#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
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January 27, 2025
TLDR: Host Peter convenes a roundtable discussion on gerovscience with experts Steven Austad, Richard Miller, and Matt Kaeberlein. Topics covered include healthspan vs lifespan, redefining healthspan, aging-focused medical research, interventions like rapamycin & senolytics, epigenetic changes in aging, geroscience funding challenges, & more.

In this compelling episode of The Drive, host Peter Attia brings together three leading experts in the field of longevity science—Steven Austad, Richard Miller, and Matt Kaeberlein. The discussion centers on the intricate science of aging, exploring the potential benefits of geroprotective molecules, lifestyle interventions, and the challenges faced in aging research.
Key Concepts Explored
The Rising Public Interest in Longevity Science
- The public's fascination with longevity has surged, attributed to both aging populations and advancements in technology.
- Experts discuss the misconceptions surrounding longevity and the critical distinction between lifespan (the length of life) and healthspan (the length of healthy life).
Rethinking Healthspan and Lifespan
- The episode emphasizes that improving healthspan should be as important as extending lifespan. Existing healthcare systems often focus on disease-specific treatments rather than holistic aging approaches.
- The panel discusses the importance of shifting the narrative from merely living longer to living healthier.
The Science of Aging Interventions
- Geroprotective Molecules: The podcast evaluates various interventions, including rapamycin and senolytics.
- Rapamycin shows promise but requires further understanding of its mechanisms and effects on aging.
- Senolytics are also explored; challenges in reproducibility and differing interpretations of results surface in the discussion.
The Role of Biomarkers in Aging Research
- Discussion on the differences between biomarkers of aging and aging rate indicators.
- Biomarkers can only indicate aging post facto, whereas aging rate indicators could assess ongoing biological aging processes.
- The need to identify effective and quantifiable biomarkers that can inform future research and clinical applications is vital.
Geroprotective Potential of GLP-1 Agonists
- The panel debates whether GLP-1 receptor agonists possess geroprotective qualities beyond their caloric restriction effects.
- Current studies suggest a beneficial effect on metabolic health, but further evidence is needed to establish long-term geroprotective outcomes.
Challenges in Aging Research
- The experts highlight substantial obstacles in funding and public perception of aging research.
- Traditional funding models often favor disease-specific research, sidelining aging-focused studies that could lead to broader health improvements.
- There’s a call for greater collaboration between different research areas like oncology, cardiology, and geroscience to unify efforts to tackle aging.
Funding and Future of Longevity Research
- Insights into the challenge of securing NIH funding for aging-related studies are discussed.
- The panelists emphasize the need for increased investment in aging research, pointing out that aging is the primary risk factor for many diseases.
Practical Applications and Takeaways
- The episode concludes with a call to action for researchers and policymakers to prioritize aging-focused studies, urging a paradigm shift in how we view and react to aging.
- For individuals, understanding the nuances of aging research can shape personal health strategies and lifestyle choices.
Conclusion
This roundtable discussion is an enlightening exploration of the complexities in longevity science, underscoring the importance of collaborative research efforts in tackling aging-related health issues. Tune in to gain valuable insights that could help inform both individual and collective approaches to healthier, longer living.
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Welcome to a special episode of The Drive. Today, we're introducing a new format to the podcast, our inaugural round table conversation. For this one, we have gathered three brilliant minds, all former guests of the podcast, to sit down and have a nuanced, funny, sometimes a little heated discussion about one of the most fascinating and rapidly evolving areas of medicine today.
Geroscience, also known, I guess, as longevity science. So joining me for this episode are doctors Steve Ostead, an expert in aging biology and author of groundbreaking research on extending health span, Richard Miller, pioneer of the study of anti-aging interventions through the interventions testing program or ITP, which you hear me reference a lot, and Matt Caberlin,
whose expertise explores the intersection of genetics, aging, and translational research. And Matt, of course, is famous for his work in the dog aging project. So in today's roundtable, we discuss a number of things such as the relationship between health span and lifespan. And what does health span actually mean? Is it something we should try to define?
Can you improve one without improving the other? What has caused a surge in the public interest in longevity science and what major barriers are preventing longevity research from reaching its full potential? This actually was one of my favorite parts of the discussion.
How do we evaluate the effectiveness of interventions like rapamycin, senolytics, or calorie restriction in humans where it's very difficult to study them for obvious reasons? Are there reliable biomarkers or aging rate indicators that can measure biologic aging, which of course is a very hot topic?
What role do epigenetic changes play in aging? Specifically, are they causal? Are senescent cells a valid target for longevity interventions? Or has their role in aging been overstated? Are GLP-1 receptor agonists, for example, drugs like tricepatide and semagluetide, potentially gero-protective beyond just their weight loss effects? How do we overcome the funding and political challenges that prioritize disease-specific research over foundational aging science?
What would it take to make longevity research more mainstream and gain broader support from the public and policymakers? Anyway, this is a new format, this idea of doing a roundtable. So we really want to hear from you. Is it something you like? If so, what are other topics you would like to see for roundtables? So without further delay, please enjoy this roundtable discussion with Steve Austin, Rich Miller, and Matt Cableman.
