most attention has been focused, there is a lot of interest potentially in looking at other body sites. And linking them not just to health effects of that site, but also to all over the body. So for example the gut microbiome has been linked to asthma and to rheumatoid arthritis, and to cardiovascular disease, all of which takes place in sites outside the gut, but are nonetheless affected by the microbiome.

And it’s entirely possible that, for example, the oral microbiome, or the skin microbiome might also be having systemic effects we’re only just beginning to understand. Whether it’s through interactions with the immune system or through release of particular metabolites, or other mechanisms.

[17:32][Damien Blenkinsopp]: Maybe it’s too early to say this, but have you seen anything that would indicate that the microbiomes are related to each other, in terms of if you have a different gut microbiome it may influence or be influenced somehow by the fact that your nose or your skin biome is different also?

[Rob Knight]: Well that’s a very interesting and controversial question. So actually, the fifth Human Microbiome Project main papers, which said that there are statistically significant but relatively weak associations between the different body sites, and then later that’s been confirmed by other researchers using different statistical methods.

At the moment there’s a lot of debate about how strong the associations are, and what effects they have on health when you’re looking at the overall configurations. But certainly some individual organisms that are very interesting. So, for example, Dan Littman at NYU has shown some very nice work linking Prevotella in the guts to rheumatoid arthritis. And so we’ll probably see a number of other associations like that with specific organisms at one site having unlikely effects on what happens, what helps with other sites in the body.

[Damien Blenkinsopp]: Very, very interesting.

I think the surprising thing for a lot of people of what you just said is that there are a lot of lifestyle factors not related to diet. Because we normally think of the biome, and especially the gut biome, being immediately related to our diet, and what do we eat, but [not] a lot of things you mentioned, sleep, age, exercise. And you said exercise indoors or outdoors can be different as well, is that correct?

[Rob Knight]: Correct, yeah.

[Damien Blenkinsopp]: So you know, it’s very interesting. These small changes in your lifestyle, nothing to do with diet, can have significant impact on the gut also, which we haven’t looked at.

[Rob Knight]: Sure, although I should clarify that long term diet has the largest effect that we’ve seen. The work with Gary Wu and others at Penn came out in 2011 in Science. What we saw there is this long-term dietary pattern had a profound effect on the gut microbiome, especially changing the ratio of Prevotella to Bacteroides, two of the major taxa in the gut. And only changing the overall configuration, more than essentially anything else.

So the only thing we’ve seen that gives you comparable changes is either antibiotics or acute infection with some kinds of pathogens. Like C. diff, for example, has a very large effect on your gut microbial community. So long term diet is really very important.

Short term diets, unless it’s something really extreme, is a lot less important than what we see in long term diet. This was maybe consistent with people’s experiences with going on a diet for a short period, losing some weight, but then going off the diet and bouncing back again. In general your microbiome is very resilient.

[20:05]Damien Blenkinsopp]: This comes to the topic of variability of the microbiome over time.

I did see one presentation of yours where you were showing the biome of a newborn baby, actually, as it was growing up. And you’re showing the changes at that stage of its life, which were quite significant at that stage. But for adults who are fully developed, in our day to day, week to week lives, are our microbiomes changing significantly? Or are they very, very stable?

[Rob Knight]: Both of those are true. So, our microbiomes change statistically significantly one day to the next. And especially when we do things like travel or take antibiotics, or if we have a chronic, immunologically associated disease. Like, for example, inflammatory bowel disease, or rheumatoid arthritis, or other conditions where there’s a lot of variability in whether you’re in remission or whether you’re having a relapse.

There can be fairly large changes there, but typically small compared to the differences between different people. So we tend to be stable in terms of, especially if we’re healthy and there’s nothing particular going on, we tend to be stable in the sense that we’re more similar to ourselves day to day than we are to other people.

But that doesn’t mean that you can’t detect the differences one day to the next. And so a very interesting question at the moment is what is the significant of those day to day fluctuations? Might it actually be more important how much you vary than what your current state is right now. And that’s one of the things that we’re just starting to investigate at the moment.

[21:29][Damien Blenkinsopp]: Yes, and in terms of how meaningful data would be for someone who’s collecting it for themselves, if they take one sample and they get one reading is that meaningful to them? Or would you suggest they take one this week, and one next week. How would you go about making sure you have something representative?

[Rob Knight]: Right. Well having one sample is certainly a lot better than having no samples, in terms of getting some information about what’s in your gut. Because even having one sample is going to do a tremendous amount to place yourself on the microbial map, relative to other people.

The question about how frequently you should sample and how many samples you should take to get a baseline, that’s something that’s actually a very active research topic at the moment. And we have collaborations with a number of different investigators exploring that in different contexts.

So, for example, one thing we’ve been doing is work supported by the Crohn’s & Colitis Foundation of America with Hans Herfarth and Balfour Sartor of the University of North Carolina, where we’re trying to address exactly that clinical question. If you have patients with IBD should you sample daily, should you sample weekly. So how does that compare to what you should do in healthy controls.

Unfortunately, the only way we can assess that baseline data is to take very frequent samples. And it’s difficult to get people to do that. So for example, I’ve been collecting my own samples daily for over six years now. It’s relatively difficult to get people to come up to that kind of level of commitment.

[22:50][Damien Blenkinsopp]: So, I’m interested. What kind of insights have you learned about yourself from that n=1?

[Rob Knight]: As you know it’s always relatively difficult to draw conclusions from a sample size of one, but it does look like things like travel have a fairly large effect. We’ve seen that for a number of different locations.

So I should clarify that only about the first two years of that have been sequenced so far. Most of the rest are in a queue for processing, but it keeps getting bumped due to things like making sure we get the American Gut results and so on. The rest of the time series is currently pending.

We’ve done the DNA extraction so that’s currently pending sequencing. And some of the things that we’re going to be really interested to follow up on, having a time series that goes that long is, for example, the seasonality effects that we seen in American Gut. And we see those even within one individual. Because if you can repeat that for many years, then you can start to see systematic patterns.

I’ll tell you about some results from another study, which is one by Lawrence David and Eric Alm at MIT, where they sampled themselves daily for a year and collected a very large number of auxiliary variables. I think they collected over 100 variables every day, including everything they ate. All kinds of things like how much exercise they did, how much they slept, and so on.

And they found very few systematic associations. So, for example, about the only thing they saw in diet was citrus, which had a significant effect, whereas many other things that they recorded did not. And they also saw associations with travel, and associations with getting GI illnesses. And that was about it.

So, I think the issue is that a lot of the effects, although they might be important, they’re probably subtle and cumulative. And so although you’re going to get very interesting information from some of these n=1 studies, like this study. And by Larry Snar here at UCSD has been doing looking at his own gut in the context of IBD, in the context of my studies myself.

Although there’s going to be some interesting stories that come out of them, those are going to be most interesting in terms of the technology development, of asking how frequently should you sample to establish a baseline, and over what interval to you need to sample to get a decent view of dynamics.

But we did a study with Noah Fierer and Rob Dunn, Greg Caporaso that came out in Genome Biology towards the end of last year looking in healthy students at the variation of the gut microbiome over the course of the semester. One thing that was very interesting about that, looking at weekly samples, was the variability itself seemed to be very important for relating to the variables that we had about each subject, and each sample.

And so it’s entirely possible that the variability itself was going to wind up being really important. But of course, it’s also a lot more difficult and a lot more expensive to look at than just looking at a single snapshot. And so the single snapshots are still very valuable, I meant to say, even though you could potentially get more information by looking at the dynamics than you would from a single snapshot.

It’s like having a video of an event can often be very informative, but that doesn’t mean that photography has vanished as a discipline despite the fact that we all carry around little video cameras on our cellphones.

[26:08] [Damien Blenkinsopp]: Great.

So in terms of the variability, is it looking that that’s a positive or a negative association? Maybe you can’t really call it yet, but have you got an idea on which way it would be going? Like, for instance, is it potentially that the microbiomes when it’s healthy it’s able to adapt a lot more to the day to day situation, travel and all those things, so it would vary more. Or have you got any insight on that yet, or ideas on which way it might go?

[Rob Knight]: Yes.

So we don’t really have enough information at this point, and as you say it could go either way. Either you might want to see a fair amount of flexibility in your microbiome to be able to adapt to different circumstances, or you might want to see more resilience, and if it’s wandering all over the place it’s more likely to fall off a cliff, and to input the community configuration.

Right now we don’t have the basis to discriminate between those two. Most of the variability studies have been done at baseline in healthy people, and that doesn’t necessarily let you conclude anything about disease.

Most of the disease studies have looked at a relatively small number of samples. Often just a single sample where you’re looking at a case controlled paradigm where you round up some healthy people, round up some sick people, and you look at the differences at that state. So, really we’re waiting for the right kinds of studies to be done for variability in these diseased populations.

[Damien Blenkinsopp]: Great, thank you very much. I mean, we could get a couple of guidelines, just for people who are already using American Gut or one of the other services.

[27:26] I’m actually just about to take some antibiotics, for instance, so I’ve got a kit I intend to use, and then once the course is finished I intend to use it again. And actually based on your presentation, I intend to do one 30 days later to see if it will recover. Is that something reasonable as a baseline experiment? Just to see what’s going on.

[Rob Knight]: Yeah, that’s certainly very reasonable.

You might want to look at Dave Relman’s paper, it came out in Pathobiology a few years ago. And what he had there was three subjects who were taking ciprofloxacin from a healthy baseline, and they measured how long it took them to come back.

What was interesting about that is three people, they all responded totally differently. But then it’s kind of difficult to figure out what you should say about that, because the sample size is only three, and they all responded very differently from one another. But it’s certainly reasonable.

One thing that’s very interesting at the moment is the concept that maybe you should freeze your stool before you take the antibiotics, so that you could potentially replenish the members of your community. And again I should point out that that’s still in its very early stages as a therapy. This is not medical advice or anything.

But the concept that you might want to have that material available in case we figure out how to replenish your microbes from it later, kind of the way people are saving their cold blood for the stem cells. It’s certainly very interesting, and has a lot of potential.

And of course, right, you’ll be hoping for is that in the relatively near future – and there’s a lot of companies and a lot of academic research groups interested in this now – the idea that you might not actually have to take the stool itself, but rather isolate just a few of the beneficial microbes from it, encapsulate those into a pill and swallow those, for example. That’s shaping up to some very interesting research direction, although at this point it is very much in the lab and not in the clinic.

[Damien Blenkinsopp]: It does sound safer, also compared to the current fecal transplants. I think one of the concerns of fecal transplants is we don’t really know what’s in them.

[Rob Knight]: Yeah, that’s exactly it.

[Damien Blenkinsopp]: You know, because just the state of technologically today.

While you might make someone better in some extreme cases, like C. difficile, obviously that’s helpful. But for someone else who has maybe taken a lot of antibiotics and they had gut issues, to take a fecal transplant could be seen as a little bit extreme, as currently we’re not exactly sure what’s in it, and we could be putting something in there that we’ll discover later is not such a good thing.

[Rob Knight]: Yes, that’s certainly a concern. I’m on the science advisory board for the American Gastroenterological Association’s Microbiome Center, and one thing we’re actively trying to set up is a long term registry for fecal microbiome transplant, essentially so that we can track people who’ve had them over time, and make sure that it remains effective.

So for Clostridium difficile associated disease, it’s remarkable effective. Like 90 to 95 percent effective in many different studies. And the last large scale study comparing it to antibiotics for C. diff actually had to be stopped early because the people who got the FMT were responding so well that it was unethical to continue withholding FMT from the people who were on the antibiotics.

So, how widely that’s going to work for other conditions, we don’t really know. One thing you can do for antibiotic associated diarrhea that’s very effective is probiotics. There’s a number of different ones that are now pretty well supported by clinical trials at reducing both the severity and duration of antibiotic diarrhea.

And so in general, it’s not because the organisms themselves are establishing in your gut, but they’re creative a favorable environment where they can crowd out the weeds, like the proteobacteria and things that often come back after antibiotics. And essentially they’re creating more favorable conditions for your own microbes to come back.

[Damien Blenkinsopp]: Great.

[31:06] So, to kind of backtrack a bit. So in the presentation I saw, you saw after the antibiotic treatment, which was a baby with earache I believe it was, the microbiome pretty much came back to where it was before.

[Rob Knight]: Yup. But remember that’s an n=1 study, because we just had one kid in there. Yup.

[Damien Blenkinsopp]: So is that a possibility for some? We always talk about antibiotics like it could be potentially permanent. Because everyone’s pretty concerned. I’m pretty concerned when I’m going on a course of antibiotics now what kind of impact down the line is it going to have.

But it seems like it can depend on the severity, because antibiotics are used in many different cases. They can be used for a couple of days in some cases, sometimes, and there’s lots of different forms of antibiotics, which have different impacts as well, and potentially more severe or less severe.

It seems that in some cases the microbiome may be able to recover, and in other cases it’s not able to fully recover, and it’s quite variable for the moment, I’m guessing. Or do you have any insights as to the insights of antibiotics and how it varies?

[Rob Knight]: Basically what we know at this point is that different antibiotics have very different specificities, so they’ll target different bugs when they’re growing in the lab in isolation. We know a lot less about what effects the antibiotics have in more complex settings. And so the same microbe might only be targeted by antibiotics in some stages in it’s growth cycle.

And so Pete Turnbaugh, he’s now at UCSF but did this work while he was at Harvard, did some very interesting research looking at the effects of the same antibiotics microbes in different communities, that had come from different individual people. And so what he found is even if you have the same microbe, whether the same antibiotics would target that microbe depends a lot on who it came from.

And that’s very interesting. It just suggests that there’s a lot of complexity that we don’t understand at this point about how microbes are going to be targeted by a particular antibiotic, or will escape that depending on what other microbes are around. Depending on whether it’s expanding its population or contracting it, and all kinds of other factors.

So I think we’re just right at the beginning of understanding what’s going on in the complex situation of the human body itself.

[Damien Blenkinsopp]: Yes, absolutely.

[33:16] I think a bit of context to that is if you look at the size of DNA in our genetics versus the microbiome, right the microbiome is a lot bigger, and we don’t fully understand DNA yet. So, basically is it a much bigger task to understand the microbiome?

[Rob Knight]: Yes, it’s a tremendously more complex task. So each of us has about 20,000 human genes, but the size of the microbial gene catalog is somewhere between 2 and 20 million. So, by that measure you could say that we’re only about one percent human, and about 99 percent microbial in terms of the gene counts that we’re carrying around with us.

And so, on the one hand understanding it is tremendously complicated. On the other hand, if you look at other fields where there’s tremendous complexity, like say nutrition for example, but if you ran a potato through the mass spec you’d see all these compounds that you’ve never seen before, and that you don’t understand, and that don’t appear in any catalog from any chemical company. On the other hand, that doesn’t mean that we don’t know a fair amount about what happens if you rely on potatoes as your main food source.

And additionally, if you look at, for example, a lot of chronic diseases from a century ago, so things like rickets, goiters, and so on. A lot of those kind of diseases have just been completely eliminated by knowing that there’s some nutrient that if you give it to the whole population, like for example iodine in salts or fortifying milk with vitamin D, fortifying flour with thiamin, and so on, you can just eradicate these diseases from the whole population.

And so, in the same way it’s going to take us a long time to understand the microbiome, but it might not take that long before we understand how replenishing some of these microbes might potentially be really important for addressing some of the chronic diseases that affect us now, including many of the chronic diseases still linked to the immune system.

[35:11][Damien Blenkinsopp]: Great, great. And there are also macro levels. It’s a pretty good example, I think, you just gave nutrition, because we look at the macros and there’s lots of discussions about proteins, fat, and carbohydrate breakdown in diets. And in the same way there’s macro levels of our microbiome, right? There’s groups of Firmicutes and Bacteroidetes and others on a macro level, which I guess you could see patterns with those as well, and don’t necessarily have to dig down to the fine levels.

[Rob Knight]: Yes. That’s exactly right. Although in the same way that micronutrients are really important, some of the rare organisms might be really important.

And a useful analogy is something like Yellowstone National Park, where the reintroduction of wolves caused a profound change to the ecosystem. But if you go to the park – and not without, but you’d never get permission to do this right – but if you went to the park, and you round up say a cubic kilometer of material and then run that through DNA sequencing, you wouldn’t find a lot of wolf DNA.

And the reason why we know their important is you know people shot them all and the ecosystem changed, and they reintroduced them and the ecosystem changed again. So on the one hand, what technology is that we have right now, we’re probably missing the equivalent of the microbial wolf that could be playing really important roles.

On the other hand, if you were trying to understand that ecosystem, you’d be crazy to ignore the pine trees and the bison and the other really abundant taxa as well. So you can tell a lot looking at what’s common as well as needing to know what’s rare to fully understand the system. But I think we’ll be able to do a lot with the understand that we have now.

And it’s important to remember that that understanding has increased dramatically just in the last decade. So in 2005 it was a major achievement to sequence the gut microbial communities out of three people. And that was expanded by a fifth to hundreds of people, and then to thousands of people. And we’re just getting a much broader picture of what kind of microbes are in there, and what their roles are in responding to different things.

And so, the idea that you might be able to look at the microbes in somebody every single day for a year, would have been an impossible dream in 2005 but the technology has gotten so much better that it’s been done for a number of people now. And the prospects for developing further technology to open that up to the whole population I think will totally transform what we can know about microbial sides of yourself.

So, being able to push that additional technology development forward I think is one of the most critical things we can do at this point.

[Damien Blenkinsopp]: Excellent, thank you very much.

[37:44] One of the things we kind of skipped over but I thought might be interesting for the audience is you spoke about probiotics being useful in connection with the antibiotics treatment, and specific types of probiotics.

Do you know specifically what those are? Or could you point us to any papers which highlighted those? And in terms of the timing, do you take them while on the antibiotics, or is it a post treatment?

[Rob Knight]: The different studies that have been done at the moment haven’t really had a lot of consistency in methodology, so it’s difficult to make specific recommendations. It’s a fairly complex topic. I cover this in a reasonable amount of detail in my book, Follow Your Guts, which is just coming out tomorrow. But essentially I give a few examples of pointers to studies that have been focused on individual probiotics that have shown to be effective for particular conditions.

So one thing to remember with this is although there’s a tremendous amount of enthusiasm to probiotics and they’re very widely available, most of the specific products don’t have any particular evidence backing them. And so it can be a bit daunting to wade through the literature and try to find the ones that are actually supported by clinical trial data.

At the moment, at least to my knowledge, there’s no really good resource that summarizes the clinical trial information to tell you what species, what strains, and what products containing those strains have actually been shown to be effective. Although that’s something that’s a clear opportunity, where if someone sets it up that will be tremendously valuable for the public, especially given the level of enthusiasm.

One problem at the moment is, in the US at least, that the FDA’s official stance is that a dietary supplement can’t modify a disease endpoint. So as a result, if you find that your product actually does modify a disease endpoint, then it gets re-regulated as a drug, and so the manufacturing standards are certainly much more stringent.

And so if you want your yogurt with live and active cultures to continue to be a buck or two a cup, rather than being a thousand bucks a cap, which is about what it would cost if you had to manufacture it as biologic, there’s that issue to consider as well. So, that’s also a substantial problem for research in this area.

[Damien Blenkinsopp]: Right, so again, in that case we’re kind of hoping that no one tries to do clinical trials with the probiotics in products. It’s kind of no-win situation in that respect.

[Rob Knight]: Well it is a bit of an issue. It’s sort of like the issue with dietary supplements for athletic performance. So any time one tends to actually be effective, like say steroids, for example, it gets banned immediately. So you can draw your own conclusions about the effectiveness of the ones that are still on the market.

[Damien Blenkinsopp]: I guess one of the nicer things about that is currently when we take antibiotics it’s not really acknowledged that it causes any specific disease, although people may have gut upsets and any issues like that.

So I guess if these supplements continued to be marketed, and perhaps trials are just done on the basis of changing microbiome, that wouldn’t interfere because it’s not a disease endpoint. A specific disease endpoint, as I understand it, would be a specific classified disease, which is currently basically regulated today. So as long as they stay out of those disease areas, is it not a problem?

