[Damien Blenkinsopp]: Yeah, it’s great to have you here.

So, you’re involved in this big project called the Palo Alto Longevity Prize. Could you give us a run down. What is the vision behind that, and why have you put this together now?

[Dr. Joon Yun]: The vision of the Palo Alto Prize is to nurture innovation that improves the homeostatic capacity as a gateway into promoting healthy longevity, and health span.

[Damien Blenkinsopp]: Right, so, I think a lot of people aren’t exactly sure what homeostatic capacity is. So how would you describe that, and why is it particularly this homeostatic capacity that you’re linking to longevity?

[Dr. Joon Yun]: Most people are familiar with the word homeostasis. So think of homeostatic capacity as a network of traits in our body that enable us to achieve homeostasis.

Now homeostatic capacity is something that’s endowed by nature. It’s been shaped by evolution. And you can think about it as robustness, resilience, coping mechanism, dynamic range, anti-fragility. These are all kind of similar concepts. But the basic notion is that we have an incredible set of traits that enables our bodies to self tune.

One of the ironic things about homeostatic capacity is that we don’t really realize we have it until we start losing it, typically in mid-life, where all the sudden you start to feel things that you didn’t feel before. At nighttime, it’s a little too dark, the sun shines a little too bright during the day. [When] riding a roller coaster, you may come out of it nauseous, because your body doesn’t re-calibrate. Altitude sickness starts emerging around then. The bouncing back from injury or jet lag, or a late night.

All these things are suggestive ways that we start to experience the loss of something that we didn’t have. That we didn’t used to feel. The loss of something that we didn’t feel when we were younger.

In fact, when we’re 12 years old, another way to define health is the feeling of nothing. When we’re young and we’re healthy, what we feel is nothing. It’s when we start feeling something that we realize something’s going on.

[Damien Blenkinsopp]: Right, right. So in a sense, this is balance, and you’re just feeling well without any negative symptoms, or negative feelings, I guess.

[Dr. Joon Yun]: Yes. So you can think about homeostatic capacity as your body’s ability to self tune, and get back into balance or homeostasis. But think about all the things that happen…well.

So we’ve described the things that are subjective that you can experience. There’s also a lot of objective things that you can’t feel, but start to emerge by the middle of life, again that’s defined by the mid-forties.

When we’re young and our blood pressure’s high, or our blood sugar is high, the body has the homeostatic capacity to return those numbers to a normal baseline. But as we age, a lot of those numbers no longer return to baseline. They remain high.

And we call those situations diseases like hyper-tension and diabetes. The thing about a lot of the diseases of aging as reflections of the body’s declining intrinsic ability to get back to homeostasis because of potential underlying and inevitable erosion of homeostatic capacity.

Now what we do in the health care system today, we provide an external mechanism called the health care system, we trying now here in the US to help the body get back to homeostasis. But because we’re trying to restore homeostasis, and not necessarily focused on restoring homeostatic capacity, the inevitable loss of homeostatic capacity continues manifesting in increasing features of aging. And in the long run the health care system can no longer help the person make the homeostasis, and then death ensues.

So the gambit of the prize is to target and nurture innovations that improve homeostatic capacity. That we restore homeostatic capacity instead of restoring homeostasis, to see if this could be a gateway into improving health, and sustain health, and longevity could be an outcome of that.

[Damien Blenkinsopp]: Great. So this is an area you feel is undervalued, under-utilized, and currently when it comes to health and health care, and it’s something you want to promote.

What is the kind of vision behind the prize? For instance, we had an interview with Aubrey de Grey recently, and he’s talking about extending lifespan considerably. Would you put it along those kind of lines, or is it more kind of making sure that we live to our prime years 80 years old, 90 years old, 100 years and we live really well, versus having the current diseases which plague a lot of people these days?

[Dr. Joon Yun]: Well it’s really about promoting health. Longevity might be an outcome, but there’s a difference between something being an outcome and a goal.

Our goal is to improve health, and helping longevity may be a consequence of that. So I do think that the target is a little it different. And I also think that the target, the homeostatic capacity, is different than homeostasis.

To give you the example of high blood pressure. Think about high blood pressure or hyper-tension as it’s called medically as the lab error reported by the body of the blood pressure being too high. And the way we fix this is in the modern medical system is we give patients drugs that normalize that blood pressure. Meaning, return it back to a number associated with homeostasis.

But because we are externally providing that capacity, when you miss your dose of drug, or when you come off a drug, in many cases your baseline has progressed, and may be even worse. Because the one thing your body knows how to do is to homeostasis against all the external challenges. The more it sees blood pressure lowering drugs, in many ways the body rebounds. It’s called toxic phalasis.