Gentlemen, this is a lot of fun. I am excited to be sitting down with you guys today. Where do we want to begin? Let me start by saying the following. The term longevity, someone sent me something the other day that was like list of, I don't know, whether it was how many times the word longevity was searched on Google or something like that, but it literally looks like Bitcoin. So we are clearly at peak longevity in terms of public interest.
which for all of you who have kind of devoted decades, plural to this, I just want to kind of get a reaction from you, each of you, on what that means, why you think it's happening and maybe even extending the metaphor a little bit. Is there a bubble going on? We'll start with you, Steve.
It's a surprise to me that longevity has become so big because for a long time, we try to move away from that in the aging field because we were worried that people were thinking of longevity as well. We're going to keep frail, feeble, old people alive longer. That's what longevity meant.
when really what we want to try to do is extend health. So I'm kind of surprised, but I think it's because there are certain people of a certain age who've started to think about their own longevity. And then I think there's a whole new generation of tech entrepreneurs that really feel like this is a problem that will allow them to live healthily for several decades, at least longer than they are now. So I think it's a combination, it's a multi-generational thing.
That kind of surprises me. And you haven't seen this before to be clear. So 30 years ago, you didn't see glimmers of this. No, 30 years ago, I would have said, let's not even say the word longevity. Let's say health span, but that's changed quite clearly as more and more people have been from the outside. They're sort of peeking in at the field. I don't think the people in the field itself have changed the way they talk that much, but the people eavesdropping on the field certainly have. Rich, is that your experience?
Well, I think there are two aspects that I would want to emphasize in response both to your question and to what Steve said. In response to the question, I think people have always been fascinated for millennia or on things they could do to stay alive and healthy as long as possible.
But there were actually scientific discoveries in the 90s that showed that it could be done. And then in the last 20 years, there's evidence that it can be done at least in mice with pills. So that naturally should lead to speculation that there could be pills you could give to people that would postpone poor health for a substantial amount of time. 20 to 30% is what we're seeing in mice and 20 to 30% would be very important for people.
So I think that is a part of it. The other part is that there are now people who are making a lot of money by selling stuff that is untested to be polite about it or is useless to be less polite about it to gullible customers. And so people who want to make a lot of money have finally found that there's impetus.
that will allow them to sell stuff even if there's no evidence that it works, that they control an enormous amount of advertising dollars, both formal and informal. That's a big part of the difference. The one comment I wanted to make with regard to something Steve said has to do with the alleged
balance between health span and lifespan. It's become fashionable for the last 20 or 30 years to imagine that you get one or the other, that you have to make a choice. It's a decision and that if you give up on lifespan, that allows you to extend health span. I think that's ridiculous and controversial by all the available evidence that is all of the drugs at least that extend lifespan
in mice and could potentially do so in people, do so by postponing diseases, both the diseases that will kill you, that's why they extend lifespan, and the diseases that won't kill you, but which will annoy you and make you very unhappy to be old. Which is true, by the way, of non-molecular tools as well. That's true of exercise. Yeah, absolutely. That's a good point. Not being insulin resistant. I agree with you.
So the notion, it's time to put behind us and to make fun of the notion that I'm not interested in lifespan. Don't put me on that boat. I am interested in health spend because they are linked together and they go up and down together, getting people disabused of that false metaphor, the seesaw metaphor is probably an important goal for the public interface between longevity scientists, aging scientists.
Now, I just want to push on one thing, though. You talked about, obviously, the discoveries of molecules. You've been personally central to that work, but there was still a lag, Rich. I mean, it was 15 years ago, the first ITP was published showing the overwhelmingly surprising and positive results of rapamycin. Those results were repeated.
Why a decade, let's be generous and charitable and call it a still decade long lag from that. And by the way, I'll throw one more thing in there. If you go back to Cynthia Kenyon's work, which may have been the thin end of the wedge into the idea that lifespan was malleable, albeit through a genetic manipulation in a less relevant model, there's still a lag. Do you buy Steve's argument that it's a confluence of technology, tech entrepreneurs? Let me answer your question first.
Why the leg? I think there's a whole batch of reasons and they're important and they're easy to spell out. One is the prevailing attitude is that aging is there. There's nothing you can do about it. I'm going to not be able to outwit aging, though I may be able to be maybe.
healthier in my older years. The notion that aging is not malleable, though wrong and provably wrong, is still the overwhelming opinion, even of reasonably educated scientists and certainly of the lay public. Then commercially, there are companies that make a ton of money selling stuff that doesn't work by pretending with a wink and a nod and a lawyer that it might slow the aging process down. And since they can make a lot of money, they don't actually have to spend
valuable marketing dollars on doing research and stuff to prove that it works. Some of the drugs that at least in the hands of our mouse group the IP interventions testing program. Some of the drugs are the patent is owned by another company or out of patent or it's a natural product none of that says take me to whoever owns a big pharmaceutical firm.