[Rob Knight]: Yeah, that’s exactly right. And that’s in part why as a consumer, it’s often very frustrating to see what claims are being made because those claims are now typically very carefully worded and very carefully negotiated.

[41:05][Damien Blenkinsopp]: So I know that you’re also involved in the Ancestral Microbiome Project.

[Rob Knight]: Uh-huh

[Damien Blenkinsopp]: Could you give us a quick update on how far you’ve got with that, and also what it is for the people at home.

[Rob Knight]: Sure, absolutely.

So the goal of this project is essentially to compare the microbiomes of different people living relatively isolated lifestyles and seeing whether they contain microbes that we as Westerners have lost with the hygiene or antibiotics. Or diets perhaps, that cause us to lose some of those kinds of microbes that could be beneficial.

There was a paper that just came out two weeks ago led by Cecil Lewis at the University of Oklahoma on the Matses who are a group of hunter-gatherers in Peru. There’s another one coming out soon that I can’t tell you about because it’s embargoed. But there’s some ongoing work that we’re doing with the Hadza in Tanzania, and the project that’s led by Jeff Leach.

So the Hadza are the last hunter-gatherers in East Africa in the Rift Valley where, of course, humanity evolved. So they’re the last group that’s still exposed to the microbes and to the mammals and to the plants that we would have evolved with during our early evolution. And so they’re very exciting to look at from that standpoint.

But basically the idea is to compare different groups and to understand first there’s still anything that they have in common that we might have lost more recently. And then the second thing is that try to understand similarities and differences in different human populations in terms of their microbiomes and how those microbes relate to different lifestyle features, to human genetics and to other factors.

It’s going to be incredibly fascinating from a science point of view. And from the point of view trying to figure out how our microbiomes should be shaped to optimize health.

[Damien Blenkinsopp]: Yeah, this is great.

I understand that Jeff — have you spent time with the Hadza as well, or has it just been Jeff that’s spent the time with the tribe?

[Rob Knight]: I went there for a week last year. It was just a spectacular experience.

[Damien Blenkinsopp]: I understand that Jeff, at least just spending time there, his microbiome changed. And he also used a fecal transplant from the Hadza to see a more extreme change.

But what I thought was interesting was just living amongst them and spending time with them, he saw some changes in his microbiome also. But I guess you haven’t had your sequenced yet, but potentially over that week you would have seen the same changes.

[Rob Knight]: Possibly. We don’t have the sequence data for that, although that would certainly be interesting to look at.

I should note that’s also true if you start living with a new partner, for example. You’ll converge on their microbiomes relatively rapidly. And one thing of interest at the moment is trying to figure out how much your microbiome records about the people you’ve lived with and the places that you’ve lived.

We don’t really know the answer to that at this point, but it’s certainly interesting to think about.

[Damien Blenkinsopp]: Well it is, just from a health perspective as well. Especially as it’s getting quite common to have IBS and things like that these days. It kind of makes you question these kind of things. How communicable is it, or not? I guess there’s a lot.

[Rob Knight]: Yeah, that’s a great question. I don’t [think] there’s been done a lot on communicability of IBS, but there are some probiotics that have done pretty well in clinical trials for IBS.

[Damien Blenkinsopp]: Yeah. So we’ve got a solution anyway.

[Rob Knight]: Yeah, and it has been linked to the microbiome by a number of different studies including some work we did with [unclear 44:25]. So yeah, it’s definitely a fascinating area. And the potential that some of these conditions could have microbial cures as well as microbial causes is very interesting.

[Damien Blenkinsopp]: Great, thank you very much Rob.

[44:40] So what are the best ways for people to connect with you, and learn more about you and your work?

[Rob Dunn]: Well, my TED Talk is a really good starting point. There’s a book associated with that Talk called Follow Your Gut, which is going on sale tomorrow actually.

[Damien Blenkinsopp]: Is that on Amazon?

[Rob Knight]: Through Amazon, and also I think it’s available as an iBook through the Apple Store. That’s a good way to find out more. It’s a relatively short book. The idea is to make it a friendly general introduction rather than going into a lot of technical detail about a whole lot of names that you’ve never heard about.

And also it’s got an Appendix that gives you a good overview of how you should interpret your American Gut results, and what things you can and can’t learn at this stage, and what we hope to be able to find out from us in the future.

[Damien Blenkinsopp]: Great, we’ll put links to all those in the show notes.

[45:22] Are there any other good books or presentations for people interested in the microbiome in general, and learning more about it? Are there any references that you commonly give out to people, which are good resources to check out?

[Rob Knight]: Yeah, Marty Blaser’s book. So Marty Blaser’s book Missing Microbes is fantastic, and really gets into a lot of detail about how hygiene and antibiotics may have led to the rise of a lot of autoimmune diseases, and other chronic diseases that are a problem today. And also one specifically about the dangers of over prescription of antibiotics. So I definitely recommend that one.

Ed Yong’s blog, Not Exactly Rocket Science, routinely covers microbiome topics. As do Carl Zimmer’s columns. Michael Pollan wrote a very nice piece in the New York Times in 2012 called “Some of My Best Friends are Germs,” and he’s continued to cover the microbiome on and off since then. Those pieces are all very good.

Jonathan Eisen and Jessica Green both have talks that are available through TED. Jonathan’s talk gives a very good introduction to what microbes are and what they do out there in the world. And Jessica’s features, it’s focused more on the built environment. And it’s talking about the relationship between the microbes in our bodies, and in the spaces we inhabit, and how we might want to design buildings that are green not just in terms of the plants, but also in terms of the microbes. So not just energy, but also microbial use.

So those would be some really good places to start. There’s definitely a lot of more technical resources out there, but you can probably get to those from the ones that I mentioned. And especially the references in Marty’s book and in my book are a good place to get started with more technical material.

[Damien Blenkinsopp]: Great, thank you so much for that. That’s very extensive, clearly.

[47:11] So I’m also interested what your personal approach is to body data, whether it’s for your health, your longevity, or your performance. Do you track and metrics or biomarkers for your own body on a routine basis?

You’ve already said that you take stool samples every single day. Is there anything else you do? And those stool samples, just by the way, for instance if you go to the toilet twice per day, do you take two stool samples, or are you taking one per day?

[Rob Knight]: Initially I was taking one per day, and I’m trying to capture all of them to the extent possible.

So in terms of auxiliary data I must admit that I’m not nearly as diligent as some other people who are interested in this sort of thing have been at tracking every single thing they’re doing every day. In part that’s informed by some of the studies where people have tracked a tremendous number of measures and not seen a lot. So that’s been relatively difficult to justify that level of additional time commitment.

Mostly what I’m tracking are things like, so periodically I’ll do a food and dietary inventory. Tracking things like travel is important. I would track medications except I essentially haven’t had any during that interval. But it’s the sort of thing that I would keep track of if it became relevant. That kind of thing.

[Damien Blenkinsopp]: Great, great. I’m guessing that most of these things are something that you’re doing in the realm of science, because you’re exploring the specific subject.

Do you think you would control for any of these if you weren’t involved in the science itself, out of a personal interest? How would you kind of modify that, if you weren’t currently studying you as an n=1 experiment to further the science? On a personal level, what kind of things do you think you would be doing?

[Rob Knight]: All kinds of things are interesting, it’s just a matter of how much time you’re willing to put into it, and how much money. So it would be very interesting to do blood and urine metabolites frequently, perhaps even daily.

It would be very interesting to get finer grade resolution on fitness, like with an activity tracker, that kind of thing. Given what we’re now starting to find out about brain microbe links it might be really interesting to, for example, track EEG readings over time and draw those microbial data.

You could even imagine doing like an MRI of yourself every day to see whether that complex multifarious specs tracks what the multifarious specs to find biomarker biome. Although that’s definitely a level of efforts and expense that it’s just not worth it at this point.

But what I think this is one of these things where the more data you have, the more potential you have to find out something really interesting that you wouldn’t have expected.

[Damien Blenkinsopp]: Great, thank you so much.

[49:44] The last question, what would be your number one recommendation to someone who is trying to use data in their life for better decisions about their health, their performance, or longevity? Something about their body. What would be your number one recommendation on how to use data effectively?

[Rob Knight]: There are a lot of different ways that could answer that question, but I guess my number one recommendation would be that what’s in the literature, like randomized controlled trials about what works and what doesn’t, are probably a really good guide as to what you should do initially.

Now, you might want to modify that based on observations of your own body, because anything that’s in the literature has got to be based on population averages. And one thing we know about people is that there are tremendous amounts of variability. So what works on average in the clinical trial is not necessarily going to be what works for you individually.

So, start with solid evidence from clinical trials, especially randomized placebo controlled trials, and then modify that based on your own observations about your own health whether it’s meticulously recorded, and you have over a long enough period of time that you have reproducible observations, not just off one anecdote.

[Damien Blenkinsopp]: Thank you there for some great insights into randomized controlled studies, and the averages also, which comes up sometimes on this show. Averages don’t necessarily mean you. So thank you for reinforcing that point.

Rob, thank you also for making time available today. I really enjoyed this show. You’ve obviously got a very, very deep background in this stuff, and we covered a lot of material. Looking forward to read your book also.

[Rob Knight]: Okay, great. Well thanks Damien, and thanks again for your interest in this, and this is only going to get more exciting as we find out more and more about the microbiome.

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Water fasting or ketogenic therapies may be effective with some cancers, and not with others. Learn about the PET scan and how it can provide insights into whether a cancer is likely to be responsive or not to the water fast tactic we’ve covered in previous episodes.

In this episode, we return to look at ketosis and water fasts as a tool to help treat cancer. This builds on the previous episodes looking at Ketosis with Jimmy Moore and the impact of water fasts on cancer with Dr. Thomas Seyfried.

In this episode, we dig deeper into the cancer topic looking at how ketogenic or low-carb diets may contribute via mechanisms related to insulin and ketones to inhibit cancer growth. We look at why only some types of cancers may benefit from these types of ketogenic treatments, and the data behind it. The data backing up this episode, is that of the PET scan — Positron Emission Tomography. PET Scans can be used to understand what type of cancer a person is dealing with and more importantly, whether it is likely to respond to ketogenic therapies or not.

For cancers that are dependent on glutamine more than glucose… They can be aggressive… and they may not show up on a PET scan, and they also may not be responsive to a low carbohydrate diet.
– Dr. Eugene Fine

Our guest is Dr. Eugene Fine. He’s currently a professor of Clinical Nuclear Medicine at the Albert Einstein College of Medicine. Most recently, in 2012, he published a study in the scientific journal of Nutrition on 10 cancer patients treated with a low-carb diet. He’s currently expanding his research by working on the use of low-carbohydrate diets combined with chemotherapy in animals.

This is all linked through his area of specialism, which is PET scans — positron emission tomography — where he has been identifying and monitoring cancers for the use of this type of scan. We’ll also touch on some of his studies looking at the impact of ketones, in vivo, on normal cells and malignant cells, and how that differs compared to glucose.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!

itunes quantified body

What You’ll Learn

  • Reducing carbohydrates in diet and reducing insulin secretion in the body may inhibit cancer growth (4:06).
  • How ketones inhibit cancer cells (10:06).
  • Why are cancer cells over-expressing uncoupling protein 2 and reactive oxygen species (12:35)?
  • Dr. Fine explains how he uses PET scans to identify many different types of cancerous cells and severity by using fluorodeoxyglucose, or FDG (17:32).
  • If the cancer does not show up on the PET scan (as is the case with prostate cancer and glutamine dependent cancers) it may not respond to a low carbohydrate diet (23:57).
  • Dr. Fine discusses quantitating the PET scans (30:50).
  • Any inflamed area might also show up on the PET scan associated with the FDG (32:36).
  • This research is in the beginning phase and needs to be studied on a larger scale as the next step (34:11).
  • Dr. Fine describes his “recharge trial” where cancer patients were put on a low carbohydrate diet to observe the effects of the diet (35:00).
  • During the trial the patient’s blood levels were measured to determine whether they were ketotic (37:42).
  • Dr. Fine discusses the results of this recharge trial by identifying that inhibiting insulin may have effects on cancer progression/remission (40:31).
  • Cancer may adapt to the environment where it “grew up”. So if you develop cancer already on an low carb diet, will not be affected by a low carb diet as an intervention (45:05).
  • Damien and Dr. Fine discuss other ways to change ketone/insulin levels (49:44).
  • High calorie versus low calorie diets are discussed (53:13).
  • The biomarkers Gene Fine tracks on a routine basis to monitor and improve his health, longevity and performance (1:03:29).
  • Gene Fine’s one biggest recommendation on using body data to improve your health, longevity and performance (1:09:14).

Eugene J. Fine, MD

Tools & Tactics

Drugs & Supplements

  • Metformin: A drug which is used to improve blood sugar regulation in diabetes. Researchers are looking at its wider applications with cancer treatment as it has been found to inhibit insulin secretion.
  • Ketone esters and salts: A new range of supplements making ketone bodies directly available to the body and thus inducing ketosis. There are various forms including Beta Hydroxybutyrate Monoesters (BHB monoesters), and Beta Hydroxybutyrate mineral salts (BHB combined with Na+, K+, and Ca2+). One available for purchase is Ketosports KetoForce and Ketosports KetoCaNa.

Diet & Nutrition

  • Low-carbohydrate diet: this programme limits carbohydrate consumption to increase ketosis. This was the main discussion point for this episode.
  • Ketogenic diet: The ketogenic diet is a low carb diet which also raises the level of ketone bodies in the blood.

Tracking

Biomarkers

  • Beta-Hydroxybutyrate/β-hydroxybutyrate (Blood ketones): Ketone bodies can be used as a source of energy, similarly to glucose, for most cells in the body. However, now it is recognized that ketone bodies might inhibit the growth of cancer cells instead of fueling them. Some information about testing ketone levels can be found here. Normally, there should be little to no ketone bodies in the blood or urine. However, ketone bodies increase during a low-carb diet. The most accurate way to measure ketone bodies is through a blood draw but urine tests are also available. More information on ketones and ketogenic diets can be found in episode 7.
  • Insulin: Insulin is a hormone produced in the pancreas and released in response to blood sugar levels and metabolism of carbohydrates and fats. This hormone controls the glucose blood levels to attempt to maintain normal levels. Fasting insulin levels are normally less than 25 mlU/L. After a spike of glucose in the system (after eating) insulin levels will rise but should normally not reach levels higher than 275 mlU/L. Glucose production in the body is inhibited when more insulin is released. Hyperinsulinemia occurs when there is too much insulin circulating in the body.
  • Hemoglobin A1c (HbA1c): Measure of glycated hemoglobin, or hemoglobin to which glucose has become attached – a process that occurs when blood sugar levels become excessively elevated. A proxy measure used to assess your average blood sugar over time. Since hemoglobin is part of the red blood cells it is exposed to blood sugar over the lifetime of the red blood cell, thus giving a measure of exposure over the cells average lifetime (approx. 3 months). As such this measure is used to identify blood sugar control issues. Standard lab reference ranges show anything below 6% as fine, however this already represents blood sugar dysregulation. Optimum HbA1c levels are below 5%. HbA1c has been well researched.
  • Blood Glucose Levels (mg/dL): A measure of the level of glucose in the blood at one point in time. Fasting blood glucose levels are specifically taken when you have not eaten for at least 8 hours and optimally would be between 75 and 85 mg/dL. Health concerns with blood sugar regulation such as diabetes risk start to rise over 92 mg/dL. Levels can be measured at home using a glucose monitor and glucose testing strips (an explanation for the use of glucose monitors can be found in this episode).
  • Cholesterol-HDL and LDL: The cholesterol biomarkers include lipoproteins and triglycerides which are found in the blood. There are standard markers that all doctors and labs will run, and some newer specialist labs that are more specific and accurate. There are two main types of lipoproteins, HDL and LDL. We covered these markers extensively in episode 7.

Lab Tests, Devices and Apps

  • Positron Emission Tomogrophy (PET) scan: A PET scan is a functional imaging technique used to image body processes. As described in this podcast, a PET scan can be used to identify cancer presence and severity. A radioactive tracer, fluorodeoxyglucose, is used to tag these cancerous cells. As discussed by Dr. Fine, the cancerous cells identified in this way may be treated using a low-carb diet as a supplement.

Other People, Books & Resources

People

  • Steve Phinney, MD, PhD: Dr. Phinney has completed research regarding low carb diets.
  • Jeff Volek, PhD: Dr. Volek has also participated in research about low carb lifestyles. Together, Dr. Phinney and Dr. Volek wrote a book called The Art and Science of Low Carbohydrate Living.
  • Douglas Spitz, PhD: Dr. Spitz is a radiation oncologist who has studied the ketogenic diet as an additional treatment for cancer. His research can be read here.
  • The Caveman Doctor: Colin Champ, MD is a radiation oncologist who has researched the role diet plays as a supplemental treatment for cancer.
  • Otto Warburg: Warburg hypothesized in the early 1900’s that aggressive cancer growth is due to energy generated by the breakdown of glucose.
  • Thomas Seyfried, PhD: Dr. Seyfried is interested in fasting and diets used to treat cancer. More information can be found in The Quantified Body podcast.
  • Valter Longo, PhD: Dr. Longo has published many articles regarding fasting benefits for cancer patients.
  • Dominic D’Agostino, PhD: Dr. D’Agostino is well known for his research with ketogenic diets and performance. More information can be found here.
  • Richard Feinman, PhD: Dr. Feinman is a professor at the State University of New York. He has collaborated multiple times with Dr. Fine. Dr. Fine wrote two blog posts on Dr. Feinman’s site: Part 1 and Part 2.


Full Interview Transcript

Click Here to Read Transcript

[Damien Blenkinsopp]: Gene, thanks so much for joining us on a call today.

[Gene Fine]: Oh sure. Good to be here.

[Damien Blenkinsopp]: To give a better background, we spoke to Dr. Seyfried about his ideas and his work on ketogenic diets, fasting, and cancer. And what I found interesting about your work is you’ve dug into different areas, and you’ve differentiated cancers and I wanted to get up to speed about what you’ve been up to. And potentially, also, you’ve got some slightly different views on the whole thing.

So, first of all I wanted to talk about what do you see as the mechanisms of effect behind, if we’re inducing ketosis to inhibit the cell growth of some cancers. How is that working from your perspective?

[Gene Fine]: There really are three linked mechanisms, I believe, that have the potential to inhibit cancer growth. And two of them — well actually all three of them — one is that by reducing carbohydrates in a diet. And we have to realize that most of the carbohydrates we consume are sugars and starches, which digest the sugars — about 90 percent of them.

[And] that if we strictly limit carbohydrate to very low values, we’re inhibiting insulin secretion. And insulin alone is a stimulus to cancer growth. So, if you inhibit insulin you’re reducing one of the important stimuli to cancer growth through that alone. The insulin receptors on cancer cells will be inhibited, and so the growth signals will be inhibited.

[Damien Blenkinsopp]: Is that differentiated? Normal cells have uptake of insulin and they respond to insulin also. Is it that the cancer cells respond to a greater degree? Or what’s the difference there, if there’s any?

[Gene Fine]: No, not at all. In fact, I think the concern would be that the cancer cells may respond to a lesser degree. However, the important thing is that as adults we need some insulin. Without any insulin, we’re Type One Diabetics, but we don’t need much insulin at all.

We need insulin when we’re kids, because kids grow up when they have carbohydrates and protein and insulin helps them grow. When you’re an adult and you eat too much carbohydrates it tends to make you grow sideways. So excess insulin in an adult is not such a good thing; it contributes to obesity and to diabetes.

[Damien Blenkinsopp]: I guess we would throw in body builders in there as well, because they’re always trying to stimulate insulin to stimulate greater muscle growth.

[Gene Fine]: Yeah, well I mean if you’re extremely physically active, you probably can eat whatever you want. I’m not talking about recommendations for body builders; I haven’t studied that. I know that others have. Jeff Volek and Steve Phinney have looked at athletes, and they recommend low-carb diets for them as well.

But the main group that I’m really talking about is the average person who is, unfortunately, a little bit more sedentary than they used to be. And in this group we really don’t need very much insulin to go about our normal activities. And so carbohydrate restriction is probably safe.