And this is a challenge with most pharmaceuticals that the body remodels against the drug. So when you come off the drug, your lag error can even be worse. You can have rebound hyper-tension, something called addiction decompensation.

The way nature addresses high blood pressure is by exercising. Meaning the natural way to treat hyper-tension is to leverage your homeostatic capacity as a way to lower your blood pressure. Meaning, when we exercise, we’re actually increasing our blood pressure by challenging it. And in this sense, the homeostatic capacity can be stronger. And so the baseline blood pressure actually gets lower the more times you raise it. So it’s almost a mirror image of what we’re doing with the medical system today.

And when we think about the diffuse benefits of aging in, really, all those views of aging, including longevity itself, it’s generally suggested that using homeostatic capacity as a treatment for aging, rather than tools of homeostasis, may actually work in terms of expanding health for society and expanding longevity.

[Damien Blenkinsopp]: Great, great. Thanks. We’ve spoken about hormesis quite a few times on the podcast before. Would you say it’s related to hormesis? When you were talking about exercise, it sounded very similar to the kind of hormetic discussions we’ve spoken about. So are homeostasis and hormesis linked?

[Dr. Joon Yun]: Some people may find some overlapping ideas. Hormesis I first learned of it through some some great body by Ed Calabrese, out in the East Coast. My understanding of it is that it’s the notion that at different ends of the curve your going to have differences in response.

I guess there’s some relation to it, although I think the mechanism attributed to hormesis has been debated out there. But the notion that challenges to the body that, many challenges to the body can actually paradoxically induce competitory strength, or induction of homeostatic capacity. But I do think that there’s some overlap in the ideas.

[Damien Blenkinsopp]: Great, great. Thanks for that. Helps to situate our audience better.

Okay, so coming back to the Palo Alto Longevity Prize. Is there a specific reason why you decided to do it this year, and could you explain a bit more about the background? So you already have many teams participating in this challenge. Have they got any rules around defining the participation? So, have you said that there’s any restrictions to what they can do in order to compete? Or is it kind of very, very broad?

[Dr. Joon Yun]: The Palo Alto Longevity Prize is run by a team, including some of the scientific experts and industry experts in health care, and they’re the ones who convened to determine both the criteria, and they’ll represent the independent judging panel as well. And those final parameters will be announced to the public sometime this year. And there they’re accepting public comments.

Remember this is a new area, homeostatic capacity. It’s kind of a new word, although I think it is a phrase the scientific community understands, and it can embrace, and can develop innovations around. So we’re in the early stages of all that.

As to why do it this year? Well, we know that every year we wait, there’s enormous amounts of suffering that goes on around the planet associated with age and loss of life. And so we know that every week we wait, a million people have succumbed to aging or aging associated conditions. So, we think this is a very significant time, and the sooner we start, the better.

We do think that this is going to take some time, and maybe a series of prizes, with a lot of different starts. And we think it will be a long journey, but the earlier we start, the more people can benefit from improved health.

[Damien Blenkinsopp]: Great, thank you very much. I understand that you’ve put your money, or is it Palo Alto Investors that have put the money in for the prize to stimulate? We’re seeing a lot more prizes now, as a method for stimulating innovation in other industries. I think this is the first one that’s tried to do it in health care, and certainly longevity. Or have you seen other ones before?

[Dr. Joon Yun]: I think there have been other prizes before. The [inaudible 11:56] Prize, Aubrey de Grey, the Methuselah Prize. I’m new to prizes. I’m the sponsor of the prize, and I learned about prizes with some of the experts in the prize community.

And one of the things I like about it is that it mirrors how evolution works, Darwinian evolution works. There’s a niche, there’s a diversity of options that compete for the niche, and there’s a winner.

[Damien Blenkinsopp]: Great. Coming back to the rules of the prize, you’ve decided to focus the prize on using heart rate variability, HRV, which we’ve covered quite often in this podcast before. Why did you decide that this was the biomarker you were going to use for the focus of the prize?

[Dr. Joon Yun]: Exactly. So whenever you want to nurture innovation, you need to have metrics. And homeostatic capacity is a new phrase, and there are some existing biomarkers or diagnostic tests that could represent proxies of homeostatic capacity.

But homeostatic capacity is a diffuse network of many, many innumerable traits. Such as physiological level, tissue level, systems level, molecular level, cellular level. It’s a composition and the inter-relationship between all of them. It’s a composite that reflects an overall organismic homeostatic capacity. So the challenge is how do you take and define biomarkers that represent copies that affect the surrogates for homeostatic capacity?