And also, even if you do it right and you really want to do it and you've got a very large budget, it's not an overnight kind of thing. Any one drug, a leading agent that, like Rapa Meisen, which you mentioned, and the half a dozen others that we've shown work, at least in mice,
finding something in that same family that works really well, that is safe for people, that's the member of the 20 congeners of that drug that's best and most potent and safest, that's not at all trivial. That takes a long time and it takes a commitment of money and time and effort and intellectual resources, where the place where we can start to make an argument that that's a good idea
But make a good argument that that's a good idea to people who actually have the resources to carry it out as not so far been enormously successful, unfortunately. Can I push back a little on what Rich said about health span versus lifespan? Several papers have come out recently showing that the gap between health span and lifespan in people is actually increasing and it's increasing the fastest in the United States and it's increasing faster among women than men.
So in humans, this is a very real gap and it's a growing gap. And I think one of the advantages of the kind of gyro science, the stuff that we do is that rich is right. We don't see this in our experimental systems. So this to me emphasizes the fact that we need to change the focus. I think one of the reasons that the gap exists is we're getting better and better and better.
at treating heart disease and cancer and all these things and keeping people alive when they wouldn't have been alive 10 years ago. But this is a really important factor, I think, about thinking of public health globally. But I think you're both right. I think you're looking at it from different angles. So, Steve, you're pointing out that you can make people live longer when they're sick. I think what Rich is saying, which I agree with, hopefully I'm going to paraphrase you correctly, which is
If we target the biology of aging, I haven't seen anything to make me believe that you can separate health span and lifespan, meaning that I haven't seen things that slow aging increase lifespan, don't increase health span. I don't actually think that's plausible. I think that's an important point that if we target aging, we're doing something different than
with the way that medicine is operating now, which is targeting individual diseases after they occur. This is a very important point. It came up in a recent podcast that I did with Psalm Suteria talking about healthcare costs. In that discussion, one of the things that emerged, which I think most people are sadly familiar with this statistic today, is that among the OECD nations, the United States has the lowest life expectancy.
Which is ironic given that we are spending on average about 80% more and in some cases double what most other developed nations spend on health care. So how do you reconcile this? Well, some made a very interesting point, which is that's aggregate life expectancy. But why is that the case? That's because the United States has by far the greatest rate of death in middle age.
So when you look at maternal and infant mortality, we're horrible. When you look at gun violence and suicide and homicide, we're horrible. And most of all, when you look at overdoses, we're horrible. When you kill a whole bunch of people in their 40s and 50s, you cannot have a very high life expectancy understood. But what some pointed out was once an American reaches the age of, and I forget the exact age, I think it was about 65, all of a sudden they jumped to the top of the list.
That was very interesting to me. In other words, if you look at the blended life expectancy, we're not doing very well. But if you look at life expectancy, just immeasured as years alive, once you escape those big causes of death in middle age, which you do quite well, and it comes down to what you're saying, which is we get very good at delaying death in chronic disease. That's what I call the medicine 2.0 machine at its absolute finest.
We are going to keep you along an extra six months once you have cancer. We are going to get you through that third revascularization procedure. And so now the question is, because my intuition is where yours is, Steve. I don't think we're getting any healthier, even if we're incrementally figuring out ways to extend life in the face of chronic disease. I don't see it being a quality of life. Now, part of this might be, how do we define health span? Yeah.
I agree with you and i think it's even worse though than the way you laid it out so if you look at the statistics if you accept that sixty percent of americans have at least one chronic disease and the median age in the united states is thirty eight point something and then you think about how long are people living on average.
That would suggest if you say that, and again, this is what you're getting up with the definition of health spent, I would not define health spent as ending once you have your first chronic disease, but that's the definition most people would use. If you use that definition, most people are spending three decades or more.
in the absence of health span or in sick span. So the situation is even in the United States where life expectancy is relatively short compared to other nations, a big chunk of that life expectancy is not spent in good health. And it's exactly for this reason. But the two different issues that are being confused here in the discussion, one is the issue of whether you can help middle aged people live longer.
And everybody's agreed that we're getting better at that. We're pretty good at it. And that certainly contributes to whatever you think health span might mean. That's an issue, however, that is quite different from a concoction that slows aging do so by extending health span. Those both have the word health span in them.
but they're different and shouldn't ever be confused with one another. The other point in this question, you asked us, what is health spent? My own personal answer to that is it's a useless term. And that is because no one can define it. It's not because no one is smart. It's because the term itself is vacuous and nebulous. If you have somebody that gets a certain chronic disease here and then another one, and then they fall down and bump their head. And by the way, they go to the hospital with COVID, et cetera, et cetera.
Defining when in that 20 to 30 year period, they flick the switch. Now they have gotten to the end of the health spend is impossible. And of no interest, the general notion that people are interested in is whether you can do stuff to keep people healthy for a long time either.
without changing their life expectancy or by changing their life, with changing their life. Those are interesting, but you don't have to assign a number, a health spend digit. I don't like the medical definition of health spend, which I believe is, quote, the period of time in which an individual is free of disability and disease. I find that to be a very unhelpful definition.