[Damien Blenkinsopp]: Right. So would you put protein in there as well? Because protein also can stimulate insulin.

[Gene Fine]: Yeah, that I think is an interesting and maybe more controversial area.

Protein certainly can stimulate insulin. And the question about how much protein to consume in a diet is really an important one, but an independent question which I think has not been answered. I mean, if you look in the literature recommendations for protein in the diet are all over the page; they vary from 20 grams a day to 150 grams a day.

So I don’t know that I’m really in a good position to comment on that because it hasn’t really been adequately studied by anyone, including us. In our own study we didn’t limit protein, so we might have done better than we did if we had.

But nonetheless, our human study did show that the patients that had the highest level of ketosis were the ones who did the best in terms of stable disease or partial remission of their cancers. And those who had the lowest levels of ketosis had progressive disease.

[Damien Blenkinsopp]: So you’re talking about how insulin inhibition mechanism, are they basically opposite correlates? So when insulin goes down [it is] in response to ketosis going up? Is that basically the rough mechanism, so that you could map those to each other? That’s why with a low carbohydrate diet, ketosis goes up and insulin goes down.

[Gene Fine]: Yes. I didn’t actually clarify that. I was saying, yes, that’s the general idea.

I didn’t quite complete the thought that really there are three mechanisms by which a very low carbohydrate diet could inhibit cancer growth, and one of them is, as I say, by reducing carbohydrates in the diet and reducing insulin secretion.

Insulin by itself is a stimulus to cancer growth, but very low insulin will at least have the potential to slow that. So insulin by itself would slow the cancer growth. And there are two cellular mechanisms, so I could insulin twice.

But in addition, there are systemic effects in the whole body, and very low insulin causes mobilization from fat cells — in fact, that’s how you end up losing weight — and the fat gets broken down in the liver. And increased breakdown of fat in the liver leads to production of ketone bodies and ketosis. And ketosis independently, we’ve shown at least in metabolic studies in cell culture, that ketosis itself can cause inhibition of cancer cells. So it can inhibit cancer cells; it leaves normal cells alone. And as I say, we also showed that in our human study.

[Damien Blenkinsopp]: Yes. Yes, thank you. So there’s three mechanisms.

[Gene Fine]: Yeah. Well two of them I consider to be insulin, because there are two different insulin pathways that could be inhibited. And the third mechanism is the systemic effect of low insulin causing ketosis in the liver.

Increased fat mobilization causes ketosis in the liver, and the ketone bodies circulate in the body. Normal tissues tolerate it very well and can use ketone bodies as a fuel, but the cancer cells — at least that we’ve shown in vitro — can be inhibited by them.

[Damien Blenkinsopp]: Great. It’s interesting to look at the mechanisms, just in case later on people discover different tactics for modifying insulin, for example. I mean, like there’s drugs and stuff. Or, for introducing additional ketones or something.

So, we were talking just before the call about the study where you were actually looking at how ketones inhibit some of the cancer cells. Could you talk a bit about that? Because I know there was some glucose and ketones involved, and it was interesting how it’s done.

[Gene Fine]: Yeah. In cell culture studies, when we started this a few years ago, we studied three different normal tissue lines that were fibroblasts, which are normal connective tissue that we have in our body. And we also studied seven different cancer lines. Five colorectal cancer line variants and two breast cancer lines.

And what we found was that all seven of the cancer lines — well we grew all of the tissues for four days in a cell culture in glucose medium. And we saw how much they grew. But in parallel with that, we also grew the same cells in glucose medium but with added ketone bodies.

And, as I mentioned before, ketone bodies are a nutrient for normal cells, so we didn’t expect there to be any problems in the fibroblasts, and in fact the fibroblasts continued to grow normally when we added another nutrient.

However, all seven cancer lines showed growth inhibition. And they had differing degrees of growth inhibition when we added the ketone bodies. And we found that the degree of inhibition of the cancer lines was proportional to how much they over-expressed a particular protein called uncoupling protein 2, which actually reduces the efficiency of the cell in producing ATP.

So it turns out that the cancer cells were producing less ATP than they ordinarily would when we added ketone bodies. So the ketone bodies were metabolically inhibiting ATP production, and in proportion to their over expression of this interesting protein.

And the degree of ATP inhibition was exactly proportional to the degree of growth inhibition, which makes a lot of sense. That it requires ATP to grow. So that seemed to be pretty good evidence that we had at that point that it could be metabolic inhibition of cancer cells by these ketone bodies.

[Damien Blenkinsopp]:Yeah, that’s interesting, because, like you said, you’re actually adding something, you didn’t change [anything else]. You’ve got the same amount of glucose, so theoretically, even if cancers couldn’t process the ketone bodies very efficiently, they have the same amount of glucose there. So, in theory they could have been okay. But you’ve actually shown that somehow the ketone bodies are inhibiting that.

Would it be fair to say that the cancer cells are trying? It’s like they’re taking in the glucose and the ketone, and that they’re trying to process that. But because of the inefficiency, they’re not able to. Because it’s kind of interesting that it’s got this inhibitory mechanism there. It’s like they’re trying to, but they’re not very successful at it.

[Gene Fine]: Right, and one of the big questions is, of course, why are the cancer cells expressing uncoupling protein 2. And this has been observed that cancer cells were expressing uncoupling protein 2, for at least 10 or 15 years. There were studies in the early 2000s that I first saw that got me clued into the fact that they were doing this. And I thought well what could uncoupling protein 2 do to a cancer cell, and why would they do that?

The general explanation that I’ve adopted is that cancer cells also overproduce, what are called reactive oxygen species. And reactive oxygen species are chemically active molecules that are produced in all tissues, normal cells as well. But they’re higher in cancer cells than they are in normal cells.

And the thing about reactive oxygen species is that they actually act as sort of a two edged sword. They’re required for normal cell signaling. They’re a signaling molecule that helps cells grow, and develop, and proliferate, and so forth. However, they also are very chemically active and can cause mutations.

And mutations are also somehow the life-blood of cancer cells. Cancer cells become cancerous on the basis of mutations, and in fact they’re sort of evolutionary masterpieces in that they continue to evolve because of mutations. If a particular cancer mutation kills a singular cancer cell, well that’s fine, that cancer cell dies. But if another mutation that happens to be caused in another cancer cell makes that cancer cell even more aggressive, well then the cancer becomes more aggressive.

So, reactive oxygen species when over-expressed in cancer cells actually provide a mechanism for continued growth and continued development as an aggressive cancer. The problem, of course, is much too high reactive oxygen species will kill a cancer cell, as they will kill any cell. In fact, it’s very high levels of reactive oxygen species that are caused by chemotherapy, and are caused by radiation therapy.

So there has to be a limit on how much reactive oxygen species a cancer cell can actually produce. And what I believe, and I can’t say that I’ve proven this at all, is that the increased expression of uncoupling protein 2 — uncoupling protein is in fact, or believed, to limit reactive oxygen species. So it makes sense to me, but without proof, that the reason — quote unquote reason — for the increased production of uncoupling protein 2 is to provide a natural limit. A higher limit than a normal cell, but a limit on the amount of reactive oxygen species that the cancer cells produce.

So that’s my my overall belief. UCP2 is there for a reason. But it happens, it just happens, that that reason, which is important for the cancer cell, may actually be exploitable in terms of diet, because it also reduces the efficiency of production of ATP. I don’t know if that exactly adds up, but that’s what I believe.

[Damien Blenkinsopp]: Yeah, my understanding is — I’m just trying to re-summarize from what I understand and how it fits in — mitochondria create reactive oxygen species, and they tend to do that more with glucose fuel than with ketone fuel at a higher rate. And also when they get damaged they tend to create more reactive oxygen species, so they’re not as efficient. Does that fit in with what you just said?

[Gene Fine]: Yes.

[Damien Blenkinsopp]: Okay, great. So, somehow it seems like when the ketone bodies are being used though, in this scenario it’s potentially creating more reactive oxygen species via ketones, because of the protein change there?

[Gene Fine]: I think that’s not really clear. I don’t believe the ketone bodies… Other people who have looked into this a little bit, I think, are somewhat ambiguous about it as well.

I don’t believe that ketone bodies cause increased reactive oxygen species, but I can’t say that I know that for certain. I do believe, from at least the mechanisms that we’ve explored, that ketone bodies provide a complementary way of inhibiting cancer growth metabolically. If they also produce increased reactive oxygen species, and therefore contribute to higher levels of reactive oxygen species that are cell killing, that would be interesting.

But I don’t have direct proof of that. I believe that’s been suggested by others. Possibly Doug Spitz who’s a radiation oncologist, and I don’t know but Colin Champ, who is also a radiation oncologist. He’s written about this, but I’m not sure he’s described increased reactive oxygen species production through ketone bodies. It’s possible.

[Damien Blenkinsopp]:Alright, so great. There are some mechanisms you’ve been looking at there.

And another that’s been interesting about your work is that you’ve been looking at the differences between the different cancers in your studies with PET scans, which is of course your background and your area. Could you talk a little bit about the PET scan and how you use it to assess the cancer?

[Gene Fine]: Yeah, sure.

Most cancers — most aggressive cancers I should say — end up becoming, well first of all they begin to outstrip their blood supply. Their blood supply becomes erratic, and instead of having blood vessels well supplying nutrients to the cancer cells, the cancer cells become relatively hypoxic; they don’t usually have enough oxygen. And hypoxia will interfere with the ability of a cell to use the Krebs cycle as a means of developing energy.

So most cancer cells actually depend on glycolysis, which is anaerobic glucose metabolism, in order to develop their ATP. Now, because they’re using so much glucose and they over express glucose transporters and glycolytic enzymes, because they’re using so much glucose, if you inject a glucose like tracer — a radio tracer — whether it’s carbon-11 glucose, or another one that we liked to use in general nuclear medicine, fluorine 18, fluorodeoxyglucose.

This is a glucose analog, and it gets taken up very avidly by cancer cells that are aggressive. These aggressive hypoxic cancer cells take up FDG very avidly. There’s also something called the Warburg effect, which Otto Warburg, famous biochemist, demonstrated 100 years ago that aggressive cancers, in fact, they may be hypoxic but that even if you expose them to normal oxygen conditions, they still retain this glucose and glycolytic dependence.

In any event, the result is the same that aggressive cancers light up on a PET scan if you inject a patient with FDG, with fluorodeoxyglucose. And a PET scan is basically a nuclear medicine study. These radioactive tracers give off emissions, which allow you to see where the radio tracer goes.

So FDG distributes through the body. Glucose is used by a lot of tissues, so you can also see the heart, you can see the brain because these are often glucose utilizing structures. However, you don’t expect to see FDG in locations where it shouldn’t be. But if you have metastatic disease, which these kinds of hypoxic glucose dependent cancers, FDG will go to those sites as well.

And in fact this one image can be used, or a total body PET scan using FDG can be thought of as a one step metastatic workup, because you can actually see the full distribution of cancer cells throughout the body.

[Damien Blenkinsopp]: So is this the gold standard for assessing the severity of cancer? Could you give us an idea of when you would use this kind of scan?

[Gene Fine]: Yeah, everything in medicine really is very empiric. So if it works, it works. And certain cancers are particularly avid for this kind of tracer, where they do become hypoxic glycolytic cancers. And it’s turned out to be useful in management of cancers in one way or another.

For example, in a solitary pulmonary nodule, you’re trying to determine if this is likely to be a cancer or not or if it’s a benign module. Benign nodules don’t tend to take up glucose that avidly, but the malignant ones do. So an FDG scan can be very useful in just a diagnosis of whether a lung nodule is in fact cancerous.

But PET scans are useful in the management and decision making processes of breast cancers, of uterine cancers, actually a variety of lymphomas, in particular, are usually quite avid and PET scans can be quite helpful. Esophageal cancers, gallbladder cancer, colorectal cancers, PET scans can be quite useful because they light up, and they show you not only where the tumor is, but where the metastases are.

[Damien Blenkinsopp]: And the other thing, I guess it would simply appear bigger if it’s getting worse? So on your PET scan, if you did one every three months with a cancer patient and it was getting worse, you’d see it getting bigger and potentially spreading to other areas of the body. Is that how it comes back?

[Gene Fine]: Yes, you can definitely see how it spreads.

And nowadays I should actually say that most PET scan devices are actually two devices in one. They’re PET and CT, CAT scans. So you actually can get even better information, because the CT scan is really a computerized three-dimensional x-ray. So you’re actually able to see exactly where in the body.

The PET scan doesn’t have a road map of the anatomy, it’s just where the fluorodeoxyglucose goes. But on the CT scan, it gives you the underlying anatomy, so you get the anatomy as well as the functional arrangement at the same time and in the same locations. So you can identify exactly where you’re seeing it. And that’s very helpful.

I should actually mention that there are certain cancers that PET scans are not useful for. For example, pretty notoriously, prostate cancer is an unusual cancer. It’s unusual in a lot of ways.

Actually 80 percent of prostate cancers are rather slow growing and indolent. And probably for at least that reason, that may be one expression of the reason why they don’t actually take up glucose that avidly. It’s usually the aggressive [cancers] that take up FDG.

But also some other cancers, such as mucinous cancers that are filled with so much mucin that you lose out the effect of what you see on a PET scan. So mucinous cancers of the colon and the of the lung often don’t take up much fluorodeoxyglucose.

Squamous cell carcinomas of the lungs of course are very avid, but these mucinous ones are not. And endocrine tumors, very functional, they’re often not as glycolytic. They often operate on oxygen and they can have a normal Krebs cycle and normal metabolism. So thyroid cancers, unless they’re extremely aggressive, are not this slow growing, and they take up much less FDG. So PET scans with FDG are not as useful for certain kinds of cancers, such as these.

[Damien Blenkinsopp]: That’s important because — tell me if this is over simplifying — anything that doesn’t show up in a PET scan, would it be less likely that any type of low carbohydrate diet or inhibition of insulin and up-regulation of ketone is going to have an impact on it, as we’ve been talking before?

[Gene Fine]: Yes, true.

In fact that’s very interesting because — I was mentioning prostate cancer before — prostate cancer actually, it’s not even approved for PET scan use, I should mention. Because they say 80 percent of prostate cancers don’t take up FDG. But in fact prostate cancer is also not associated with obesity. It’s not associated with hyperinsulinemia. It’s not associated with high glucose levels in the blood.

In fact, interestingly, there’s an inverse association of diabetes with prostate cancer. Patients with diabetes — it’s a little bit odd to use the word, because I’m not sure that it’s accurate, it may not be cause and effect, but it’s at least an association — are so called protected with diabetes against prostate cancer.

Now I don’t want to recommend getting Type 2 Diabetes to protect yourself against prostate cancer, but the point is that not all cancers would respond to a low-carb diet either. It doesn’t seem to have anything to do with the mechanism of that particular kind of cancer.

[Damien Blenkinsopp]: Right. The mechanism you described earlier was higher insulin would lead to more aggressive cancers, but in this case you’ve described, Diabetes 2 you’d have higher insulin, but it’s actually reducing the likeliness of getting prostate cancer. Is that correct?

[Gene Fine]: Yeah, it appears to be. As I say, at least epidemiologically, it fits the mechanism of the — I should also mention that 20 percent of prostate cancers are actually very aggressive.

So this is a distinct minority of prostate cancers. I don’t know that anyone has done much study of whether these aggressive prostate cancers, this subvariant, which grow much more rapidly, actually are glucose dependent. They may well be, but I don’t know that they’ve been studied this way. So I can’t comment on those. But they might be FDG avid.

The other thing though is that actually aggressive cancers, very aggressive ones, not uncommonly develop a taste for, not glucose, or not just glucose, but also an abundant amino acid that circulates in the blood called glutamine.

For cancers that are dependent on glutamine more than glucose, they might have even bypassed. They can be aggressive, and they may be glutamine dependent, so they may not show up on a PET scan, and they also may not be responsive to a low carbohydrate diet. So there are other subtleties here that have to be explored before knowing exactly what to do in these kinds of situations.

[Damien Blenkinsopp]: Well I’m guessing potentially restricting glutamine might have a kind of impact there. I guess there’s no studies that have been done on that.

[Gene Fine]: That’s hard. It’s hard to do that, because glutamine is synthesized by the body, and it just comes out of ordinary metabolism.

Glutamine and Glutamate are products of protein metabolism. Glutamine can actually be synthesized, glutamate can be synthesized from alpha ketoglutarate, which is a product of ordinary metabolism. So it can actually be synthesized, and is, and then circulates in the blood steam in high concentrations. And you can’t really restrict glutamine in a diet and expect glutamine to go away; it won’t happen.

I think there are approaches that are trying to figure out how to limit glutamine in the blood, but I’m not sure how successful they are. It seems to be an important metabolite and substrate for a lot of different mechanisms. It’s actually used by the brain, indirectly at least. And so, there really are glutamine restrictions, I think, is something still for the future.

[Damien Blenkinsopp]: In summary out of everything you’ve been saying, that the fasting approach or the low carbohydrate approach is, in your view, only applicable to some types of cancers, and typically the most aggressive ones.

[Gene Fine]: Yes, I would agree with that.

The other thing I should mention is that the fact that there are plausible mechanisms where cancers could be inhibited by a low carbohydrate diet, cancers of the types that we’ve been discussing, doesn’t guarantee that it would be inhibited.

And I should also mention about the PET scan, that a PET scan in the way we used it in our clinical pilot study in 2012 with 10 patients was that the PET scan indicates that we can at least identify a cancer that is glucose dependent. We can do that on a PET scan. So those, from the perspective of our hypothesis are carbohydrate, or at least have the potential to be carbohydrate restriction sensitive.

It doesn’t guarantee it, because we don’t actually know which cancers will have the appropriate characteristics and qualities. Maybe not all cancers will express uncoupling protein 2, or whatever other mechanism we were describing earlier. So we can’t guarantee it.

And in fact, if I would describe the hypothesis that I believe, it’s that — I actually have this on a slide in front of me because I like getting the wording exactly right — that large cohorts of individuals with cancer in the developed world do not experience sustained ketosis, or other features common to the insulin inhibited very low prone state. We’d expect many cancers to express a range of plausible vulnerabilities, and accidental adaptations to this unfamiliar metabolic microenvironment.

So, I think that’s the broadest statement that I feel comfortable making, that we can’t guarantee that an individual cancer is going to be responsive to this, even if it has a positive PET scan, because we don’t yet know all of the characteristics that are required. But we do believe that those kinds of cancers are at least eligible for that possibility.

[Damien Blenkinsopp]: Right. Well so it sounds like at the moment there’s nothing really concrete on this, but we think there’s a higher probability of some types of cancers, so that the most likely cancers to respond to this would be ones which tend to be more glucose dependent.

[Gene Fine]: The ones that show up on PET scans would be the ones that would have eligibility. So, we actually treated in our 10 patient study a range of patients, and there were several with lung cancers, there were several with breast, several with colorectal. There were a couple with esophageal [cancer]. So those were the ones that we actually treated.

This was a very small study, so it’s a little hard to generalize from them. But in addition, as I say, the ones that are associated with hyperinsulinemia and hyperglycemia could also be eligible, I would say; endometrial, uterine cancers, perhaps pancreatic cancers, and others have actually begun studying that as well. Possibly kidney cancers, and maybe gallbladder cancers as well.

So these are the ones that I would consider to be at least potentially eligible for this, depending on what else we learn.

[Damien Blenkinsopp]: Great, great.

Particularly in those cases, if I have cancer I’d probably want to get a PET scan to see if it lights up.

I don’t know if you have an index there or if it’s just something visual you use. Do you have any kind of index you use with PET scans to understand the severity, like how much is lit up?

[Gene Fine]: Yeah, there are ways of quantitating PET scans, and you can eyeball the uptake, which is often done for purposes of saying whether the cancer has spread to a location or not. If you have a primary.

But if you have a, I like using the solitary pulmonary nodule because so many of them are benign and others are also malignant. And so people have attempted to develop quantitation, and there are a variety of different ways. One of the common ones is called the standardized uptake value.

And you compare the uptake there, essentially, to the average uptake in the whole body. And a value has been assigned by a number of investigators as a cut off that can be useful, and that’s an SUV of 2.5. That’s two and a half times the average value in the body is assigned as being a cutoff for cancers.