The reason HRV was chosen was, first of all, it represent a… Well, so HRV is heart rate variability. It is a biomarker of autonomic capacity, which itself is a surrogate of overall homeostatic capacity. So it’s just one variable that happens to have a number of features that make it interesting.

Number one, we have decades worth of heart rate variability data. It’s been in clinical use since 1963 to monitor fetal stress. And when HRV goes low, it’s one of the criteria for determining fetal stress and associated infant-fetal mortality. So it’s notable that it’s not used in the post-natal life, adulthood. I mean there are very few labs around the world that actually monitor HRV in patients as they get older.

And there is good cohort data, population level data, that suggests that declining HRV is also due to a chronologic age. And many of the diseases of aging are also associated with aberration in heart rate variability. None of this is established in a causal way, but the degree of association of HRV decline with some features of aging suggest that it might be an interesting biomarker.

But there’s some additional practical reasons why HRV was chosen. Unlike most biomarkers in health, HRV can be measured continuously, contextually. You can measure it for 24 hours. Most biomarkers, as you know, are done through blood tests, body fluid samples. You only get a snap shot in time. And given the dynamism of the system, most biomarkers have a tremendous amount of variation, even in a 24 hour cycle.

So the fact that [with] most biomarkers, it’s impractical to get continuous monitoring, and you can’t detect changing patterns, and changing dynamism over 24 hour life cycle, as well as in a very different context, make it less useful than HRV, which can be measured non-invasively, continuously.

There’s also a global footprint of devices, including consumer devices, that help measure HRV. What that does is opens up the aperture in terms of the breadth of teams that can apply for the prize. If we make the biomarkers too narrow, it limits the number of labs and groups around the world who might have an innovative idea on the intervention side to be able to process their innovation.

So there is a tradeoff between specificity of a biomarker for homeostatic capacity versus this practically of the diversity of options that we may be able to solicit. So, HRV, again, there’s been empirical association with aging. Mechanistically because it’s associated with autonomic capacity it is a feature of homeostatic capacity. It’s global footprint, non-invasive, continuous monitoring, and relatively inexpensive to obtain, unlike some biomarkers that are proprietary, it’s pretty costless.

[Damien Blenkinsopp]: Great, thank you for that. Are there any other biomarkers that you looked at, and you considered for measuring homeostatic capacity?

[Dr. Joon Yun]: Absolutely. There’s only a small subset of modern diagnostic tests that actually assess homeostatic capacity. And you can think of a lot, well, actually get an annual checkup, but indirect proxies. But more direct proxies, more direct surrogates, really require tests themselves be dynamic.

So, an example of another potential surrogate is orthostatic hypo-tension. So it’s your ability of the cardiovascular system to recalibrate blood pressure from a sitting to a standing position, or lying to a sitting position. When we’re young, we have tremendous real time system dynamism that allows us to adjust to quite the rapid demand. And you really don’t have much else raising your blood pressure.

But as we get older, it’s observed that the body’s ability to adapt to those change in conditions deteriorates. So it’s associated with aging, and that’s one way to infer that there’s declining homeostatic capacity. And this may help explain why as you get older there’s one of the contributors to syncope, one of the contributors to declining ability to perform a lot of more strenuous physical tasks.

You can also start to think about the cardiac stress test as an example of a homeostatic capacity test. This is one of the ones that is more standard practice out there for the medicine of today. Essentially, one of the things we’re measuring is the body’s heart rate response to an exercise challenge.

And in some cases the heart rate response is too rapid. So that could reflect some dysfunction in the Diego Connor Response. And in some cases the heart rate increase is insufficient. So, BP is reflective of a system that is less dynamic than it used to be. And these things are associated in a lot of, on toward clinical outcomes in the long haul.

Anything where the heart rate declines after exercise. And one of the things we look for is does the heart rate return to normal, does it look like a normal heart? Does it happen in a normal amount of time? Because as we age and our intrinsically homeostatic capacity declines in which case this is a non-capacity there is abnormal return to normal as well.

So these are small subsets of the overall diagnosis landscape used in clinical medicines today, that we think already reflect homeostatic capacity. But those things require, there’s a higher burden in terms of throughput to asses innovation, and the tests themselves require more involvement.

And furthermore, the data in those areas are strong, although there are many others, but we certainly need more data across the spectrum. So one of the hopes for the competition is that we help promote the idea, that we gather more, and develop more biomarkers for homeostatic capacity.

[Damien Blenkinsopp]: Alright, great. Great, I didn’t realize that was part of the project. Have you defined the exact standard? Because there’s a few different standards of HRV out there.