But part of the reason it's awful is its binary. Yeah, exactly. You got it. But if we made it analog instead of digital, I'm not saying that makes it easy. It's still very challenging, but now it allows us to start talking about things. Except it's a concept. It's a qualitative concept. I think we should try to make it.
to where we can actually come up with a way to measure whether we call it health span or not. That doesn't really matter. I kind of agree with Rich. I agree with what you're saying, except I think it's a really useful term as a concept. I think it's a really useful way to communicate to a broader audience what one of the goals is, which is to increase the healthy period of life. Yeah, I kind of like the term.
Health for that. I have a way that helps you out with your health and you don't have to pretend you can define it as a number. But I think we all could agree there's a period of life where you are in relatively good health and then there's a period of life where you aren't and so I think the idea that we're trying to increase that component of life is really important. So I don't think we're actually disagreeing on much other than whether we like the word.
Right. Well, I also think there's an individualization of this that we're missing. To me, health is a state of your physical being that you can do the things you like to do. Therefore, if you like to climb mountains, your health span is going to be different than if you like to play golf, for instance.
And a lot of this is personal. If you can't run a marathon anymore, some people will say, Oh, my health is never pay attention to the mental health piece, at least the biologist. What is my health spend? I would only be able to ask you that. So we do this exercise, guys, because I completely agree with you, Steve. We call it the marginal decade exercise. So we say to every one of our patients, and I write about this a lot in the book, everyone will have a marginal decade, which I define as the last decade of your life.
So obviously by definition, everyone has a marginal decade. Most people do not realize the day they enter it, but most people have a pretty good sense when they're in it. Okay. So the exercise we do is we go through with the patient and we say, what are the things that are most important to you to be able to do in your marginal decade? And they generally fall into three buckets with a sub bucket, physical, cognitive, emotional, social.
The physical bucket we kind of divide into activities of daily living and recreational activities. So that's where, again, most people obviously into it that, boy, I would really not be happy if I couldn't take care of myself. If I couldn't get out of bed, get dressed, shave, cook, that would be disappointing to me. But then, of course, you have different levels of ambition within the recreational side. I've got patients who say, when the day comes that I can't heli-ski, I'm going to be devastated. And other people are like,
I just want to be able to garden. That's going to create a very different standard. On the cognitive side, you have people who say, I want to be able to run my hedge fund and still make money and make really important investment decisions. And other people are like, I want to be able to do crossword puzzles and read the newspaper. I agree with you. You can't define it, but it doesn't mean we shouldn't try to personalize it.
Okay, but I want to come back to you, Matt, with the original question. Why are we at a point where- Why is longevity gone mainstream? Yeah. Yeah. Yeah. For a lot of other ways. Yeah. So, I mean, I think both of the points that Stephen Rich raised are part of the equation. I mean, I think it's a convergence of all of these factors and maybe a few others. I do think
The science has matured to the point where more people are believing that we can actually modulate the biology of aging. I think the concept of biological aging has become popularized through a variety of mechanisms, including some influencers, individuals who I personally think often err on the side of being a little bit less scientific than they should be, but I think they've helped popularize the concept. So I think it's been a combination of these factors.
And why it has taken so long, I mean, I just think that's the pace that science moves and the rate at which these concepts can sort of permeate the public sphere. So it's frustrating in a sense that it's moved so slowly. I also wonder, because you sort of said, are we at a longevity bubble? I don't know. I think maybe we're still kind of in the early days of this hockey stick moment, where you're getting this exponential increase in attention. My hope is,
As we go forward, it will become more scientific and less snake oily and suspect them. There's this huge gray area in the field right now of what's real and what's not real. And I think none of us at this table actually can really define exactly where in that gray area that line is, or is there a line?
To that point, Matt, what is the collective wisdom of the group on the funding appetite for that? Because I agree with you completely. If we could channel this exuberance away from the highly commercial speculative grifting towards the budget-increasing, legitimate, investigative, that would be awesome. What is the appetite right now of NIA with respect to this?
I think it's hard to say it. And I mean, NIH is a moving target. And as we all know, there's going to be a lot of change coming in the near future. So cautiously optimistic, I would say if you look historically, it's been really pretty terrible. The percent of NIH budget that goes to biology of aging, I think is still probably around half of 1%. Sorry, just to put numbers in perspective, NIA gets what percent of NIH? No, I understand. Within NIA is a sub-fraction that goes to biology of aging. Yes, yes, yes.
but I'm saying there are 17 groups of NIH. NIA being one of them gets what fraction of NIH budget roughly? I think it's roughly 3%. 3% of NIH budget is NIA. Within NIA, how much goes to this type of research? It was about 350 million a few years ago. It might be a little higher than that, but I don't think it's ticked up any more proportional to the increase in NIH budget since then. So it reaches about half of 1%. Wow. What's your level of optimism, Rich? You're obviously very close to this.
that NIH will wake up and start to pay attention to aging research the way they should. It's near zero. It's been near zero for 30 years now. Even with this outside attention.
Well, it's gone up. I mean, they funded the ITP, the inheritance testing program 20 years ago, and they liked it and they doubled our budget about 15 years ago. So that's something, and I'm very, very grateful to them for that. But there's still an enormous untapped potential for making progress in the basic biology of aging. And the reason is, again, a matter of defending turf.