Now all these cutoff values have overlaps, and some of them turn out to be benign, but the frequency tends to be much higher. And the higher the SUV the higher the likelihood for cancer.

The reason that there can be uncertainty in this is that the uptake of fluorodeoxyglucose can also be seen in inflammatory tissues, and inflammatory situations, for example even in pneumonia. You can see pneumonias take up FDG. You can see benign granulomas take up FDG, although they usually take up less. But in fact you can get false positives.

[Damien Blenkinsopp]: Oh, so could this be any type of inflammation in the body? Basically where white blood cells are active?

[Gene Fine]: Yes.

[Damien Blenkinsopp]: And there’s a lot of inflammatory conditions in the gut these days. Is that something that would potentially influence it?

[Gene Fine]: Yes. You do in fact. With the colon there are also patterns of uptakes, so the thing is inflammatory conditions in the intestines and the colons, for example, usually there are patterns of uptake, and you actually see an outline of the colon with FDG distributing itself throughout the colon and basically showing the shape of the colon.

Whereas cancers usually have a site of origin and they can be somewhat irregular. But they generally have a round or a spherical type of initiation and shape. And come in clumps. So there is usually quite a big difference between what you see intestines and that as well.

But these are non-invasive diagnostic tests, which are absolutely marvelous because things used to be much more invasive. But they do have false positives. Your goal in a non-invasive test is to be able to screen well, and therefore identify those patients who may have this condition.

And if it’s negative it can be extremely helpful because then the patient doesn’t have it. But if you do have it you may still have to, in some cases, go on and do a invasive biopsy in order to determine what’s actually there.

[Damien Blenkinsopp]: So I guess, just to be practical for anyone at home that might be related to some cancer case or perhaps working with cancer patients. So if it does come up a positive PET scan, it may be worth using a ketogenic diet, a low carbohydrate diet as one of the tools. Could you just confirm more, and tell me that that’s not correct. And then talk a little bit about your recharge trial, where you were actually looking at this.

[Gene Fine]: Sure, okay. I think that it’s hard to generalize. I have spoken, patients have found me on the internet and have called me and discussed their particular cancer situation. And I don’t consider myself explicitly an advocate for this, simply because a 10 patient study — which I’ll talk about in a minute, our recharge trial — is a very small study, and it’s pretty hard to generalize from a study of 10 patients.

But it’s not appropriate to make a scientific conclusion when generally the standard of evidence is that you have to do large, randomized controlled trials. However, that would be the direction I’d like to go to find out more information. And also the fact that it certainly is uncertain whether this works in all patients with PET positive cancers.

But I can talk a little bit about the recharge trial, as preliminary as it is. And what we did was we studied 10 patients with advanced cancers, which is to say they all had PET positive studies and they all had failed several rounds of chemotherapy and were still progressing. So they had had chemotherapy, they were therefore eligible for an experimental trial of the diet, because nothing really was working anyway.

And these patients signed informed consent and they were told that we didn’t know what the outcome was going to be, but we were going to put them on a 28 day trial diet of very low carbohydrate. And so the patients agreed to this, and for 28 days under nutritionist and dietitian guidance they were taught to change their diet.

They had a two to three day trial diet, just to see if they hated it, to make sure. If they didn’t hate it then they could go ahead, but we didn’t want to have people who were clearly not going to be able to complete the diet. We limited it to 28 days because change in diet is hard for anybody. It’s not easy. However, just about anyone can stay on a diet for a month.

So we figured that this would give all the patients a chance to succeed. And principally, the first goal we had to have was safety and feasibility. Was this actually safe? There wasn’t really a lot of reason to believe that it wasn’t safe, but you still have to try that out before you can do anything else.

And it was, there were no unsafe adverse effects. The worst effects that sometimes were reported in this, that we did see were some patients had some reversible constipation — as I say reversible — and reversible fatigue within a couple of weeks. And that’s generally the worst that happened.

So the patients were able to span the diet. Half the patients stopped a little short of 28 days, like 26 or 27 days. We considered that really a successful completion. They didn’t stop because of the diet, they stopped because these were patients with advanced cancers who had planned before they had heard about this trial to go on vacation.

They had bought tickets and thought this might be the last vacation they would be taking. So we weren’t going to interfere with that, and we got the PET scan two days earlier than we had expected and they then left the next day for vacation. So really everyone completed the trial without any adverse effects.

Now, what we did see was that, and we measured ketosis as the standard for how compliant they were. Patients would report their food intake and they would tell us what they ate, and the dietitians would record that. But food recall can be inaccurate.

The most reliable way we could determine whether they were on a ketogenic low-carb diet would be to measure ketone bodies in the blood. And we did find that all of the patients were ketotic. In fact all of them became ketotic — and we measured this weekly for four weeks, a baseline and then four weeks — patients became ketotic really by the end of the first week. So we know that they were ketotic for the period of the four week trial.

[Damien Blenkinsopp]: Were you measuring blood levels?

[Gene Fine]: Yes, these were blood levels. We felt that that was going to be a more accurate measure because urine levels can be influenced by hydration state. If you’re very hydrated you’ll dilute your urine, if you’re dehydrated you’ll concentrate it. So this is more accurate.

[Damien Blenkinsopp]: Yeah, absolutely. We discussed this with Jimmy Moore, who you know well, in a previous episode.

[Gene Fine]: Oh yeah, that’s right. And he actually interviewed me one time as well. That’s right.

So the goal, as I say, was the 28 day diet. And what we did find was that, one patient we actually had to exclude from analysis because, it took us four years to recruit 10 patients. Most patients are on chemo and they don’t really have this opportunity.

And we also didn’t want patients who were too thin because that would have trouble getting past the investigational review board. These are thought of as weight loss diets and you don’t want a cancer patient to lose too much weight. So we had to restrict our patients to patients who were normal weight or above.

Now finding patients with advanced cancer who had not lost too much weight took a long time to get this group of patients together. It took four years to recruit them, there was a lot of time in that.

So beggars can’t be choosers, and we didn’t notice that one patient had had advanced breast cancer with chest wall invasion, but she’d had it for 14 years. And this was different from all the other nine patients, who had failed multiple chemotherapies. She’d had this for 14 years and had never sought any treatment for it at all. She had no surgery, she had no radiation therapy and she’d had no chemo.

So in retrospect we realized, oh my gosh, this patient clearly has much more indolent disease. Even though it’s advanced, it’s progressing so slowly we would have to exclude this patient from analysis because in one month she wouldn’t show change.

She was stable from that point of view, so we couldn’t show progression of disease in this patient in a one month diet. And it turns out she wasn’t very compliant with the diet anyway, and she showed very little change. So the reality was we had to exclude this patient. So we really only evaluated nine patients.

Anyway, getting to the gist of that, of the nine patients the results on the face of it were really not terribly impressive; five patients showed, well four patients showed stable disease, one patient showed a partial remission on the PET scans. We had a baseline PET scan indicate the patients had glucose dependent cancers, and we had a follow up PET scan to monitor the change in the PET scan as an index of whether these patients responded in some way.

But four patients had continued progressive disease. So on the face of it, this is really not that impressive. However, the interesting thing about the difference between these patients is that the patients who had the stable disease or partial remission had three times the levels of ketosis compared to those who didn’t.

So the fact was that whether this was an issue of compliance or metabolic effect, whatever that was with the level of compliance they achieved, the reality was that the patients who showed the best responses were those who had the most ketosis. So that was also consistent with our hypothesis that the ketone bodies and the effect of low insulin levels, which would include ketosis, would have some varying on the outcome.

[Damien Blenkinsopp]: So did the same thing show up? The higher the inhibition of insulin the better the result?

[Gene Fine]: Yes,that’s essentially what we’re saying. That the more it was inhibited, it’s effects were best measured by measuring ketone bodies. Insulin itself varies so rapidly that unless you time it exclusively the same way, timing after a meal and so forth, you have to be very careful. So we use ketone bodies as a more robust measure of the effects on insulin inhibition.

[Damien Blenkinsopp]: So is that pretty concrete then? That there will always be an inverse correlation? That that’s been established very well in science?

[Gene Fine]: An inverse correlation between ketone bodies…

[Damien Blenkinsopp]: Because as you say, insulin can go up and down very quickly so it’s kind of difficult to know where it is. But in scientific studies it’s been pretty well established that insulin is inverse to ketone bodies, so then it’s okay to assume that.

[Gene Fine]: Right, but they act on different time scales. Insulin spikes very rapidly after a meal, and ketone bodies gradually build up over a period of days after chronic low insulin levels.

So you can go out of ketosis fairly quickly, but not as quickly as you can spike. You can spike an insulin level pretty level and the ketone bodies will decrease over a period of hours, the insulin levels change rapidly over a period of minutes. It’s a little bit different time scales, but yes there is a general inverse relationship for chronic insulin levels and ketosis.

The other thing I wanted to mention about this is that the patients who did show progressive disease also showed evidence of, which we weren’t really looking at, we wanted patients who did haven’t coincident other diseases, particularly diabetes because we didn’t want to be treating two conditions at the same time. So we basically made sure that the patients were not diabetics and were not taking diabetic medications.

However, in retrospect we did notice that the patients who showed progressive disease had evidence of pre-diabetes. That these were patients who were the four heaviest, they actually were the four heaviest of the group of 10 patients. They also had baseline glucose levels 100 and above.

There was more evidence of pre-diabetes in this group than there was in the group that showed a response. And there were lower levels of ketosis. So, overall, we don’t know for a fact that this is the way to screen patients, whether this is actually a biomarker. I would suggest that it makes sense that in patients who have pre-diabetes, pre-diabetes is marked by high insulin levels, and it takes quite some [time].

So that in this group, a low-carb diet didn’t seem to have much benefit. In fact, it didn’t have any benefit at all, they had progressive disease.

Now of course the way you want to treat, at least the way I like to treat patients with pre-diabetes, is put them on a low-carb diet. But I think that that would take several months to improve their insulin insensitivity, and if they already have cancer that’s probably not what you want to do in this particular group. If they have cancer and they have pre-diabetes, you’d probably have to treat the cancer as a separate entity.

[Damien Blenkinsopp]: Right, because it’s going to take a longer time to have the metabolic impact that you want.

[Gene Fine]: Right, and you don’t want the cancer to be progressing during that time, so you probably have to make your choices in that case.

[Damien Blenkinsopp]: So, from your study I remember one thing you were doing was in order to assess the better performers was you were looking at the relative ketone change.

[Gene Fine]: That’s right. And we actually, we used relative ketosis, interestingly, rather than absolute. Now, the absolute ketosis was not very different in the two groups. But I actually believe the relative ketosis is more important, mainly because — let’s see if I can describe that succinctly.

When you looked at the baseline ketosis, baseline levels of ketone bodies, absolute values.

[Damien Blenkinsopp]:: So this is before you start the low-carb diet?

[Gene Fine]: Fasting levels, right.

There were some patients who had issues of values, who had like 0.04 millimolar. And then there were others who had 0.4 millimolar. So that’s factor of 10.

Now, the absolute levels of ketosis rose in most patients to about 1.0 millimolar. A patient that only went from 0.4 to 1.0 went up by a factor of just two and a half. A patient that went from 0.04 to 1.0 went up by a factor of 25. So there is a much bigger change in the overall metabolism, and the change of the metabolism in a patient that started at a lower value.

I would propose — and this is what I actually believe — is that the patients who were living with a baseline ketone body level of 0.4 were actually acclimating their cancers to a higher level of ketosis during the period of the cancer’s growth, initiation, and development. And in fact that these cancers may be well acclimated, in other words adapted to, that they grew up in a level in which they were used to these levels.

And so that you can’t expect — well, put it this way. Whereas I do believe that people who live in environments where they eat mostly meat and fat during the year — let’s just say Inuits for example that haven’t been exposed to McDonalds and Laps living in northern Finland and live on reindeer meat all day long — that people who live under those conditions I would suggest, and I don’t know what the evidence is exactly, that they will have lower incidences of cancer.

However, should a person under those circumstances develop cancer, you know you sure as heck would not put them on a low-carb diet, because you know that they developed cancer already on a low-carb diet.

So that’s what I’m basically saying. If you have somebody who already is in a state of higher levels of ketone bodies and cancer develops in a person like that, then you certainly wouldn’t expect that patient to be as responsive to a low-carb diet.

[Damien Blenkinsopp]: It’s interesting because there’s a lot of things in biology, like somatic signals, where, like if you think about the treatment of antibiotics, right, you basically have to pulse it. You have to pulse it and do it one go has to be done effectively. If you get chronic antibiotics for a while then it stops having it’s impact, and you don’t get the benefits, and so on.

So it’s interesting that you identified this mechanism where a body could be a lot more beneficial to, let’s say do something. I mean I’m sure you’re aware that Dr. Seyfried recommends a five day fast, which is a more extreme version of what you did in your study, and potentially may be more beneficial because it is more extreme. As you said, and maybe there will be a higher therapeutic value.

[Gene Fine]: Yeah, that’s right. And Dr. Seyfried is one, also Valter Longo in California has recommended calorie restriction and fasting as well. And I think that those methods may have some other unique benefits that carb restriction may not have. They also may not be as easy to implement, but I think that they’re all in the ballpark, and there may be values for all of them.

[Damien Blenkinsopp]: So one thing I did want to bring up is when we were talking to Dr. Seyfried he mentioned he’s using an index now, which is called the glucose ketone index. I don’t know if you’ve spoken to him about that, or come across it.

It’s simply glucose divided by ketones in millimolars. And he’s been using that to look at his approach to metabolic therapy and see if it’s effective. I’m just wondering if you could compare that to the relative ketones. Would that make sense for you, or you haven’t looked at this?

[Gene Fine]: I haven’t done that, so I really don’t feel up enough to comment on it. I didn’t do that. I actually might want to go back and calculate that as well in these patients to see if I can get those numbers and make some correlations. But I haven’t actually done that yet.

[Damien Blenkinsopp]: Yeah, it strikes me it just might be interesting because, as you said, some of the diabetic patients went up, potentially high glucose. So you might see something similar there. Based on it.

[Gene Fine]: Yeah, that’s right. I was just thinking about that.

[Damien Blenkinsopp]: Great, great.

There’s a few things I wanted to bring up here in terms of the other tactics people might use. Which I don’t know, you may not have an opinion on these. But there are other things that can change the levels of ketones in our body. You can use MCT oil, or ketone esters, exogenous ketones basically, or a high fat diet.

My personal experience with these, for instance, is I’ve been on a high fat diet for a while and in my fasting insulin tests, my insulin is pretty low compared to the average. And I understand that that’s pretty standard. So I was just wondering what you thought of these kind of approaches. Also, if you’ve seen anything that might say there would be similar impact. Because they’re basically mimicking the effects of a low carbohydrate diet.

[Gene Fine]: Well yeah, I actually don’t know what way a high fat diet is distinguished from a low-carb diet. There are three macro nutrients, and basically a low-carb diet is a high fat diet. I don’t know if a high fat diet necessarily is also a low-carb, but it must be lower in carbs because you don’t really make up the difference in protein.

[Damien Blenkinsopp]: Right, you’re right. The question is the protein. That’s the missing…

[Gene Fine]: Right. And as I say, I haven’t tested the protein values. We didn’t restrict protein in our group. I think we could have.

We were dealing with patients who, as I say, had advanced cancers, and we were getting them as through referrals from their oncologists as volunteers, and we really didn’t want to give them something too complicated to do, so we just tried to [simplify it]. But yes, protein, certainly restriction might have had further benefit.

But as far as inducing ketosis with medium chain triglycerides, coconut oils and the like, ketone esters, I think these are interesting approaches. They can certainly, possibly offer more convenience, rather than going through a low-carb diet. And that I think has value.

The other thing to note is that they don’t actually mimic the full effects of a low-carb diet because they don’t inhibit insulin. So, there is that aspect of it. While there may be value, I’m not sure that they’ll produce the full effect.

[Damien Blenkinsopp]: Great, great. Thanks for the commentary.

Now the other thing I wanted to just bring up was metformin, I don’t know if you’ve looked at all at that.

[Gene Fine]: Well, yeah. I mean, I’m aware that this is being used, at least in trials, as another potential mimicker. And it has it’s own value. I think what it does for me is it illustrates the value of low-carb diets, because what it really does, metformin, is it limits glucose and thereby insulin secretion. So, it’s fine. To me it’s major mechanism is the same mechanism as a low-carb diet.

It has some independent mechanisms. It seems to up-regulate AMP kinase, which happens also to be done by low-carb diets. So metformin may have some advantages. It’s a drug. It’s a very well tolerated drug, but it’s not a universally well tolerated drug.

There are some side effects that have been reported. Not frequently, but some patients develop lactic acidosis, which can be very serious. And some patients develop hypoglycemia. So, I think overall it would be considered a very safe approach, it just has to be tested, like everything else.

[Damien Blenkinsopp]: Great. Thank you.

I was wondering if you had any opinion on calorie deficit versus high intake of calories. I could be on a high fat diet, or a low carbohydrate diet, and still have a surplus of calories versus a deficit. Do you think that’s anything that could be either affecting your results, or something to look at?

[Gene Fine]: Yes, it is something, definitely, to look at. The calorie restricted approach has been advocated…well, it’s just been advocated. I can’t say exactly whether the mechanism is the same, overlapping, or somewhat different.

But I can just say this, that in our study we actually wanted patients to not lose weight. We encouraged them to overeat. Overeat a low-carb diet, but overeat. So to eat as many calories as they needed to sustain their weight.

So the only comment I can make about this is that all the patients lost weight. We did not intend for them to lose weight, that was not our goal. We encouraged them, we would be weighing them weekly and we’d tell them, “Eat more, eat more. You’re making these shakes, add more cream to it. Add more oil to your foods. Put butter on everything.”

Well anyway, whatever it is that we encouraged them to do, all 10 of them lost weight. They lost on average about four percent of their initial body weight. The interesting thing about that, I just suppose that this is why these diets are effective as weight loss diets.

No one knows exactly why they work, but you certainly can speculate some pretty plausible mechanisms. One is that ketosis may inhibit appetite. Another is that your inhibiting insulin, and insulin, as I say, under the influence of carbohydrate makes you fat and keeps you fat. The absence of insulin does the opposite. It releases lipids from your fat cells, and metabolizes them in the liver. So the fact is that low-carb diets intrinsically may be weight loss diets.

We believed in our study that it’s possibly to defeat this. That there’s such a thing as overfeeding, and maybe if one is particularly conscious about this, one can do this. But the other interesting factor is that seven out of the 10 patients were above a body mass index of 25, which is to say they were overweight. Only three of them were in the normal weight range, between 20 and 25.

And as it happens, the patients who lost the most weight were the heaviest. Frankly they were delighted with their weight loss, even though we were trying to maintain weight just for the principles of our study.

The patients who were in the normal weight range, the two who were the higher two in the normal weight range — I should say, the heaviest patients lost about five to six percent of their body weight. The patients who were in the normal weight range, the two heavier of them — 25 BMI and 23 — lost about three percent of their body weight. And the patient who was 20 lost no body weight at all.

So what this tells us is something we all know also, which is that the closer we approach our ideal body weight, the harder it is to lose weight. I don’t know whether you’ve observed that yourself, whether you have gained, lost or are stable in terms of your body weight, but I believe that high fat diets do not necessarily cause weight loss, particularly in people who are approaching their ideal lean body weight.

[Damien Blenkinsopp]: I’ve been on this diet for many years, just as an n=1 experiment. I think I lost a bit of weight when it first started, but ever since I’ve been really stable, ever since. And I’ve never paid attention to the number of calories. Sometimes I’m sure I’m eating a lot of calories, and sometime I’m not eating so many, for whatever it’s worth.

[Gene Fine]: I should also mention one other thing, which is that in our study, when we calculated what the calorie intake was on the basis this is of course on the patients self-reports, that all the patients reduced their calorie intake as well. Now, we didn’t want them to, but the measured calorie intake on the basis of their self reports was reduced, in fact by about one third.