One of the ones we’ve discussed quite a lot is is the natural log, RMSSD, which is multiplied by 20 and used by a lot of consumer devices at the moment. Have you defined that as yet, or are you going to be defining that at one stage as a criteria for use in the project?

[Dr. Joon Yun]: Yeah, we’re deferring that to a team of experts that have, they did the exact same topic. So, I’ll leave it up to them

[Damien Blenkinsopp]: Great, great. How can people get involved in the Palo Alto Longevity Prize? I understand there’s already 15 teams which have signed up? Maybe there’s a few more already. What’s the timeline before, for instance, you stop accepting new teams, and then for the other steps of the project?

[Dr. Joon Yun]: Yeah, you know, I don’t have that information at my fingertips. Again, all of that, the process is being managed by the production team. And I’m a sponsor of the prize. So for those details I’ll have to refer you to the team.

[Damien Blenkinsopp]: In terms of your own personal use of biomarkers, are there things that you use, or you track on a routine basis for your own health, longevity, or performance?

[Dr. Joon Yun]: You know, I actually haven’t. I haven’t thought about this project relative to my own health yet. It’s something that I probably will consider. But no, I’m not doing any personal tracking right now.

[Damien Blenkinsopp]: Maybe that’s because you’re really healthy and your homeostasis is pretty good, so you know you don’t feel out of sync, and the need to do it.

[Dr. Joon Yun]: Oh no, I definitely feel it. But yeah, these are early days, and I think a lot more science has to happen. And I think, I think we will learn about it, if nothing else, from this process.

[Damien Blenkinsopp]: Great, great. If someone is interested in getting involved in this, perhaps putting together a team, should they just go to the website for the Palo Alto Longevity Prize, or I understand it’s still available for signing up, as a project team. So would that be the best place to go?

[Dr. Joon Yun]: Yeah, I think the best way to engage is to read through the website. And I believe all the details are there, at the paloaltoprize.org. I believe all the teams have signed up through the website process.

[Damien Blenkinsopp]: Do you know if there’s other ways people can participate beyond just putting together a team?

[Dr. Joon Yun]: I don’t know, I don’t know. Again, I will defer that to the team, the way the public can engage.

[Damien Blenkinsopp]: Great, great. What do you think will happen in the next five or ten years in this area? Have you got some kind of vision or hopes, or are there any things that you’re excited about? The opportunities that are going to occur in this area, biomarkers or longevity, in the next five or ten years?

[Dr. Joon Yun]: I do hold out some hope that there’s a small chance that there are some major breakthroughs coming. And you can sense that even in talking with teams. Scientists tend to be pretty conservative, and also for reasons of competitiveness they tend to under-share hypotheses and preliminary data. And after you hear enough of these really intriguing, unique ideas, you realize that the scientific field is more advanced than the public realizes.

And one of those things that prizes are trying to accomplish prizes such as ours and the initiative such as ours is to accelerate those ideas and actions. So it’s possible that there’s some major breakthroughs that are possible in the five year time frame.

The thing that we know for sure, is that we’ll learn a ton, and the idea to create new paths and new avenues of research that give us more shots on goal in terms of improving people’s health.

[Damien Blenkinsopp]: Great, great. Thanks for that. Do you have one biggest recommendation or insight that you’ve used some kind of data, or you’ve learned about your biology when it comes to health, longevity, and performance, that would be a recommendation for other people when they’re using data?

You’ve mentioned a few things as we’ve gone through this talk about why you selected HRV, for instance. And what would be your one biggest recommendation for using data effectively to improve health, longevity, or performance?

[Dr. Joon Yun]: Well, for now I like HRV because it’s affordable, and it’s also accessible from a technology perspective. And I think the access is growing throughout the world. I like the convenience factor. It’s more practical.

Most other biomarkers, I think the distribution isn’t as broad, and the effect is not at real time. And in terms of in lifestyle habits that, in a way that also match to improving someone’s health…. exercise is still my favorite. And there’s good data suggesting exercise improves the measures of HRV.

We also know that our improvement of HRV as well as exercise itself is also with the amelioration of the stages of aging. So, based on what is known today, I think that’s probably the most practical thing that a person can do to enhance their health.

[Damien Blenkinsopp]: Great Joon, yeah. Exercise is very important. Thank you so much for your time today. I really appreciate it, I know you’re a very busy man. We’ll put together some information on the project, some of those references, in the show notes so everyone can get access to that. Is there anything else that you’d like to share about the project that we haven’t covered already?

[Dr. Joon Yun]: No, that’s great Damien. I appreciate your time, and thank you for having me on your show.