If you are a cardiologist, researcher, or an oncologist, researcher, or an AIDS researcher, or an Alzheimer's researcher, anytime somebody says, the smart play is to reduce your budget by 10%, or your institute's budget by 10%. We're going to go there faster if we spend money on aging and its relationship to the disease you care about. You get the porcupine defense. You don't take any of my money because Alzheimer's is important. Little kids with leukemia are important. Breast cancer is important. You go away.
And that is the predominant feeling most of the people making those decisions were not trained in aging research they view it as something interesting I read something about that in time magazine the other day. But they don't understand that to actually conquer or slow down or affect.
or protect against the disease they care about, the smart play is to do aging research. And so they view your suggestion, which I, of course, agree with 100%, as an imposition and invasion to be repelled at any cost. No one in a position of power has had whatever it takes to reverse that. And if he or she tried to do that, Congress would, even a good Congress, would smack them down. The Alzheimer's
Group has a hundred lobbyists. The cancer group is a hundred lobbyists. The AIDS group has a hundred lobbyists. The aging group has two lobbyists, one who's a lawyer and one who takes the calls and it's not enough to do it. Can I just add something real quick? I agree completely. And I think as well, the reputation of the field has hindered that transition as well.
So historically, the field was viewed as not very mechanistic, kind of phenomenological, became much more mechanistic, starting around the time of Cynthia Kenyon's work. And since then, but has continued to have a reputation problem as not being as rigorous as other areas of research. So I think it is absolutely a turf war. And there's this overcoming the reputational problem, which makes it harder for
serious people in funding and policy circles to give it the attention it deserves, in my opinion. I've got a different take on this. I actually think that this is a very good time for aging research funding. That's not because of what's going on at the NIA.
but it's what's going on in the private sector. There's more and more money. There's even interest now in big pharma that was very spotty in the past. So I think if we focused entirely on the National Institute on aging, we would get a false impression of what the funding climate is in the field now. And I think we need to take advantage of that. Got to make sure that it doesn't get captured by the people who are doing the flashy, but bad science.
You're saying, look, Calico, Altos, other private companies, especially within biotech and pharma that are looking at your protective molecules building on the work of the ITP, yeah, I think it's safe to say the amount of money that's being spent privately, probably out does public spending. I mean, in a given year two to one, easily. It could, although how much of that is actually going to biology of age? I think it's still an open question. You mentioned Calico and Altos, right? No, we don't know exactly.
I actually agree with Steve. I don't think what Rich and I were communicating is opposed to what Steve was communicating. There are a lot of opportunities right now. And again, this is sort of what I was alluding to is are we at the beginning of this hockey stick moment? And I think Steve's right, there are real opportunities for more resources to be focused on the scientific side and hopefully less focused on the non-scientific aspects of what are going on.
And you asked the question of, can we shift resources from the more consumer facing, maybe not as rigorous stuff and into the more rigorous stuff? I'm not a fan of that stuff at all. But maybe you need that stuff to kind of move the needle and get people's attention. And at least people are talking about longevity now.
Naive question. I'm embarrassed. I don't know the answer because I spent more than two years working there. What's the mission statement of the NIH? It's to preserve and enhance human health. I mean, it's basically the same thing that we do that we're supposed to be doing. Yeah. And I didn't actually get to give you my spiel here, but what I started to say about the NIA budget is if you look at the major causes of death and disability, and it's again, we talked about how it's hard to define health spend. So if we just look at causes of death, if you look at the top 10 causes of death in the United States,
Nine of them have biological aging as their greatest risk factor, and it's not even close. Yet, half of 1% of the research budget that's supposed to be focused on improving human health goes to study that risk factor. I think it is extremely frustrating to all of us sitting at this table that that hasn't changed, but there's reason to be optimistic that maybe it will change in the near future.
Let's state that again, because it is so profound. I want to make sure not a single person missed that statement. The top 10 causes of death in the United States are well enumerated and incredibly predictable, and they increase by category, by decade, 3 to 8 percent monotonically with no exception. Point being 90 percent of and more than 90 percent on an adjusted basis of what causes death goes up with age.
And yet, a few basis points of federal R&D goes to addressing that. Let me give you an example of what the sort of point that Matthew and you have been making. About once every five years, I give a talk, an invited talk at the University of Michigan Cancer Center, and I point out that we have drugs now, anti-aging drugs,
in mice and they extend mouse lifespan and they do it mostly by postponing cancer because most of our mice die of cancer. And if you look at age-adjusted cancer incidence rates, our drugs reduce these by a factor of 10. Wouldn't they like to know why? As cancer scientists, we now have a batch of drugs that postpone cancer. Wouldn't they like to study them?