The other interesting thing though is that the stable disease effect and partial remission, those patients who showed stable disease or partial remission had three times the ketosis. But the degree of weight loss in the two groups was the same. They both lost about four percent. So although there was weight loss in all the patients, weight loss, or calorie deficit, did not appear to correlate with the effects that we saw.

[Damien Blenkinsopp]: Well that’s a great point then.

I think the other point you illustrated, if we’re talking about your studies, is how difficult it is to set a good cancer study up, given the situation with the patients and you’re trying to control for a lot of things. So, as you say, it took you four years to recruit the patients for the last study. So I think it gives us a much better appreciation of how difficult it is to do these types of studies.

[Gene Fine]: Yeah. I think it is the fact that physicians are trained to treat with drugs and that’s very understandable. Drugs generally work well. And in cancer, it would be naive to start off with the assumption that diet is going to be a successful therapy. It has to be tested.

And so, whereas there was some reluctance, there wasn’t entirely, and many of the oncologists were very helpful and cooperative and referred patients when they were on a chemo holiday, or chemo break. That’s what was needed to get this study done. And also the fact that I didn’t want patients who were too thin and too sick.

But I think going forward, I think that we can count on, perhaps, some additional support. And we are actually aiming for human studies going forward as well. Right now, as I say, we’re also trying to couple diet with drugs in animal studies. So this combination, we hope, will lead us somewhere.

[Damien Blenkinsopp]: Yeah, Great. So is it the first time someone’s been trying to couple chemotherapy with diet? Or are there existing studies that you’re basing your current work on?

[Gene Fine]: Coupling a low carbohydrate diet with other therapies has been done. I know that Colin Champ and Doug Spitz, I believe, have coupled low-carb diets with radiation therapy. As far as coupling with drugs, I’m not actually immediately aware that anyone has done that. I think that we may be the ones who are looking at that right now.

[Damien Blenkinsopp]: Great. Wrapping up a bit, thanks so much for your time today.

Where could we learn more about this subject? Are there other people you would look to to learn more about this? Perhaps people you’ve worked for who are doing a lot of studies in this area. You mentioned Valter Longo, of course who was mentioned in Dr. Seyfried’s as well. Or are there any books or presentations on the subject that are good?

[Gene Fine]: I’m trying to think, other presentations. I know that there are some other people working in the area that I know have been doing good work.

Dominic D’Agostino in Florida. I think he has a website, and it would be interesting to look at some of the work that he’s done. A somewhat, I hope, accessible discussion of what we’ve talked about.

I have a couple of guest blog posts that I wrote. My colleague Richard Feinman has a generalized biochemistry and metabolism web blog, and he invited me to write some guest blog posts for his web blog. So I wrote two.

One which is on the general hypothesis, which I didn’t even discuss today. I mean, I discussed it in the broadest forms, but I didn’t discuss some of the details. And the other one is more on the clinical trial, on the recharge trial. So it gives more detail on that.

And I think Colin Champ has an interesting website as well, Caveman Doctor. I think I’d look at that. These are other resources. I think I’ve mentioned most of those that I know.

[Damien Blenkinsopp]: Great, great. So, we’ll put links to all of that in the show notes, thank for those.

Well how about you? What are the best ways for people to connect with you? I mean you mentioned the blog posts, which we’ll put in. Is there anything else? Do you have a website, or are you on Twitter? Is there anywhere you are active where people could learn more about what you’re up to?

[Gene Fine]: Let’s see. The website that I have is my website at Albert Einstein. You can also, through the blog posts that I mentioned it gives other links to papers that I’ve written as well as to my website. So I think that probably the most complete portal, you can look me up just at Albert Einstein and find my website there. And that will also link me to the dietary studies and the blog posts and the papers. They all connect to each other.

[Damien Blenkinsopp]: Great, great. We’ll put those on the show notes.

Something we spoke about just before the interview, your perspectives are a little bit different to Dr. Thomas Seyfried that we’ve already had on the show. Could you briefly summarize where you think you might have a different opinion?

[Gene Fine]: Well, I just think that we really are in the same camp. I think that we both believe in metabolic therapy, as do the other people that I’ve mentioned. I think that he believes that when he describes cancer as a metabolic disease, he believes that the fundamental problem is it starts as a metabolic disease in abnormal mitochondria. That may be true.

The only thing that I think that I would differ is that that abnormality in the mitochondria, I believe, is a genetic abnormality, even in the mitochondria. That you still have, what’s happening in the mitochondria is that, to me the fundamental problem in cancer is actually a genetic mutation that leads the cells to increased proliferation and growth and unlimited growth and immortality, and so forth.

The source of these mutations, I believe, could certainly be in the mitochondria, but in fact if it is, and that would make sense to me, it would be increased reactive oxygen species. And increased reactive oxygen species can cause mutations in the genetic portions of the mitochondria, and that would cause abnormal mitochondria. Or it could cause mutations in the DNA of the cell. Certainly hydrogen peroxide, peroxide can migrate over distances and can migrate into the nucleus.

So, I actually believe that the fundamental problem that leads to the cancer may initiate in the mitochondria with reactive oxygen species, but nonetheless results in the fundamental change of cancer is in a mutation. So I think that [in a] certain sense we’re describing the same phenomenon, but we have a different emphasis on which syllable we’re emphasizing.

[Damien Blenkinsopp]: Right. Potentially where it starts and where it finishes, and so on.

[Gene Fine]: Yeah, yeah.

[Damien Blenkinsopp]: Great. Great, thanks for that clarification.

Before you go, I just wanted to look at a bit of what you do on a personal level with your body data. I was just wondering if you track any metrics at all for your own health, biomarkers, or anything like that on a routine basis. Maybe yearly, or more so?

[Gene Fine]: When I started studying this in, around 2003, and I got interested in it, by the way, from my friend and colleague Richard Feinman. He’s a biochemist, and he’s been interested in this principally from the point of view of the effects on metabolic syndrome, diabetes, lipid disorders, and so forth.

However, I came in from the nuclear medicine background, and PET scanning and Warburg effect, and hypoxic cells. For me it was attractive for the possibility that this may have some effect, low-carb diets in inhibiting glycolosis, and as I mentioned earlier through the uncoupling protein 2 having a unique inhibitory effect on cancers while sparing normal cells.

So in 2003 when I got interested in this, and I decided that — you know, I never really had a weight problem, but I had gradually put on a few pounds over the years. And I have a small frame, so I’m about five foot nine, and 165 pounds. For me that was carrying excess fat.

So I figured well, you know, if I’m going to study this in others I might as well experience what it’s like for myself. And maybe I’ll even have some benefit in terms of overall body composition.

To make a long story short, I’ve been on a low-carb diet of various degrees of strictness over the years. In some cases I’ve been ketogenic, I’ve been very strict. In other cases, I’ve just been low-carb, but not likely ketogenic. I haven’t been under 50 grams a day, I’m not quite sure.

But the short story is that over a period of now, what 2003, really 2004, about 11 to 12 years, I’ve lost 33 pounds. Sometimes it’s been in fits and starts, but I’m very, very happy and comfortable with my weight right now. I like myself at 132. I have a small frame. I feel that for me I am lean and fit, and that’s a good thing.

There’s that aspect of it. In terms of other biomarkers, the numbers that I like to look at, in particular, are those that have risk profiles for, well my glucose and my hemoglobin A1C has dropped. In addition, my fasting blood glucose.

[Damien Blenkinsopp]: So if you remember, where did they start and where are you at now? And are you happy with the numbers now?

[Gene Fine]: Well yeah. I mean, I think I’ve been stricter lately and more consistent, so I’ve only been monitoring them really. I don’t think I’ve really been taking very close watch of them.

But I think over the past year or two my blood glucose, a couple of years ago had actually been at 100, and my hemoglobin A1C I think at one time was around 5.7. I’m sorry, this was only about one year ago.

The hemoglobin A1C changes slowly, but in two successive measurements, I’m about to come up with a third, it’s dropped to 5.7 to 5.6 now to 5.5, and I’m expecting it will continue to be going down because I’m doing this. And my fasting blood glucose is now about 94. So it’s dropping, and I’m satisfied with that.

I used to eat what was recommended. I used to eat a low fat diet, which of course means a high-carb diet, and I think I suffered the consequences. But little by little that has been reversing.

From the point of view of my lipid profile, the things that I’m most interested in are those that are atherogenic, that contribute to risk of cardiovascular disease. And I think the current thinking, which makes some sense to me, is that it’s not so much LDL which is targeted by the cardiologist, because LDL is a mixed bag.

Low density lipoproteins really consist of two major fractions. One of the light, buoyant LDL, which is really not harmful, and the other is the small dense LDL, which is. And what happens on a low-carb diet is you reverse the ratio. You reduce the amount of small dense LDL.

And the good measure of that, because it’s hard to get that measurement directly. There are only a few labs in the world that actually measure small dense LDL directly. You have to send away to specialized testing for them. However, there’s a good index of it and it’s the ratio of your triglycerides over your HDL.

[Damien Blenkinsopp]: So there’s a proxy?

[Gene Fine]: There’s a proxy for small dense LDL, yeah.

[Damien Blenkinsopp]: Oh, great.

[Gene Fine]: And so when I started, I guess when I first measured my triglycerides to small dense LDL when I had been not very compliant at all, my triglycerides at one point were about 150, and my HDL was about 50. So the ratio was about three. And since going on a low-carb diet, my triglycerides fell in half, to 74, and my HDL went from 50 to 75. So basically my ratio is now one.

[Damien Blenkinsopp]: That’s pretty high.

[Gene Fine]: So all the things went in the right direction. I’m very pleased that the HDL went up, without any major increase in exercise, just the diet alone. And my triglycerides fell in half. So those are both just exactly what you would expect on a low-carb diet, and what you want.

[Damien Blenkinsopp]: Great, thanks for those.

They’re very useful, especially the triglyceride HDL ratio. Because it is difficult to get the, I guess you were talking about the NMR, nuclear magnetic resonance. We spoke about that in a previous episode. And then there’s the LDLP to get the number of particles. But as you say, there’s only a few specialized labs, so it’s not as accessible. So it’s great to know that there’s a proxy to use also.

Last question here. What would be your number one recommendation to someone trying to use some kind of data to track, whether it’s biomarkers or something else, to make better decisions about their own health?

[Gene Fine]: Yes, well I mean it depends on what aspect of the health you’re talking about. But I don’t know if ketosis is necessary.

As I mentioned, any change of diet can be difficult to sustain over the long term. I don’t even know what it takes. Willpower is something that, what is it. So, it’s hard to know how to do that.

And by and large the reason I would say it’s hard to change diet is people eat what they like. And you want to eat what you like, and so changing your diet means you’re, by definition, changing it to something that you didn’t prefer. So it seems as though there’s a fundamental issue there.

On the other hand, I think that if you have a weight issue that you’re not happy with, or your doctor reports blood lipid markers or glucose markers that you’re not happy with and evidence of pre-diabetes or diabetes, and you’re on meds, so forth — let’s not consider meds yet. Let’s just talk about without being on meds. Because low-carb diets, if you can actually go on them and you’re also on meds, you have to do that under supervision because you might actually become hypoglycemic, and you have to be careful about that.

But without considering meds if you just want to, say, improve your health in terms of obesity or aspects of metabolic syndrome, lipid disorders, blood glucose levels, pre-diabetes. Without going on a strict low-carb ketogenic diet it’s not as hard, I think anyway, to reduce the quantity of carbohydrates that you eat.

You can have a breakfast where, you can cut out, well cut in half the size of the desserts that you eat. You can cut in half the amount of mashed potatoes that you eat. You can eat one slice of bread instead of two, or you can not eat bread. Although that sometimes is hard for people, but if you eat the bread and don’t eat the mashed potatoes, you’ve reduced the number of carbs that you eat.

So if you just start by reducing certain portions of carbohydrates. And I actually found I still have carbohydrates a little bit now. I have a sort of modified Atkins Plus, I call it, or South Beach Plus. I have a little ice cream at night. It’s my treat.

Overall, I probably eat about 60 grams of carbs a day. But, I treat myself to a little bit of ice cream at night. I’ll find out what that’s done to my lipid profile, by the way. But I don’t think it’s going to have a major effect. I think that overall it’s going to be still pretty good.

So the idea of reducing the overall quantity of carbs, I think, is actually important. I think that with the average American diet, I don’t know if the same is true in UK but probably, that overall consumption of carbs is 300 to 400 grams a day. And that’s really quite a lot. And if that could be cut in half to 150, that would be a big improvement.

So, I think that that would be lower stimulation of insulin secretion. Yeah, I think that that would be my principle recommendation in terms of health.

Now as far as exercise is concerned, exercise is also something that many people do but can’t stick to an exercise regime. And overall, I think that even if you look at the overall impact on insulin sensitivity and improving metabolic profile, there’s no question that exercise helps. But it really comes a distant second to diet in terms of having a dramatic impact on insulin sensitivity and these other biomarkers of lipids and glucose and so forth.

So that, while you’ll never hear me discourage anyone from wanting to do exercise, I think that if you want to have an immediate and more dramatic effect, the thing to do would be to reduce carbohydrates in the diet somehow.

And that’s probably the best I can say at the present time, because as I say, I don’t think anyone has a magic bullet as to how to help someone go on a diet. It’s never easy, but if you can find a way to reduce carbohydrates, you’re off to a start.

And if you feel encouraged by the results that you see, you tend to continue it.

[Damien Blenkinsopp]: Absolutely. Thank you for bringing that up, because we’re introducing changes here, new habits. And as you say, it’s super difficult.

I feel one of the things that helps people is making it clearer how helpful it can be in different areas of their life. Once you’ve heard it 10, 20 times from different people who are studying these things, like yourself, in different areas. I think it makes it easier for people, just because of the repetition, for the clarity in their heads.

I think part of the problem is the mystery and the misunderstanding, especially in the media and the press. The more times you’ve heard five different stories, the less you feel like taking action against any one of them, because you’re just not sure, you’re hesitant.

So thank you for your time today, because it’s certainly helping with these type of things.

[Gene Fine]: Thank you. I’m glad that you have this program, really, to spread the word through interviewing people who are active in the field.

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Is the Fast Mimicking Diet (FMD) an easier way to get the benefits from fasting? In this self experiment I tracked lean muscle mass gains, improved metabolism (ketones, glucose), strong regeneration signaling (IGF-1) and a couple of downsides.

Last month I undertook my first 5 day water fast. It is turned out to be a really helpful tool for my health and productivity, so I committed to make it a monthly ritual for 12 months.

With each month the plan was to push the edge a bit to learn more from the experience – refining the approach to the fast with the different options available and tracking the results to see what could give me the biggest payoff for least effort.

Enter the “Fast Mimicking Diet” – an easier and safer way to get the same benefits as pure water fasting. It created a spark of media coverage around it following the publication of a new research paper on it in June 2015. Two of the articles actually had two journalists become fast mimicking diet guinea pigs for 5 days (Peter Bowes at the BBC, and Victoria Lambert at The Telegraph).

It’s clear to me that most people will never do a water fast because it looks like a psychological feat fit only for diet equivalent of extreme sports fanatics. So the Fast Mimicking Diet was an obvious choice for fasting experiment #2.

If it does make the fast much easier – I just might be able to persuade some more of you to take the jump and grab some of those upside benefits for yourself.

What is the Fast Mimicking Diet?

Prolon l-nutra
Photo: L-Nutra

The exact details of what the Fast Mimicking Diet is in terms of food breakdown aren’t available publicly. Which in part, can be explained by the fact that the main researcher behind the fast mimicking diet, Valter Longo, owns a patent on the FMD (published January 2015) and a company which has designed a comprehensive packaged FMD dietary product ProLon.

For our purposes though there is enough information available to put together our own version of it. The Fast Mimicking Diet I used and the other versions below, are based on some very specific FMD design points found in Longo’s January 2015 patent and the June 2015 study (the macro and micronutrient do’s and don’ts).

The nutrition rules established for the Fast Mimicking Diet are:

  • Each month (3 / 4 cycles in studies): 25 days eat normally, 5 days FMD
  • High micronutrient content (i.e. greater than 50 percent by weight) from natural sources
  • Ketogenic: Restricted protein and a high percentage of calories from fat

In practice this translates to:

  • Day 1: 54% norm caloric intake 1,090 kcal (10% protein, 56% fat, 34% carb)
  • Days 2–5: 34% norm caloric intake 725 kcal (9% protein, 44% fat, 47% carb)

For the nutrition geeks out there I’m sure you’re already thinking up some Fast mimicking diet recipes to play with. For most of us though, this sounds pretty much like techno-babble… Don’t worry though, there’s a much easier way to look at the FMD.

Fast Mimicking Diet Recipes

avocadosIt turns out that days 2 to 5 are pretty much equal in calorie intake and macronutrient ratios to just 2 normal sized avocados (based on NutritionData numbers here).

That’s one avocado for breakfast. One avocado for dinner. Done.

For simplicity sake, you can just run all 5 days that way.

(Note: Sizes of Avocados vary depending on origin. Florida origin avocados are larger, and California origin smaller for example. If you’re using the smaller variety, it will be 3 avocados per day).

Then you need to take care of the micronutrients. For that you take 4 tablespoons of broad spectrum greens powder (a supplement made from dehydrated vegetables).

So your day ends up looking like this.

  • Morning: 1 Avocado + 2 tablespoons of greens powder
  • Evening: 1 Avocado + 2 tablespoons of greens powder

That takes all of the thought out of it.

Note: For those who are more ambitious, Josh Mitteldorf has posted some FMD recipes that you can put together.

itunes quantified body

The Fast Mimicking Diet Experiment

The Specific Fast Mimicking Diet Variation Tested

My personal goal for this experiment was to emphasize regeneration of the immune system – and I’m impatient about it. So I used a reduced FMD this time to ensure that I was giving my body as strong as possible starvation signal, while supporting its processes. For this reasons I cut out the macronutrient intake (the avocados) and only went with the 4 tablespoons per day of greens powder (micronutrient intake).

So the experiment results you’ll see below are from a modified FMD – just the micronutrient intake.

Specifically this is what I consumed during each of the five fast days:

  • 4 tablespoons of greens powder
  • Filtered water with real salt added
  • 2 cups of black coffee
  • Activated charcoal from time to time as a gut toxin binder

Biomarkers Tracked to Understand Benefits/ Risks

For the biomarkers I used Fast Mimicking Diet study as the basis, basically copying their timing and tracking with just one – albeit quite large – difference

In the study they tracked their post intervention results after 3 cycles of FMD. I would only be doing it after 1 cycle. For this reason the results could be expected in my case to be less significant – that would be the assumption, however it’s not what happened.

Biomarkers Tracked by Area

the-tracking-fmd

5 Day Fast Mimicking Diet Results

Metabolic Switch to Ketones a Day Earlier than Fast #1

My metabolism switched from glucose to ketones one day earlier than in my first 5 day fast. Like last time the fast “felt easier” once I’d switched from glucose to ketone metabolism. So by the afternoon of day 2 of the fast the hunger pangs or discomfort had pretty much gone.

At their peak, my ketones were just a little higher than last time at 7.3 mmol/L. This was 29 times my baseline, which is a lot higher than the average 9 times above baseline noted in Longo’s Fast Mimicking Diet study. We have an interview with another guest coming up in the next weeks discussing the importance of this variation in ketones (higher variation = better).

My blood glucose dipped a little lower this time also settling in at a consistent 57.5mg/dL in the fasted state. This is 64% below my baseline vs. an average 40% below baseline from the study.

Metabolism: Blood Glucose and Ketones

Ketones and Glucose Fast Mimicking Diet

I continued to track ketones and glucose after the fast ended at the 120 hour mark (end of 5 days). So it’s interesting to note that it took my body 2 days to really switch back out of ketone to my normal metabolism once the fast was ended.

Looking at Seyfried’s Glucose-Ketone Index (GKI) (from episode 16) the fast was shown to be more effective this time round. In the chart below you see #1 Water Fast compared to #2 Fast Mimicking Diet. In this 2nd fast my body spent 18 hours longer in Seyfried’s therapeutic zone for cancer (lower than an index of 1) than in the first. That extended the therapeutic window to 71 hours – an impressive total of nearly 3 days.

Metabolism: Seyfried’s Glucose Ketone Index

Glucose Ketone Index Fast Mii

My assumption here is that it’s the fact that this is my 2nd fast that my body switched to ketone metabolism quicker this second time. It’s a pretty significant change compared to my first fast, so unlikely to be just variance. It’s possible that my version of the FMD somehow supported this also – but my bet would be that its my body having learned to adapt to the fasted state quicker. Future fasts will provide more insight around this.

Does the Fast Mimicking Diet = Lean Gains?

In my last fast I ended up being concerned that I’d lose weight every fasting cycle and if repeated monthly eventually ending up a skinny strawstick version of myself. More concerning, I was wondering if it was lean muscle mass that I was losing.

This time round I had the BodPod to control whether it was lean mass or body fat I was gaining or losing. In addition, the FMD study shows a slight lean mass gain on average for people doing cycles of FMD. Although mine was a minor version I was hoping to avoid a decline in weight as with last time.

Using my Omron scales there was a 1.7kg (3.7lb) from baseline to day 7 after the end of the fast (day 12).

Weight (Kg) via Omron Home Scales

Weight-gain-fast-mimicking-diet

The BodPod results were even more promising. It turned out that I had gained nearly 3lbs (1.3kg) of lean mass over the 12 days. The body fat change was negligible.

Body Composition (Kg) via BodPod

fast-mimicking-diet-lean-gains

Note: You’ll notice that the Omron scales and weighing scales used with the BodPod did not agree. A reminder of the importance of using the same device to track whenever possible due to inter-device variances. The BodPod is the more accurate.

Regeneration & the Immune System Reset

And we come to the last but in my opinion most important item. Did the biomarkers show an indication that my body and immune system had regenerated as has been shown in Longo’s study?

The IGF-1 results are promising. There was a nice drop of IGF-1 44% below baseline. This compares with an average of 22% reported in the study. The BBC journalist Peter Jones, one of the study’s participants, had a drop of 60%. The hope was to see a significant drop and recovery of IGF-1 like this as it correlates with the gene signaling required for regeneration. Also of note my baseline IGF-1 levels hover between 115 and 120 ng/mL – these are below the typical reference range for my age (132-​333 ng/mL) likely due to my long term ketogenic dieting (~7 years with different variations at this point).

IGF-1 (Insulin-like Growth Factor 1)

igf-1-fast-mimicking-diet

The bigger interest for me was the immune system of course. The results here were a little disappointing – very hard to judge if anything happened. In the study they noted bigger changes in one class of white blood cells: Lymphocytes. This held true in my results with a larger % drop from baseline compared to all white blood cells.

White Blood Cell and Lymphocyte Counts

white-blood-cells-fast-mimicking-diet

Anecdotally, the situation is personally clearer for me. As with my first fast I had a period of a week after the fast where flu-like symptoms and fatigue taxed me. With this 2nd fast it lasted a little longer, extending to between one and a half and two weeks.

Since that time I’ve noticed once again a bump up in my perceived wellness. Less fatigue. More energy. Less symptoms in general from the lyme and babesiosis infections I’ve documented (see the complete story behind these in the last experiment intro).

So, again, the fast has been worth it for me.

But it’s not a black and white story. As we’ll see in the next section…

The Opposition: Adrenal Fatigue

Fasting is known to stress the adrenals, and for me personally this is a particular concern, since I already have documented low adrenal function. To continue my monthly fasting cycles I decided I would have to see improvement in my adrenal function compared to a baseline I established last November 2014.

Having been on treatment since March 2015 to support recovery of the adrenals I would have expected some progress. However, I felt that the fast may counteract that progress potentially. Or exacerbate it.

This may or may not have been the case. However, the results of my adrenal functional profile show continued deficiency compared to the low normal reference range.

Adrenal Functional 4-Point Cortisol Panel (Morning & Total)

adrenal-function-panel-fasting

While the fast has in my opinion lived up to the studies in terms of reseting and regenerating my immune system to some extent – it’s probably also true that it has not helped my adrenal recovery.

It wouldn’t be wise (or responsible) to continue this cyclic fast given this downside.

Potential Confounders for these Results

I’ve discussed what in my opinion are the most likely takeaways from the results so far. However, there are other possible explanations. These are the potential biases that I’ll keep an eye out for or/ and try to eliminate in future fasts.

    Metabolic Switch

  • Positive bias: Long time ketogenic/ high fat diet (5 years) which may mean I’m an outlier compared to the population with respect to switching to ketone metabolism.
  • Negative bias: Documented high inflammation biomarkers last 3 years (this tends to disrupt glucose regulation, and indeed my HbA1c numbers and fasting glucose are not as good as before this inflammation – tropical infection driven)
  • Lean Mass Gain

  • Positive bias: Creatine Monohydrate supplementation ongoing for most of the last 3 years with some breaks here and there. Last 3 months consistently. Could the 5 day break from creatine for the fast, then retaking in post 7 days have an impact? Doubtful that it would be this significant.
  • Positive bias: Currently I have a low lean muscle mass compared to historic norm due to a large amount of muscle mass I lost the last 3 years (again infection driven). This could account for a greater increase for my personal situation as my health normalizes and may not be repeatable in future cycles.
  • [?] bias: Diet change. I’ve increased the amount of resistant starch type 3 in my diet since just after Fast 1 and a few weeks before Fast 2. This means I am eating more carbs in my baseline diet. This did not change between beginning and end of the fast 2 testing period, but it is a longer term change.
  • Adrenals

  • Positive bias: Adrenal Supports. I Have been taking adaptogenic herbs and adrenal complex since March 2015, theoretically this should have led to some improvement.
  • Negative bias: There was a 3 day coffee roadtrip binge between Fast #1 and Fast #2 where I consumed 3 X coffees plus per day. A lot of fun but pretty irresponsible given my adrenal situation. This could be a greater factor in the negative results than the fasts.
  • White Blood Cells

  • [?] bias: Documented suppressed immune system for last 3 years? (consistently bottom 10-15% of normal reference range)

The 5-Day Fast Mimicking Experience

About the experience of the FMD itself – there’s not a lot to say beyond the fact that it felt much easier.

None of the symptoms I experienced last time occurred. There were no headaches like last time. There was less dizzyness when getting up quickly. Also no skins rashes. I’m tempted to attribute this to the micronutrient support provided by the green’s powder the idea being that it provides the nutrients required for detoxification and liver processes amongst others, thus better dealing with a potential increase in toxic load from lipolysis (breaking down body fats which tend to store fat soluble toxins).

Also I did more physically. On day 5, the last day of the fast, I went on a trip to London to a couple of labs to get blood labs and BodPod tests done. This wasn’t a big deal and I didn’t feel weak in doing so. This compared with the first time where on the 5th day the physical weakness was a lot more noticeable.

Potentially on day 4 and day 5 I noticed my stomach a little more than with the water fast. In my first water fast I had pretty much dropped the issue of eating or being hungry. But with this time round, possibly because I was taking the green powder- I was more aware of my stomach, and a little grumble here and there. But it was marginal and not really uncomfortable. Just slightly different.

Personally, I’m not 100% sure that all of these differences I’ve noted are absolutely physiological. Some of it could be put down to feeling a lot more comfortable in the fasted state due to having already done it before. I’d say some of it could be just me expanding my comfort zone and getting along with things while paying less attention to the fasted state.

Next Steps – A Change of Plan

While I would love to continue the fasting cycles, and I would even feel comfortable doing it as a “life routine” given the upside benefits, for now I’m going to give it a break.

The next few months I’m going to focus on adrenal recovery – with additional supports – to try to get that parameter moving in the right direction.

Once they have stabilized or shown progress I’ll come back to the fasting cycles for more…

What I’d Like to Explore Next

I’d like to explore a few of the ideas that have come up this time in future fasts:

  • Metabolic adaptation: Will my time to switch to ketone metabolism get shorter the more fasting cycles I do?
  • Lean Gains: Is it possible to continue to gain lean body mass with repeated FMD cycles?
  • Full FMD: I imagine for my next FMD I’ll take the avocados too. This will help to make the fast safer as a reintroduction after working on my adrenals. Otherwise I’d like to know how the full FMD compares to my micronutrient only FMD.

Have you done some kind of fasting before? What was your experience like? And what other types of fasting are you interested in learning about? Let me know in the comments.

Tracking

Biomarkers

  • Blood Ketones (Beta-Hydroxybutyrate / β-hydroxybutyrate): Blood ketones are the gold standard for measuring your state of ketosis. During the fast, ketones are expected to peak in the range of between 6 and 7 mmol/L based on Seyfried’s work and experience. In episode 7 Jimmy Moore notes that values over 1.0 on your blood ketone monitor give you the benefits of ketosis, and there is no need to go over 2.0. Tim Ferriss also prefers this range, noting that his best mental performance is typically with values between 1.1 and 1.7 mmol/L.
  • Blood Glucose (mg/dl): A measure of the level of glucose in the blood at one point in time. Dr. Seyfried’s therapies target reduction of blood glucose levels to limit cancer cell growth, and according to his theories high blood glucose is a biomarker of increased cancer risk. For the fast he notes values between 50mg/dL to 60mg/dL are standard. Non-fasting values should be below 80mg/dL ideally, and at least 92mg/dL.
  • Glucose-Ketone Index (GKI): The ratio between the concentration of glucose in the blood to ketone bodies in the blood. The calculation is Glucose (mmol)/ Ketone (mmol). Dr. Seyfried created the index as a better way to assess metabolic status. Therapeutic efficacy is considered best with index values approaching 1.0 or below. Patients with chronic disease like cancer have consistent index values of 50 or more.
  • Weight (lbs, Kgs): Standard weighing scales measurement of weight in morning without clothes (to avoid biases).
  • Lean Body Mass (lbs, Kg): Sum of weight of all non-body fat weight in the body. Calculated by combining your weight with a lean body mass % estimate.
  • Body Fat (lbs, Kg): Total bodyfat weight for your body based on a calculation using your weight with a bodyfat % estimate.
  • IGF-1 (Insulin-like Growth Factor 1): In caloric restriction and fasting IGF-1 drops, while consumption of high glycemic carbohydrates and protein spike IGF-1. Measured in ng/ml (or nmol/l in the UK). Normal ranges vary by age and gender (see reference here). More info on IGF-1 and its uses here. (Note: Damien’s baseline levels are 119 ng/ml, just below the “standard reference range” for his age group).
  • WBC (White Blood Count): A count of white blood cells found in the blood, low levels can indicate immunosuppression, while high levels can indicate an existing infection with active immune response.
  • Lymphocyte Count (White Blood Count): A count of white blood cells found in the blood, low levels can indicate immunosuppression, while high levels can indicate an existing infection with active immune response.
  • hs-CRP (hs C-Reactive Protein): A common marker of inflammation. As a general rule, the closer your marker comes back to 0, the better. Consistent values of 1mg/L or over are indicative of cardiovascular risk. Measured in mg/L. We discussed this marker in detail in episode 26

Lab Tests, Devices and Apps

Lab Tests

  • Functional Adrenal Stress Profile (BioHealth 201): Damien uses this adrenal functional panel based on recommendations from practitioners and his physician on its higher sensitivity and accuracy to diagnose status of adrenal function compared to others on the market.
  • Hematological Profile: Also known as Complete Blood Count (CBC). A standard test providing information on your blood cell breakdown including red blood cells, and white blood cells. Can be run with virtually any lab test company and is used routinely as a first screen by physicians and in hospitals for diagnosis.

Devices

  • Blood Ketone/ Glucose Monitors: The Precision Xtra in the U.S. or Freestyle Optium Neo in the UK are the current recommended monitors. You’ll need lancets, ketone strips and glucose strips also.
  • Ketonix: Damien used the “Ketonix Sport” during this experiment to compare the results with those of the blood ketone results. The results from the Ketonix did not correlate very well with the blood ketones measured – so we’ll be sticking to tracking blood ketones directly in future self-experiments.
  • BodPod: An accurate approach to measuring your body composition and separating out your % lean body mass (muscle, organs, bone) vs. your body fat. You find BodPods in some high end gyms, but more often in fitness labs.
  • Omron Body Composition Monitor: Used by Damien for his home weighing scales although he no longer uses the body composition functionality as he finds the bio-impedance technology used too variable. As noted in this experiment the weight metrics turned out to be a fair bit different to the BodPod more accurate standard also.

Tools & Tactics

Diet & Nutrition

  • Fast Mimicking Diet (FMD): Also known as the periodic fast mimicking diet, since studies to date have focused on using 3 to 4 cycles of 5 days on the diet each month. The main summary paper, “A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan” was published in the Journal of Cell Metabolism in June 2015.

Supplements

  • HealthForce Greens Powder: The greens powder Damien used in the experiment. There are many greens powders on the market of varying quality. Another one he’s used in the past is Amazing Grass Greens Powder.
  • Activated Charcoal: A broad spectrum binder used to bind to toxins in the gut and carry them out. There are high cost versions such as Activated Coconut Charcoal (potentially less contaminants) and lower cost versions such as this. If you buy others check the ingredients – they often have added sugar and other undesirables.

Other People, Books & Resources

People

Additional Charts and Data

Click Here for Additional Charts

Inflammation (hs-CRP)

There was no significant change in hs-CRP which was in line with what was expected from the fast mimicking diet study. In the study out of range (over 1 mg/l) values will normalize to under 1mg/l, however in range values like mine see little change.

hs-CRP (C-Reactive Protein)

hs-crp-fast-mimicking-diet

References:

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Oxaloacetate is an important metabolic intermediate in the energy pathway of the mitochondria. Recent case studies support the use of oxaloacetate as a nutritional supplement to help regulate blood glucose levels, potentially support longevity and protect the brain.

Can you get similar beneficial results from a nutritional supplement as you can from a water fast (previously discussed in episode 16 and episode 28)? Oxaloacetate supplements (also discussed in this episode with Bob Troia) are currently being studied for their use in improving blood sugar regulation and potential anti-aging properties.

…through the clinical trial that was done. We know that 100mg [of oxaloacetate] was effective in reducing fasting glucose levels in diabetics.
– Alan Cash

Alan Cash is a physicist who has spent years researching the effects of oxaloacetate. Through his efforts and travels he has seen great success for terminally ill patients and more who use oxaloacetate to supplement their health. Cash helped stabilize the molecule so that it could be used as a nutritional supplement and continues to advocate and study its use so that more research and clinical trials can continue to support its use.

In this interview we get into the nuts and bolts of how oxaloacetate works, the current studies underway, and some different ways you can use it depending on what benefits you are seeking.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!

itunes quantified body

What You’ll Learn

  • The implementation of a calorie restriction diet may work to consistently increase your lifespan and reduce any age related diseases (6:19).
  • Calorie restriction seems to affect the energy pathway of the cell (9:20).
  • We can essentially “bio-hack” our systems by tricking the cells into thinking that the NAD to NADH ratio is high so that fat production is reduced (12:50).
  • Human trials have shown that calorie restriction reduces fasting glucose levels and atherosclerosis (13:46).
  • Reducing age related diseases will increase the average lifespan and increase the maximum lifespan for every cell in the body (14:32).
  • Oxaloacetate is an important metabolite involved in one of the energy pathways in the mitochondria, the power house of a cell (16:20).
  • Oxaloacetate is used in the Kreb’s cycle to oxidize NADH to NAD (17:09).
  • A human clinical trial in the 60’s demonstrated that the use of oxaloacetate as a nutritional supplement reduced Type 2 Diabetes symptoms (20:00).
  • As the dosage increases from the minimum 100 mg other system processes occur, such as the reduction of high glutamate levels, which is one of the damaging factors for closed head injury/stroke victims (22:33).
  • A medical food called CRONaxal contains a large dose of oxaloacetate which, when used in conjunction with chemotherapy, can reduce tumor size and sometimes stop tumor growth completely in patients with brain cancer (26:07).
  • Fasting/a calorie restricted diet is another technique that has been shown to slow brain tumor growth (27:53).
  • Some cancer patients have already seen results with oxaloacetate supplementation and calorie restriction diets, however these are just individual cases and not clinical trials (28:46).
  • Recently, clinical trials have begun to study oxaloacetate as a treatment for different conditions such as mitochondrial dysfunction, Parkinson’s disease, and Alzheimer’s disease (30:13).
  • Oxaloacetate may also work well to reduce inflammation and increase neurogenesis in the brain (32:30).
  • Oxaloacetate may also become an important supplement for athletes who encounter severe head injuries during their sport (34:30).
  • Long term potentiation, the restoration of the ability to learn, may improve for patients after a stroke or closed head injury if oxaloacetate is used in combination with acetyl-l-carnitine (36:18).
  • Alan Cash spent years proving to the FDA that there do not seem to be any negative effects found with taking large doses of oxaloacetate (38:35).
  • So overall, oxaloacetate has an immediate pharmacological effect on the glutamate in the brain and a long term genomic effect on the mitochondria (46:30).
  • When trying your own experiment, take a daily fasting glucose level for a couple weeks to see the normal variability and then follow with oxaloacetate supplementation along with daily reading of your glucose levels (48:06).
  • The biomarkers Alan Cash tracks on a routine basis to monitor and improve his health, longevity and performance (55:29)
  • Alan Cash’s one biggest recommendation on using body data to improve your health, longevity and performance (58:49).

Alan Cash

  • Terra Biological: Alan Cash’s company which produces the stable form of oxaloacetate.
  • Oxaloacetate supplementation increases lifespan of C. elegans: The original study published by Alan Cash on PubMed.
  • : you can contact Alan Cash with questions using this email address.

Tools & Tactics

Supplements & Drugs

Oxaloacetate is available in a few versions in the market today – all of these come from Alan Cash’s company since he developed the proprietary method to thermally stabilize it and as such make it usable. A number of studies on Oxaloacetate were mentioned in this interview – see the complete PubMed list here.

  • benaGene Oxaloacetate: The nutritional supplement (100mg) version of Oxaloacetate to promote longevity and glucose regulation.
  • CRONaxal Oxaloacetate: This version of oxaloacetate is a medical food (containing oxaloacetate) which, when used with other treatments such as chemotherapy, has been shown to significantly improve outcomes and quality of life for cancer patients.
  • Aging Formula Oxaloacetate: Dave Asprey’s supplement is the same as the benaGene version of Oxaloacetate.
  • Acetyl-l-Carnitine: Mentioned with respect to a study where a combination of oxaloacetate and acetyl-l-carnitine reduced long term potentiation impairment in rats.
  • Metformin: A drug which is used to improve blood sugar regulation in diabetes. Researchers are looking at its wider applications as a knock on effect from improving blood sugar regulation to cancer and aging.

Diet & Nutrition

  • Calorie restriction: this dietary regimen involves a significant decrease in daily calorie intake and has been shown to slow the aging process as described in this review article. You can learn more about the potential benefits and the arguments against the anti-aging benefits of calorie restriction in episode 14 with Aubrey De Grey.
  • Fasting: The fasts referred to in this episode were complete water fasts that were also being used in combination with oxaloacetate in order to attempt to “stack” the effects and get better outcomes. The examples given were case studies of cancer patients (no clinical trials have been completed as yet). For more information on fasting as a possible cancer treatment see episode 16, and episode 28 on our water fasting self-experiment.
  • Calorie Restricted Ketogenic Diets: In a similar light to above, the anecdotal cases discussed for cancer were patients use of ketogenic diets (that put you into ketone metabolism, by restricting carbs and protein, and emphasizing fat) which were also calorie restricted. This involves stacking two nutritional strategies: ketogenic diets have been shown to be therapeutic for some conditions like alzheimers and blood sugar regulation related problems as has calorie restriction in general. Then some of these cases were also combining the use of oxaloacetate, again to try to stack the effects from these three tactics to further improve outcomes. See episode 7 for complete details on using ketogenic diets as a tactic to improve health.

Tracking

Biomarkers

  • Blood Glucose Levels (mg/dL): A measure of the level of glucose in the blood at one point in time. Fasting blood glucose levels are specifically taken when you have not eaten for at least 8 hours and optimally would be between 75 and 85 mg/dL. Health concerns with blood sugar regulation such as diabetes risk start to rise over 92 mg/dL. After taking oxaloacetate for many weeks Alan Cash suggests that your fasting blood glucose should vary less when compared with any control levels. These levels can be measured at home using a glucose monitor and glucose testing strips (an explanation for the use of glucose monitors can be found in this episode).