Invariably, I get one call back from somebody who says, that's interesting. Maybe we should talk about that. And then it dies. And then five years later, I am asked to give the same talk or a related talk. So they know how to do cancer research. They are cancer scientists. That's how they know how to do cancer research. And you certainly don't do it by diverting your lab's attention to aging. That's insane. But that insanity is how medical research is organized and breaking that
addiction to the kinds of models you grew up on because they're a better idea, not an easy thing. It may not even be a possible thing to do. That's a major hassle. I think this is because we think about health all wrong. We think, let's wait to get cancer and see what we can do about it. That's what cancer biologists do. You have cancer. Okay, how can we better treat that? Or could we have diagnosed it earlier?
What Rich is saying and what we can know how to do in lots of model organ, it prevents you from getting cancer, delay it for a considerable amount of time. That's a little bit harder to study if you're a cancer biologist, because you want to see the cancer before you can study it. I think that's why we need aging biologists rather than people focused on certain disease to come and try to use what we do. If we prevented the cancers, they'd be out of the job. I guarantee these people or mice will get cancer. They'll just have
10 extra years of life, if they're a person or 10 extra months of life, they'll get cancer, they'll need specialists, it'll be alright. Yeah, I think that's important. I mean, I think the reactive disease care component is still going to be there, even if we're insanely successful at slowing age and people are still going to get sick.
But I think Steve's point is really important. Like Peter, you've been a leader in helping people recognize the need to shift the medical approach from reactive to proactive. I think what a lot of people don't realize is that mentality goes all the way back to pharmaceutical research, biomedical research, basic science that is ingrained all the way through. And I think one of the challenges with getting funding for aging research is that mentality on the basic science world and how deeply ingrained it is.
It's very interesting because you don't know which is the tail and which is the dog. I've always assumed that the one leading the charge is the clinical side of things. In other words, the engine, the machine of medicine 2.0 is built around the delivery of care. The delivery of care, as you said, Steve, is built around
I'm going to wait. I'm going to sit here and hang. We're going to wait when you get the disease. We're ready. You had the heart attack. Fantastic. You've got chest pain, ST elevations. We got to stand for you. Now you have cancer. We're all in. And then the research flows from that mindset. Of course, I don't know, not that it really matters, but it might be that it's flipped, right? It might be that the clinical engine behaves in that way because that's how the base of the pyramid has been built.
Again, not that it necessarily matters, but if you could be health czar and fix one of them, you might actually start with the research side of things. I would. I mean, the reality is the research flows from where the dollars are going. This has been seen over and over and over at NIH. You shift resource allocation to a certain area and the scientists will follow and they will submit grants
to get grants in the place where the funding line is the highest. So if somebody came along and said, we're going to go from 0.5% to 50% of NIH budget is going to go to biology of aging, you'd have no shortage of people. I mean, it would be kind of messy at first, but you'd have no shortage of people applying for grants and becoming experts in the biology of aging.
And the system would work. You'd get the best and the brightest that would go into that and do that. So this then begs another question that is a tired question, but I can't help but ask it at this point. Is aging a disease? Is that even a relevant question? Call me. Call me. Call me. Call me. Yes, Mr. Miller. It's important to use words optimally and to distinguish causes from effects.
One of the bad things about aging is it's a risk factor for many diseases. Some things are the risk factors for diseases. Aging is a risk factor for disease. And so saying that aging is a disease confuses that discussion. It makes it impossible to see that relationship. So calling aging a disease is a fundamental error. The question itself is incorrect. I agree completely. I think it's the wrong question.
I agree, but I think we have that idea for marketing purposes, not for scientific purposes. And the idea is, well, the money goes to diseases, let's call aging a disease, because I think what we're trying to do is we're trying to treat aging as if it were a disease, even though I would agree with both of you. I don't think it's a disease. I think that destroys the word disease if we include aging in it.
But I think there was a reason that suddenly this came because you thought, oh, maybe this will get Congress to pay attention. You're right. It's a marketing ploy. And if you think you can convince people of the importance of aging research only by crossing your fingers and saying, oh, well, it's kind of a disease, isn't it? You think you can fool them? Yes, that's what marketing is. And it's probably good for that. I just don't like lying to people.
It also creates a negative feeling about the field in some people as well. So I think that should be considered. The other point that people often raise though is we have to call aging a disease in order for FDA to approve a drug for aging, which I think is a fundamental misunderstanding of how FDA operates, but that is the other argument you will often hear among proponents of the idea that aging is a disease. Very interesting.
Well, so now let's go one step deeper on that. How do you think about biologic versus chronologic age in concept and in practice? On the right over here, Rich and I were talking about that. I don't believe there is one thing as biological age. I think there is potentially an age of your heart, an age of your liver, an age of your lungs, an age of your brain, but I don't see why we wouldn't simply call it health.
In other words, I got one of these epigenetic age clocks done on me a while ago, but I didn't know what to make out of it. I thought, is this just flattery or did it really tell me something? He must have got a good result. He's 13 years old. That may be the point.
of the whole thing, right? So I'm dubious about some number that is different than I know I'm good health for my age. I'm in very good health. So I knew that already. Now I have a number for it. I don't put much credence in that. Let me agree with Steve, but just put it in slightly different terminology. It's a matter of taking a very rich, complex data set and trying to collapse it to a number. So if someone wants to know how healthy I am, he or she would need information. How good is my eyesight?