Other People, Books & Resources

People

  • Hans Adolf Krebs: Krebs is best known for his discovery of the citric acid cycle, or Kreb’s cycle, which is the main energy pathway of a cell.
  • Dominic D’Agostino: Well known for his work with ketogenic diets and performance.

Organizations

  • Calorie Restriction Society: This organization is dedicated to the understanding of the calorie restriction diet by researching, advocating, and promoting the diet through regular conferences, research studies, and forums.

Other

  • Kreb’s Cycle: oxaloacetate is one of the components involved in this energy pathway in the mitochondria of a cell.
  • NAD/NADH: the effects of oxaloacetate in the Kreb’s cycle changes the ratio of NAD and NADH in the mitochondria which in turn affects the energy available to the cell.
  • Orphan Drug Act: This law passed in the US in 1983 has provided more opportunities for researchers and physicians to pursue drug development for rare, or “orphan”, disorders.
  • Calorie restriction PubMed results

Full Interview Transcript

Click Here to Read Transcript

[Damien Blenkinsopp]:Alan, thank you so much for joining the show today.

[Alan Cash]: Oh, thanks. It’s always a thrill to talk about oxaloacetate.

[Damien Blenkinsopp]: First of all, I’d just like to get a bit of background story as to why you got interested in this at first. What’s the story, basically, behind how you got interested in oxaloacetate, and started getting involved with it?

[Alan Cash]: That’s a pretty weird story.

It turns out I had a brain condition where nerves sometimes grow very close to arteries. I had an artery that wrapped around my nerve. Every time my heart beat it acted like a little saw and eventually cut in through the myelin sheath that surrounds the nerve and protects the nerve, and went directly into a nerve bundle that was a major nerve bundle in my neck. And the result was instantaneous pain.

I found out that I was very lucky; I was able to get it corrected. They just went into the back of my head and followed the nerve until they could find where it crossed over, and they untangled it and put in a piece of Teflon. So now I don’t stick, but the pain is 100% gone, which is really nice. A miracle of modern science, because it was pretty terrible.

In looking up this condition, I found that it was really a condition of aging. As we grow older, your arteries get about 10 to 15 percent longer, even though we’re not getting 10 to 15 percent longer. So they have to fold over, go someplace, and it was just bad luck that it folded over next to this nerve.

As a physicist I thought I’d look into aging and see, whats the current state of what we can do about aging. And thankfully at that time there was a lot going on with the basic fundamentals of aging and trying to understand this, and looking at all the data that’s out there. That’s what physicists do; we take a huge amount of data and see where the kernels of truth are. We try to think of E=MC2, or F=MA, how much that describes about the universe.

And looking at the aging literature, the thing that stood out the most is almost nothing works, which is disappointing. The one thing we did find that worked consistently throughout the animal kingdom was calorie restriction. That was discovered back in 1934 in Cornell University.

It’s not just the diet. It’s essentially establishing a baseline of what you’d eat if you had all the food available, and then backing off that baseline anywhere from 25 to 40 percent. And when you do that consistently over a long period of time, we see several things. One, we see an increase in lifespan. Not just average lifespan of the group, but the maximal lifespan is also increased.

For small animals that live short times, that could be anywhere from 25 to 50 percent increases. In primates, we’ve seen an increase in lifespan of about 10 to 18 percent, depending upon the test. So we’re thinking in humans, we’ll probably see something in that range if you calorie restrict your whole life.

The other things we see though are a reduction in age related diseases, such as cancer. Our animal models indicate that incidence of cancer is 55 percent less in animals that calorie restrict. And that’s one of the most effective methods we have of preventing cancer, that we know of.

Incidence of neurodegenerative diseases such as Parkinson’s and Alzheimer’s are either reduced or greatly delayed. Incidences of any kind of autoimmune type issue, or inflammation issues. So it’s very, very powerful this concept of calorie restriction, and it wasn’t until just recently that we figured out molecular pathways of why it’s working.

[Damien Blenkinsopp]: So, in terms of the actual mechanisms for what’s going on in the body when we calorie restrict, what happens? What is it that creates these benefits and these changes in our biology, versus disease, and longevity in general?

[Alan Cash]: We’ve been looking at that for a long time as a question, and some of the things that we looked at were does it matter if it’s the calorie restriction with fats, or does it matter if it’s just carbohydrates or proteins. And what we’ve seen is it’s pretty much across the board ‘calories’.

There are various diets out there – there’s a new diet every week it seems like – that looks at restricting one form or another of calories, or fats, or proteins, or even specific components of proteins. But what we’ve seen in general in calorie restriction is it’s the number of calories.

So, based on that it seems like it’s an energy proposition, and looking at the energy pathways there’s been focus on the ratio of two compounds that are pretty much the same. Nicotinamide adenine dinucleotide, or NAD, and it’s reduced version NADH. So that ratio, which is also known as the redox of the cell, is looking at the energy of the cell. And when we have a very high NAD to NADH ratio, we see effects very similar to calorie restriction.

[Damien Blenkinsopp]: So in terms of what that’s actually doing, do we understand why the changes in NADH create this change in our biology?

[Alan Cash]: You know we’ve been able to trace this, and what we see is increasing the NAD to NADH ratio – and you can do that through a variety of ways – but that increase is measured by a protein called AMP protein-activated kinase, or AMPK. What AMPK does is it monitors, essentially, the NAD and NADH ratio, or the redox of the cell.

Think of it as a see-saw, so with AMPK as the fulcrum of the see-saw and NAD on one side and NADH on the other side. When the see-saw is in one position, AMPK will then act with other proteins that translate to the nucleus and turn on genes. When the see-saw is in a different position, AMPK will work with other proteins that translate to the nucleus and turn on different genes.

So let me give you a specific example. If you’ve had a lot to eat, your NAD to NADH ratio will be low. And AMPK will turn on genes that help with fat storage and production, because you’ve got all this extra energy, so hey let’s store some of it. So it will actually start producing proteins that deal with fat storage and synthesis.

On the other hand, if the see-saw is in the different position, if you haven’t had a lot to eat, there’s no point in storing fat. And so your genes will not be making these proteins that assist in making fat production. So how can we use that information?

For instance, when we trick the cells into thinking that the NAD to NADH ratio is high – or that the animal hasn’t had a lot to eat even if it has – we can slow down the rate of fat production, which could be interesting for people on diets. What we see is that you still gain some fat, but you just don’t gain it as fast.

So, biochemically, there are reasons why when you go on a diet and you lose all that weight, and you stop the diet and you rebound back very quickly. We can slow down the rate of rebound if we can keep the NAD to NADH ratio up high, because then the genes that are produced that create and store fat aren’t being produced. So there’s some really neat tricks that we can use to bio-hack into our systems that are existing systems.

[Damien Blenkinsopp]: Yeah, yeah. There are quite a few potential benefits to calorie restriction. We’ve come across some of these before. We’ve spoken with Dr. Thomas Seyfried about purposefully doing fasting for this kind of work as well.

What are kind of list the main big areas which people have seen this impact, like diabetes. What have you seen in your area, areas where people are meaningfully impacting this area with calorific restriction?

[Alan Cash]: We’ve actually done human trials in calorie restriction, and what we see is a reduction in fasting glucose levels. We also see a reduction in atherosclerosis, which, considering heart disease is the number one killer in America, if we can reduce that you’re going to have people living longer. That alone is huge.

[Damien Blenkinsopp]: So that just begs the question, when people are doing these estimates of longevity, is it because you’re reducing the risk of many of the kind of diseases that kill us – like cancer and neurological disorders, and heart disease – that people are living longer, and therefore you’re getting a higher longevity score? Or are they kind of separate topics?

[Alan Cash]: It’s both, actually.

Reducing these diseases is going to bring up the average increase in survival. So that would give you your average increase in lifespan. But there are certain people who don’t get these diseases, and they live a long time. But calorie restriction has been able to increase the maximal amount of lifespan. So that’s making every cell in your body live longer.

And we see that in our animal tests. For instance we started off working with these little worms called C elegans, which are used a lot in research because we understand, somewhat, the genetics of them. And one of the interesting things about these worms is once they go into adulthood, they don’t produce any more cells. That’s it.

They only live for about 30 days, but they live with the cells that they have. So if we can extend their lifespan, it means that we’re allowing each of their cells to live longer, and to be functional for longer. And when we increase the NAD to NADH ratio in C elegens, we see up to a 50 percent increase in lifespan.

So, as I said, it’s both. It’s eliminating a lot of these diseases that are associated with aging. I mean, think of all the diseases that you get when your old that you don’t get when you’re seven years old.

[Damien Blenkinsopp]: So, I’m sure you’re aware of Aubrey de Grey? We had him on the podcast previously talking about his seven areas of aging, which are basically diseases of aging. So he’s looking at it from that perspective. So, in terms of oxaloacetate, which is the mechanism you were using to generate that, where does it actually come from? What is it?

[Alan Cash]: Well, it’s a human metabolite. It’s in something called the Krebs cycle, which is what gives us power in our little mitochondria. So, mitochondria can be thought of like a little power plant. Glucose is the fuel for the power plant.

So the more mitochondria you have, the more power plants you have, but you have to also have the fuel, the glucose, to up-regulate that. So oxaloacetate is one of those critical components within the mitochondria. So it’s in every cell of your body already.

Now, when we give it to animals, the reason we started looking at oxaloacetate is in looking at our energy pathways, oxaloacetate can break down into malate, which is another metabolite. It’s found in excess in apples. And as part of that reaction, it takes NADH and turns it into NAD.

[Damien Blenkinsopp]: So it takes it from reduced into the oxidized form?

[Alan Cash]: Yes, and so in doing that, because you’re taking something from the denominator and putting it in the numerator, it changes the ratio very rapidly. The first person who measured this ratio change was Krebs himself, back in the 60’s. He added oxaloacetate to the cells and he saw a 900 percent increase in the NAD to NADH ratio in two minutes. So, huge changes with this human metabolite oxaloacetate.

Now, oxaloacetate has got some problems. It’s not very stable, it’s highly energetic. Commercially it’s available through chemical suppliers, but you have to store it at -20 degrees Celsius. If you want to make popsicles out of it, you could probably do that. But putting it into a usable supplement has been very difficult, and that’s why you don’t see it very often.

We came up with a method to thermally stabilize it so that it can be stored at room temperature for a period of up to two years without degrading. And that’s how we were able to introduce this into the market.

[Damien Blenkinsopp]: Great. So, in terms of where it comes from, in my understanding it’s also something that is part of foods. So there are foods which have oxaloacetate in it, so it’s basically a nutrient that’s found in the environment?

[Alan Cash]: Yes. Absolutely. Although it’s only found in very, very small amounts. There are some foods that have higher amounts of oxaloacetate, and these are foods that typically have higher amounts of mitochondria.

So, for example, pigeon breast has a lot of oxaloacetate in it because you need tremendous amounts of mitochondria to power flight. That’s what one of the most energy intensive things out there, is flying around. But you need about 18 to 20 pigeons breast to get the amount of oxaloacetate that we see as the minimum for seeing some of the gene expression changes we want to accomplish. So it takes a lot of pigeons.

[Damien Blenkinsopp]: So you’ve determined the minimum effective dose, which is around how much?

[Alan Cash]: So far – and this is from a human clinical trial – one of the side effects of calorie restriction in primates is it eliminates Type 2 diabetes, which is a good thing. And it turns out they, in trying to mimic calorie restriction – which is what we’re trying to do is turn on the same molecular pathways – we looked at oxaloacetate, and there was a clinical trial that was done back in the 60’s in Japan.

This was published, and it showed that oxaloacetate reduced fasting glucose levels in diabetics. So, we knew that this is one of the side effects of the calorie restricted metabolic state, and we could look at, in humans, what is the most effective dose.

And what we found is they did a range in this clinical trial of 100mg to 1000mg. There were no side effects in the 45 day trial. 100 percent of the people saw a reduction in their fasting glucose levels, which was good because they were all diabetics. We couldn’t understand why this wasn’t commercialized back in the 60’s.

So I actually flew to Japan to interview the department that was responsible for this clinical trial. The conversation went something like this, “Hi. I’m Alan Cash, your department produced this paper on oxaloacetate working in diabetics to reduce fasting glucose levels. Where’s the follow-on work?”

They said, “Well there is no follow-on work.” And I said, “Well why not?” They said, “Well because it’s a natural ingredient.” And I said, “Yeah it’s not only natural, it’s a human ingredient. So toxicity is extremely low.” And they said, “Yes, but we can’t get a patent on it.” And that was pretty much the end of the conversation.

So, as far as knowing the dosing and what’s effective, we already have a clinical trial showing where the minimum effect is, which is 100mg, which is where we set our sights to put out a nutritional supplement.

[Damien Blenkinsopp]: Yeah.

So, was there any advantage for the people, if we take the most extreme example, the people taking 1000mg in that study, was there any advantage to it? Did it impact blood sugar regulation differently?

[Alan Cash]: Yeah, well actually, as the dosage increases, we start looking at other reactions that oxaloacetate are involved in. And one of the main other reactions is the combination of oxaloacetate with glutamate. So, oxaloacetate and glutamate link together and that reduces glutamate levels in the brain.

Now that can be important for certain people. For instance, in a closed head injury, 20 percent of the damage to your brain is caused by the actual strike to the head, the damage to the tissue. 80 percent of the damage is caused by the aftereffects. And those after effects are in your brain it releases something called a glutamate storm.

Glutamate is one of those essential brain chemicals that you need to function properly, but if you get too much of it it excites the neurons to the point where they die. So this glutamate storm is responsible for about 80 percent of the damage.

And what they’ve been able to show now with oxaloacetate is primarily in tests over in Europe – the Weizmann institute out of Israel is doing a lot of this work, and there’s also some people in Hungary and Spain that are doing quite a bit of work with oxaloacetate. But they’re able to show that oxaloacetate, if you can get it to a stroke victim or a closed head injury victim within two hours, 80 percent of the damage is eliminated.

[Damien Blenkinsopp]: Wow. What, do they just take a small dose, or what does it have to be?

[Alan Cash]: No, you’ve got to take a lot, because you have to get it into your bloodstream, and if you take, let’s say, two 100mg capsules of oxaloacetate we’ve seen the data in the bloodsteam, only about five percent gets through. The rest of it is used up in the liver and intestines. That’s not a bad thing, because you want to keep those things healthy. But to get it so that it starts reducing glutamate levels in the brain you want to increase it’s supply in the bloodstream, and so you’ve got to take a lot.

[Damien Blenkinsopp]: So, basically after that is it always five percent? If I take 1000mg, is it just going to be 15mg?

[Alan Cash]: We don’t know. There may be a point where you start overloading the liver and more passes through. I can tell you that we have a medical food that is directed towards people with brain cancer, because if we can reduce the glutamate levels in the brain we see better results.

[Damien Blenkinsopp]: Because people, just to get back to it, is it that people with brain cancer tend to die from glutamate toxicity? Is that one of the main mechanism for their death? Or is it acting on other dimensions?

[Alan Cash]: Well, one of the main predictors of survival is the amount of glutamate that’s produced because what the tumor does is it produces tremendous amounts of glutamate, and it kills the surrounding tissues so that the tumor can grow into that area. So, if you can stop that, you don’t kill the tumor, you just stop it growing.

And this is essentially what we’re seeing with the product called CRONaxal, which is a medical food [that] is a high, high dosage oxaloacetate. So you may take the equivalent of 30 to 60 capsules of the nutritional supplement per day, and we’re seeing in animal tests a 237 percent increase in survival.

So FDA gave us an Orphan Drug designation for oxaloacetate for brain cancer. In the actual human work, we’re just doing case studies right now, but in the 17 case studies that we have MRI data on, the oxaloacetate was in conjunction with chemotherapy. So you use them together, it was able to stop tumor growth, or reduce tumor size, in 88 percent of those patients.

[Damien Blenkinsopp]: Wow, so that’s pretty great statistics there.

[Alan Cash]: Yeah, considering some of these people with glioblastoma, their tumors were growing at a rate of 80 percent per month. You can do the math there, it’s not a great equation.

And we were able to bring that growth rate to, in one guy’s case – he was 42 years old, two kids, a nice guy – we were able to bring that growth rate to zero for eight months. That’s very significant when chemotherapy alone only increases survival by a month and a half.

[Damien Blenkinsopp]: Wow, right. So, you were also saying earlier, we were just discussing you looking at combining oxaloacetate with fasting. We spoke to Dr. Thomas Seyfried about this recently, and you may be seeing potentially better results with that? Or it might be–

[Alan Cash]: Well what we’ve seen so far, fasting is one of the techniques used in brain cancer to slow or retard the growth of the tumor. It’s one of the few things that has been shown to work, especially a calorie restricted ketogenic diet, where you eat more fats.

And the thinking behind that is that you reduce glucose levels tremendously with the ketogenic diet, and glucose is one of the things that feed the tumor. Now, the other thing that feeds the tumor, according to Dr. Seyfried, could be glutamate. And so if we can reduce glutamate levels also with oxaloacetate, we may see some impressive results.

And we’re already starting to see that in anecdotal cases in patients. We had one young man who had a slow growing brain tumor that’s been able to stop it’s growth with a combination of calorie restriction and oxaloacetate supplementation with our CRONaxal product for a period of two years now.

[Damien Blenkinsopp]: Wow. And so is he taking around 6000…

[Alan Cash]: No, his tumor is slower growing, so he’s taking about the equivalent of 10 capsules a day.

We’ve also had recently a woman with Stage 4 breast cancer. Her latest report from her PET scan and her MRI data, they can no longer find the tumor, or tumors; she had like four of them. And all she was doing was calorie restriction and about 10 capsules of oxaloacetate.

There’s some real promise here, but it’s very early on. We don’t have the clinical trial data that supports this in a statistically significant manner, we just have individual cases. Although those individual cases are stunning, it would not be prudent to rely upon those cases.

[Damien Blenkinsopp]: Right. Well, have you got any plans to have any clinical trials? Was that something that might be occurring soon in that area?

[Alan Cash]: Yeah, well we’re actually in clinical trial for a variety of conditions. One is mitochondrial dysfunction. There are certain people that are born with genetic defects that affect the mitochondria.

We have one infant that’s been on oxaloacetate now for nine months that is showing normal development, whereas normally with this type of defect we would expect the infant to have passed away six months ago. So that’s pretty interesting.

We’re also in clinical trial for Parkinson’s disease because anecdotally we’ve seen some interesting cases where the oxaloacetate has reduced the symptoms of Parkinson’s disease. And lastly, we’re in clinical trial for Alzheimer’s disease, so we’ll see how those all play out.

We’re getting ready to start some clinical trial work in pediatric brain cancer, because if we can get away from doing chemotherapy, it’s just a whole better quality of life.

[Damien Blenkinsopp]: It sounds like one of the main mechanisms. So if you’re looking at Alzheimer’s disease, they also use ketogenic diets, and so it’s obvious that the glutamate is helping, but do you think it’s also the aspect of improving blood sugar regulation is potentially helping in all these diseases as well? Is that one of the factors?

[Alan Cash]: It certainly could be a factor. We just published a paper in human molecular genetics that showed that oxaloacetate increased the amount of glucose that the cells could uptake in the brain, it increased the number of mitochondria in the brain. So we not only built more power plants, but we’re now having a way to fuel those power plants.

The interesting thing is that oxaloacetate is also a ketone. So you don’t necessarily need glucose to fire off all those neurons in the brain, you can actually use oxaloacetate as a power source. So, the other things we’ve seen with oxaloacetate in the brain in animal models is a reduction in inflammation, and probably most exciting is we’ve seen a doubling of the number of new neurons that are produced.

Ten years ago we used to think that the number of brain cells you have is static, that those brain cells that you lost in college are forever gone by imbibing in too much alcohol, but now what we’re seeing is that there’s an area of the brain called the hippocampus which continues to produce new neurons. And as we age, this function decreases. So our ability to repair our brains decreases.