How good is my hearing, how good is various kinds of cognitive activities, my aerobic endurance, my joints, all of that is pertinent to how my health is and also about projected future health. Then there's no need once you've got that information, which is very rich to say, ah, there's a number, a single number, a real number on a point on the number line that condenses that in any useful way.
A notion 40, 50 years ago that biological age was not the same as chronological age. For a little while was useful, it emphasized that there might well be six-year-old people who were unusually like youthful people and six-year-old people who were unusually like 70-year-old people would my drug or my genetic mutant or whatever help to discriminate those people or change them in some way. I can slow your biological aging process. That's
a discussion that was maybe of interest 40 years ago and it's now time to drop the notion, let alone the silly notion that you can count that biological age, that number which some people, too many people still think is a value. You can figure out what it is by measuring something, transcriptions or epigenetic markers or something. I can do it and give you personally your personal biological age.
That's a waste of everyone's time. And it also distracts attention from things that actually are important and need to be thought about. I got to talk because I think I disagree fundamentally. I'm surprised, but this will be an interesting conversation. So I agree that the idea of a kit that you can buy to measure biological age, first of all, the stuff that's out there doesn't work and we can and should talk about that.
But also, I sort of agree with the idea that reducing it to one number, while conceptually, I think it's possible. I think in reality is going to be really, really difficult to do. But do I believe that there is a biological aging process that is different from chronological aging? Absolutely. Oh, yes, absolutely. It sounded like you guys were both saying, no, you didn't think it was a real thing. No, no, no, no, no, no. I agree with that completely. You can agree with that and not like the idea of a number of the chance to do your biological age.
There's two things that kind of make me feel pretty confident in this idea. One is, and this is the example I use a lot among the general public is just look at dogs compared to people. Everybody's familiar with the idea that one human year is about seven dog years. What does that mean?
Means that dogs age about seven times faster than people do. But of course, chronological time is the same between dogs and people. It's the biological aging process. And so you can look across the animal kingdom and see this and dogs get almost all of the same diseases and functional declines that we do at the tissue and organ level, but also the whole body level.
We also know now there are single genes that significantly modulate what I would call the rate of aging. Now, maybe we have a different meaning to what we mean that. No, I agree. So the fact that that's possible. We talked about DAFT2 a couple of times. Tor, we can turn these things up, turn them down and animals across the evolutionary spectrum seem to age at different rates by modulating single genes. So I don't know of any other explanation other than that there is this process.
which we call biological aging that can be changed and the rate can be sped up or slowed down. Can it be reversed? That's an interesting question. Maybe we'll get to that. But I think the process is real. I think it's just really, really complicated and we probably only understand 5% of it at this point.
Yeah, I think for me, the challenge is I kind of land where Rich was, which is if a patient says to me, hey, why aren't you doing this biologic age clock on me? My response is, well, I know your VO2 max. I know your zone two. I know your muscle mass. I know your visceral fat. We did a very complicated movement assessment on you. I understand your balance. I understand your lipids, your insulin, like
I know these fifty seven things about you and i can tell you individually on each of them how you're doing that number. Doesn't tell me a single new piece of information but what if you were to come up and you probably do this in your head you come up with some sort of composite you probably don't sit down and wait each of those things and come to one number.
But you come up with some sort of composite picture of health based on all of those things. That's a different biological aging clock. I think sometimes we conflate and in part, this is because of the way that irresponsible people in the field and marketers have done this. We conflate the epigenetic tests.
with biological aging clocks. There are all sorts of flavors of biological aging clocks, including things like frailty indices or metrics of a whole bunch of functional markers. So I think those probably are pretty good readouts of biological age. Again, can you combine them all to get to one number that's meaningful for every person? That's much harder to do.
Yeah, tell us about your experience because this was, you did what I wanted to do, but I've been too lazy to do. Yeah. In fact, we exchanged emails at one point about doing this and each coming up with different names. So what I did was I tested four different direct-to-consumer biological age kits. They were all epigenetic biological age tests for different companies. And I did duplicates of each kit and it was from the same samples collected on the same day. Really tried to put my scientist hat on.
I only had two replicates. I didn't have three replicates, but it's about the best I could afford at that point. And it was kind of expensive. So anyways, sent those in, got the results back. And they were, to me, very informative, fundamentally sort of changed my views on these epigenetic age tests. So they ranged from 42 to 63. I was 53.75 years at the time I did the test. And the standard deviation, I can't remember, it was either seven or nine.
So mean of my chronological age, standard deviation of seven or nine, which I look at that data. I'm not a statistician, but I know enough statistics to say that's completely useless. They converged on my chronological age, but with a huge variation, even intro. So that varied between the tests. So I think three of the four were reasonably close to each other. Three of the four companies, the duplicates were reasonably close to each other, but the individual tests were far apart.
And one of the companies, the individual replicates was 20 years apart. So to me, and some people will say, but maybe the true diagnostic test is great, and the Elysium test is terrible, or the Talley Health test is terrible, and the other one is great, maybe. But how do we know? My take home is that the direct-to-consumer biological age testing industry is a complete mess.