Well oxaloacetate in animal models doubled that rate of production, and not only did it double the rate of new neurons, but the length of the connections between the neurons was also doubled. So, if you think about, well if a neuron can connect to a neuron that’s further away you get more interesting connections, more interesting abilities to have different variables.

It makes your brain more plastic, is what we say. And oxaloacetate has been able to show both that increase in neurons and the length of the neurons. So it’s pretty exciting work.

[Damien Blenkinsopp]: Yeah, so brain injuries – you were talking about brain injuries before – I guess a lot of us think about brain injuries as a big thing, like maybe a car crash or something, you have a big serious brain injury. But now they are also looking at athletes, for instance in football where they’ve been heading the ball and areas like that, and they’re seeing there’s a lot of damage.

So could this potentially be a tool for sports? If you’re playing in football, would it make sense to be taking this stuff whenever you’re going to a match, or something like that, to reduce the kind of damage you’re getting each time you’re heading the ball, and so on?

[Alan Cash]: I think so. I mean, my daughters play volleyball at a very high level – one’s at Pepperdine, and the other is going to be at Hofstra next year – and occasionally they get hit in the head with a volleyball. They’re middle blockers, they go up, and they just get slammed in the face. So I always have a bottle of oxaloacetate in their gym bag, and if they get hit in the head they’re told to take 10 capsules right away and to continue taking 10 capsules for the next week or so.

I don’t want to suggest that you should use oxaloacetate for any kind of disease. Mostly it’s a nutritional supplement, there is the medical food also that’s specific for brain cancer. And I just want to make that clarification that the work really hasn’t been done in clinical trial.

Now, over in Europe they are working on that. They’ve done a lot of animal studies, and the interesting thing they’ve found is that if they can get oxaloacetate into these animals that have been hit on the head with a hammer within two hours, it reduces the amount of brain damage they experience by 80 percent. They’re looking at a lot of things in Europe, and it’s very, very exciting work.

[Damien Blenkinsopp]: Yeah, it seems like this is a really interesting molecule, because it seems to be having an impact in a lot of different things. Of course, it’s all early stages of research, like you say, but it seems to have quite a lot of potential.

I saw another study where they had combined oxaloacetate with acetyl-l-carnitine and they were looking at that. Could you talk a little bit about that? I believe it was long-term potentiation it was impacting.

[Alan Cash]: Yeah, long-term potentiation is a measure of how plastic your brain is, how well you can still learn. And when they go into the brain of animal models and give them a stroke, an artificial stroke, and then measure long term potentiation, the levels drop significantly.

When they use oxaloacetate or a combination of oxaloacetate and acetyl-l-carnitine, they saw 100 percent restoration of the brain’s ability to learn again, in very short order. And this could be very important for people with stroke, closed head injuries, that type of thing.

But again, this is early work, it’s been done in animals, it’s been very successful in animals. And both oxaloacetate and acetyl-l-carnitine have very low toxicity profiles, so the risks are low there, but we still need to do this in clinical trial and make sure that there are no unexpected results in humans.

[Damien Blenkinsopp]: Right. Yeah, so ALCAR or acetyl-l-carnitine, a lot of people I know have been taking it for a very long time. So in terms of toxicity for oxaloacetate, as you said there was the trials where you had 1000mg per day. Has anything above that been tested? Because it sounds like with some people you’re actually giving 10,000 or more in specific cases.

So, in terms of toxicity, is there any evidence to say that it could be harmful in any way if someone overdoses, or potentially someone in a specific situation?

One thing I was just thinking about while you were talking was in terms of glutamate, you say it helps to deactivate glutamate. In some people who are normal and have normal levels of glutamate, could that impact them in any way in terms of their brain performance, memory, things like that?

[Alan Cash]: That was a multiple question, and let me address them one at a time.

[Damien Blenkinsopp]: I’m sorry.

[Alan Cash]: As far as toxicity, in order to bring the supplement into the United States we had to prove to the FDA safety because this is considered a new dietary ingredient, even though it’s in just about every food we eat but not at the levels that we’re giving it to people at. So we had to prove safety, and we spent quite a bit of money and three years of my life proving safety to the FDA.

One of the things we had to do is feed animals as much oxaloacetate as we could stuff into them to see at what point in time 50 percent of the animals would die. And what we found out is we got up to about 5000mg per kilogram of body weight in animals, and we still couldn’t get any of them to die.

[Damien Blenkinsopp]: Did you get any negative reaction at all?

[Alan Cash]: We couldn’t find one. Now, what we are seeing in humans, especially in some of these people with brain cancer that are taking the equivalent of about 60 capsules a day, we do see an increase in burping.

[Damien Blenkinsopp]: That’s interesting. It’s kind of random.

[Alan Cash]: Yeah, well it relaxes the upper sphincter muscle in the stomach, and we see an increase in burping in some of the people.

[Damien Blenkinsopp]: That’s interesting.

[Alan Cash]: But that’s about all we’ve seen so far. So, from a toxicity standpoint, this appears to be a very safe molecule.

[Damien Blenkinsopp]: Well, that’s great. Do you remember the multi-part question, or shall I repeat it?

[Alan Cash]: Yeah, the second part was what if you take a lot of this and you’re just a normal person, what would you expect to see? Some of the things we’ve seen are really interesting.

We have an R&D project where we’ve developed an oxaloacetate tablet that goes under your tongue. And so we deliver a lot more oxaloacetate to the bloodstream, which preferentially reacts with glutamate. And what we see with that tablet is an increase in the ability to [unclear 40:04] because if you can turn down glutamate levels a little bit in your brain, you don’t have some of that repetitive cycling of questions, you’re able to focus more, you’re able to pay attention better.

It’s kind of like, the way I can explain it, it’s like you’ve been meditating for a half an hour, so you have this incredible focus but it’s not jittery. Like if you have 10 cups of coffee you can also have more attention, but your whole body is shaky. This is more, you’re very relaxed, and you just have that increased ability to focus. It’s pretty cool.

[Damien Blenkinsopp]: It sounds like you’ve been testing it yourself.

[Alan Cash]: Yeah I test it always on myself, because if I’m ever going to give it to somebody else you’ve got to feel confident enough in it’s effects to try it on yourself first.

[Damien Blenkinsopp]: Yeah. You know, it would be nice to hear, how do you use oxaloacetate yourself? Do you have some kind of routine, or what do you do with it?

[Alan Cash]: Yes, I use it primarily for anti-aging, because I’m after that [00:41:11 – 00:41:14:17 audio error repeated “we see an increase in burping in some of the people.”] I take like three caps a day, which is a little bit more than our recommended one cap a day, but I get it for free, so what the heck, right.

I’ve also started working with this sublingual dose whenever I’m tired. Like if I have to drive somewhere and it’s late I take one and immediately I’m awake and my focus is there. Or if I’m in a conference and its 4 o’clock on the third day of the conference I find that it helps quite a bit. So that’s how I use it.

A lot of athletes are using this now because we’ve been able to measure a decrease in fatigue and an increase in endurance. We don’t see an increase in strength, just an increase in endurance. So a lot of endurance sport people take one to two capsules about 15 minutes before competition, with about 100 to 200 calories.

[Damien Blenkinsopp]: So it sounds very quick acting, in terms of you’ve take it in and within a very short period it’s going to have that impact. Are you talking about it feeding the mitochondria, basically?

I mean, you spoke earlier about it basically being like a ketone. Do you think that’s the mechanism there, or is it because it’s stimulating the mitochondria somehow?

[Alan Cash]: Well there’s been some work out of UCSD showing that oxaloacetate activates pyruvate decarboxylase and allows the citric acid cycle to process faster. So you get more ATP production, which would tie with the endurance effect.

We’ve been able to measure the endurance effect almost immediately, and we published that in the Journal of Sports Medicine. We saw about a 10 percent increase in endurance. And you think, you know, 10 percent is not all that much, but in a lot of athletic competitions 10 percent is huge.

So that’s the short term effect, and that actually only lasts about two hours. And then if you want it again, you have to reapply.

[Damien Blenkinsopp]: Yeah. So a marathon runner would be dosing every couple of hours?

[Alan Cash]: Yeah, about every two hours.

The second effect though is longer term. We’ve seen that oxaloacetate supplementation increases the number of mitochondria, or the mitochondrial density in the cell. So it produces more of the power plants so that when you feed it more glucose, you can turn it into fuel faster.

But that takes typically, you know, anywhere from two to six weeks to see the effect on that. And you have to take it daily. What we’re doing is we’re increasing that NAD to NADH ratio, which then activates AMPK, and chronic AMPK activation has been shown to start the process of mitochondrial biogenesis, or producing more mitochondria.

[Damien Blenkinsopp]: Is there any reason we want that activated? Anything you know of like in the research, where it says like chronic activation of AMPK could lead to any downsides?

I have another question, just to kind of give you a bit of context to that. Is it worth cycling oxaloacetate? So having a month on, or a couple of months on, a couple of months off, or anything like that?

[Alan Cash]: Yeah, a lot of supplements that deal with stressing your cells in order to get an effect they work better if you cycle them. For instance, echinacea. Echinacea works because it’s an irritant. So you turn on your stress response and get a response, but if you take it all the time, your body gets used to it.

Oxaloacetate doesn’t work as a stresser, it works to turn on genes and turn on the development of more mitochondria. So no you want to take it all the time.

[Damien Blenkinsopp]: Great, and so we were discussing earlier, I was just asking you about potentially doing a lot of experiments with oxaloacetate, and you were saying that for most of the effects it’s really this aggregated, this cumulative effect.

We want to be using it for between two and six weeks before we see the effects. And then, if we stop it’s probably going to take that amount of time before those effects disappear. But they will disappear, so it’s something that you really kind of have to take on an on-going basis.

[Alan Cash]: Yeah, yeah. Because it’s, well there are two effects. One is a pharmacological effect, like for instance the reduction of glutamate in the brain. That happens almost immediately, so some people when they take this they get that feeling of peace because they’re just reducing their excitatory chemical in their brain.

But the other effect is a genomic effect, and while your genes start producing these proteins right away it takes a while for the proteins to be enough in number that we see measurable effects. We can see those effects in typically four to six weeks.

For instance, blood glucose levels would be one that we’ve been able to trace that down to activating AMPK, which is the same thing that the diabetic drug Metformin does but through a different pathway, and the up-regulation of a gene called FOXO3A, which deals with glucose stability. But that takes time, it takes usually four to six weeks.

[Damien Blenkinsopp]: So, for the people at home, if they were going to design their own little experiment, it would be basically measuring blood glucose stability, is that the main, is it the variant which is reduced, or is it actually lowered in general?

[Alan Cash]: One experiment that they could try is start off with a baseline. Go to the drugstore, get a glucose meter and some little paper strips, and take your fasting glucose levels for maybe a couple of weeks. You see the variability, because even in fasting glucose levels, you’re going to see the levels bounce all over the place.

And then start oxaloacetate supplementation, one or two capsules a day for a month, and take your daily glucose levels. You won’t see much change for about three weeks, and then what we typically see is a slight reduction – in non-diabetics – in fasting glucose levels.

And more importantly, a reduction in the swing. So you don’t see as high a high, and as low a low. And that reduction is typically on the order of 50 to 60 percent, so you have better glucose regulation. And in normal people, that’s not a bad thing.

[Damien Blenkinsopp]: Right. Just if we’re talking in terms of performance, just throughout the day I think people’s performance goes up and down. Some of the reasons people try new diets such as Paleo and Ketogenic and so on is to try and even out their blood sugar a bit more so they don’t have these typical dips people get after lunch when they need another shot of caffeine to get through the afternoon.

So I’m sure probably you can see how that could impact their performance in that way. That would be interesting.

[Alan Cash]: Yeah. Absolutely.

[Damien Blenkinsopp]: So how would you recommend someone takes oxaloacetate? Would it just be 100mg one capsule? Would it be in the morning, once daily?

What would be the recommended way to try this out, for someone who is just normal and healthy, and they’re just more interested in the long term benefits, and so on.

[Alan Cash]: For the long term benefits, we looked at the minimum amount that you could take – I believe in small measures for big effects – the minimum amount over time, and we know that through the clinical trial that was done. We know that 100mg was effective in reducing fasting glucose levels in diabetics. We’re turning on those genes that we want to turn on.

So, one capsule a day. It doesn’t matter if you take it in the morning or the evening, what does matter is that you take it every day, because we’re trying to increase that NAD to NADH ratio and keep it pretty steady, so that we continuously activate AMPK. And that continual activation is what turns on the genes and gives us the gene expression that we want to see to see extended lifespans.

[Damien Blenkinsopp]: Great, great, thank you. Are there any situations where you would recommended people – because you’re taking 300mg yourself, and obviously you don’t have the costs that other people would have – but are there other situations where you would think it would be interesting for people to take a slightly larger dose?

[Alan Cash]: Yeah, but I really can’t recommend that, as I’m not a physician, I’m a physicist.

[Damien Blenkinsopp]: Right, right. We’re getting outside of the nutritional realm again.

[Alan Cash]: Yeah, and that [can] be a dangerous thing for us to do.

[Damien Blenkinsopp]: Absolutely.

[Alan Cash]: Definitely our CRONaxal medical food for [treating] cancer, they would take a lot more oxaloacetate.

[Damien Blenkinsopp]: Great, great. If someone wanted to learn more about the topic of caloric restriction and oxaloacetate, where would you say, are there any books or presentations or is there any other resources people could look up that would help them to learn more about this?

[Alan Cash]: Absolutely. There’s quite a bit in PubMed, so they could go to www.pubmed.com, or .gov, and just type in ‘oxaloacetate’ and ‘calorie restriction’. We’ve got some papers in there that we’ve published.

And they can also look at oxaloacetate and other things like Parkinson’s, Alzheimer’s, cancer, you know, if they’re interested in that, and see what animal data there is out there right now. There’s not a lot of human clinical work done yet.

We’re in the middle of some of that ourselves. They can also email me. My email address is acash@benagene.org. I typically get back to people in a couple of days with questions.

[Damien Blenkinsopp]: Great, and I can attest to that, because we’ve been in contact before and I know you make yourself very much available, and that’s really appreciated.

Are there other ways that people could connect with you? I don’t know if you are on Twitter. You have a website, of course, which is benagene.com?

[Alan Cash]: Yeah, we have a website benagene.com. There’s not a lot of information on that because the FDA discourages that. For instance, we can’t legally put any animal data on our site, even though I consider humans animals. I think it’s relevant, but the FDA does not.

[Damien Blenkinsopp]: Right, right. Of course. So, is there anyone besides yourself that you’d recommend to learn about this topic? I don’t know, calorie restriction, longevity. Is there any interesting stuff you’ve read over the years, or have you referred people’s work?

[Alan Cash]: There’s tremendous amounts of data on calorie restriction. And there’s a society, the Calorie Restriction Society, where these people have been restricting their own calories for years, seeing tremendous results, especially in reducing atherosclerosis. In human clinical trial we’ve seen a major drop in atherosclerosis and blood pressure.

[Damien Blenkinsopp]: Do you know if that’s reflected by the CRP? The C-reactive Protein biomarker? Because you spoke about inflammation earlier, I wasn’t sure if that was that marker or another one.

[Alan Cash]: I’ve seen a decrease in inflammation in our studies really through the M4 pathway. I don’t know if C-reactive protein levels are down. We did have a case where due to a genetic dysfunction an 11 year old girl, she was in critical care, her CRP levels were up around 20,000.

[Damien Blenkinsopp]: Wow.

[Alan Cash]: Yeah, yeah. She was…

[Damien Blenkinsopp]: That’s insane.

[Alan Cash]: Yeah. Yeah. She was eating herself alive, essentially. And she was in critical care. They tried just about everything. And this was work done out of University of California San Diego Mitochondria Dysfunction Department. They’re doing some breakthrough work there.

They ended up giving her some oxaloacetate and in two days her CRP levels dropped to zero, and she was released from the hospital and went home. Once again, that’s a case of one person and specific genetic anomaly.

[Damien Blenkinsopp]: Yeah, yeah. Interesting. That’s pretty impressive.

In terms of your own personal approach to data and body data – because we’re always talking about data on this show in terms of our biologies and so on – do you track any metrics or biomarkers for your own body on a routine basis?

[Alan Cash]: Glucose levels. And for a guy, I’m 57 years old, my blood glucose levels are typically in the low 80s, which is pretty good. That’s about the only thing I track regularly. I mean I track my weight, which is very stable. I don’t count the number of hours I exercise or anything like that. I should.

[Damien Blenkinsopp]: I guess. Have you tracked your blood sugar over time? Before you started taking oxaloacetate, or is it since, so you probably wouldn’t see the effects? I’m just wondering if it would be a cumulative effect from you having taking it, I assume, for years now.

[Alan Cash]: I have been taking it since about 2007, which is when we introduced it into the Canadian market. Basically it just dropped. Initially I was up in the upper 80s to low 90s, and over time I’m just pretty much consistently in the low 80s now.

[Damien Blenkinsopp]: So you have seen some kind of steady decline, or did it decline when the genes turned on and then it stayed there?

[Alan Cash]: It pretty much declined when the genes turned on and stayed there, yeah.

Now there’s ways to lower it even further if I went to a ketogenic diet. I know some people who have been doing this, like Dominic D’Agostino. I think his blood glucose levels are down in the 40s.

[Damien Blenkinsopp]: Wow.

[Alan Cash]: Yeah. But he does a very strict ketogenic diet, and he’s feeding his cells with ketones instead of glucose.

[Damien Blenkinsopp]: Yeah, so I was interested – just before we started the interview – also in just cancer prevention, so we had Thomas Seyfried on here and he recommended a five day water fast twice a year.

So it would be interesting to combine that with the oxaloacetate. It might have a potentially beneficial upside, you know, combining those two rather than doing them separately.

[Alan Cash]: Yeah, we’re seeing that in patients now. Hopefully we’ll be able to get some funding for some clinical trials to combine calorie restriction with oxaloacetate in some of these patients. To take the science from our animal data, which is very promising, but it’s not human data. And so hopefully we can continue our research and help some people here.

[Damien Blenkinsopp]: Yeah. I’m guessing it takes quite a while to get these clinical trials going. Would you expect this to be done over the next 10 years? Is there anything that could help you with that, in terms of getting funders, or what could help to push that along faster?

[Alan Cash]: We’ve taken the unusual step in brain cancer of making oxaloacetate available for a disease through the Orphan Drug Act in the US. So this allows for various medical conditions that have scientific basis to be used for a specific disease. In this case, we’re using it for brain cancer, which is an orphan disease.

So that’s helping get the word out, get some anecdotal cases, which I’ve discussed with you a little bit, and increase the interest in getting a clinical trial out there. We’ll see how that all evolves.

[Damien Blenkinsopp]: Great, great. Thank you. Well, one last question Alan. What would be your number one recommendation to someone trying to use data, in some way, to make better decisions about their health and performance, or their longevity?

[Alan Cash]: I think that’s a great place to start. You know the benefits of calorie restriction, and so just counting calories and reducing calories where you can would be one strategy of using data to improve your health. If you keep track of that information.

Keeping track of blood glucose levels, because having lower glucose levels rather than higher glucose levels is going to positively affect your health. The amount of time you exercise.

One of the ways we’ve seen to increase the NAD to NADH ratio is chronic exercise. So calorie restriction is one way, chronic exercise is another way. A drug such as Metformin can increase your NAD to NADH ratio, or activating AMPK anyway.

And oxaloacetate as a nutritional supplement over the long term. So there are quite a few ways that you can use data and monitor your data to positively affect your health.

[Damien Blenkinsopp]: Alan, thank you so much for your time today. It’s been really amazing having you on the show with all of these interesting stories about these case studies about the work that you’ve been doing.

[Alan Cash]: Yes, and just as, again, as a disclaimer, we don’t want to recommend this nutritional supplement, which we manufacture, called Benagene, which you can get at www.benagene.com, for any disease.

Not to diagnose, treat, prevent, or cure any disease. It’s primarily, we developed this to keep healthy people healthy.

[Damien Blenkinsopp]: Great. And I take it myself too, so I’m kind of following in your footsteps there.

Well Alan thanks again for your time today, and I look forward to talking to you again soon.

[Alan Cash]: Alright, thank you very much.

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