And I have no idea who to believe or if any of them are actually giving accurate data. I know some of the people at some of the companies and I have my personal feelings about who's trying to do it right and who's sort of a charlatan. But across the industry, it's really hard to know. The last thing I'll say on this is the where I've sort of landed is I think these are really good research tools. I think the direct to consumer component has gotten way ahead of itself. And I think I align with what you were saying about the way you think about these tests. I don't think there's a lot of value.
in clinical practice right now because we don't know precision or accuracy. And I don't think you can make actionable recommendations based on these tests. Furthermore, they fail in the one thing that I think they're attempting to do. And I usually use this illustration with patients. So if I have a 40 year old patient who says, I really want to do one of these tests, I say, if the answer comes back and says you're 20,
Is your expectation that you will live another 70 years? Conversely, if the answer comes back and says 60, is it your expectation that you will live another 30 years? In other words, is this number predictive of future years of life? Because right now we have this thing called chronologic age that is the single best predictor of future years of life. So do we think biologic age as determined by these tests is better as a predictor of future years of life?
Which, by the way, would be very testable. How many people have contacted you to get ITP sample data to say, can we predict how much longer these mice we're going to live? The answer to the question is obvious and very well known. You can tell if you have a 40-year-old patient and he or she is fat, doesn't exercise. It's mostly cheeseburgers. You know that their life expectancy is probably not as good as a 40-year-old patient in your next waiting room.
that has extremely healthful habits on whose parents live to be a hundred. And there's tons of problems. I don't need a biologic age to tell me. Right. That's what I'm saying. Yeah. There are tons of things you can measure on individuals for five of them or all you really need to ask of a 70 year old. Yeah, MetLife does this really, really well. Because their buddies all the lie there. They're writing life insurance policies.
So it's not at all hard to figure out a very small set of tests to tell you how long a seven-year-old is likely to live. There's nothing to do with methylation clocks. That's the gold standard. When life insurance companies start using biologic clocks as the cornerstone of their actuarial algorithms, I'll start to move it back far away from that. I'm going to sound like a broken record here, but you guys keep saying biological age when what you mean is epigenetic age or epigenetic.
Not necessarily. And we should explain to people that there is a difference. So some of these clocks use solely epigenetic measurements. Not all. Most of the direct-to-consumer ones are epigenetic. But some of these tests use a litany of biomarkers inclusive of epigenetics. So they'll say, we've sampled your methylation pattern, but we also looked at your vitamin D level, your glucose level, your cholesterol level, and a whole bunch of other things. And we compressed all of that into a number as well.
So I guess let me frame it as a question to you. So let's take the epigenetic piece out again. I do think we will get to a point where the technology is developed far enough and the quality control is good enough on the consumer side that these tests will be better than just chronological age. I think we can get there.
That's a big statement. I don't know that I'm disagreeing with you. I just want to make sure we understand. I think it's clear from the research, unless you think that all of the research that's been done on these epigenetic aging clocks is somehow flawed, it's clear that you can create algorithms that can predict specific methylation patterns that are more highly correlated with life expectancy than chronological age. But I think the big but here is that even if that's the case, they would not be as good as what Peter would predict after all the tests
Biological age, that's what I want to get to. Yes. And I think what you are actually doing is looking at other biomarkers that have a long-term clinical history that you're using to come up with a surrogate, but really is reflecting largely biological age. Maybe not completely. And this is the other point I wanted to make is I don't think biological age and health are equal. I think they're strongly overlapping. And certainly you can identify many ways to reduce health without accelerating biological aging.
I think that's easy. We can all think of ways to do that. So let's take a minute and try. Yeah.
Let's think about this for a second. I have seen very impressive data where we can look at tissue samples of organs and we can tell, okay, I'm going to show you a sample of nephrons. And just based on nothing but the methylation pattern, we know that if I just said to you, one of these is a 20 year old, one of these is a 50 year old, and one of these is a 70 year old, it's very easy to predict based on the methylation pattern, which nephron came from which person completely agree with that.
There are a lot of things that change with age. The literature has 25,000 things that change with age. Average amount of methylation at these 10 spots is number 11,407 of those. So great. You've got another thing that changes with age. So that's the question. That's not enough. Right. So do you believe that all of the research we're seeing on the epigenetic clocks is going to be
the 78th variable that we would include in our Gestalt. I don't know. Yeah, it's a good question. So I am hopeful that epigenetic algorithms can get to the point where they can replace many, certainly not all, but many of the other biomarkers that are being measured. I think the thing that gives me hope is we know that epigenetic changes are part of biological aging. This, again, is a different question, but if we look at the hallmarks of aging, epigenetic dysregulation is one of the 12.
Some people argue it's the most important one. That's a different conversation, but it's at least part. So that gives me some hope that we are in fact measuring something that plays a causal role in the aging process. And I think what's missing, I think what would give all of us a lot more confidence is if we had a mechanistic connection to the specific methylation changes and some cause of aging or age-related disease. In other words,
This change in methylation changes this particular gene's expression level, which changes the rate of biological aging. Think if we had that, we'd feel a lot more confident. Yeah, you and I spoke about this very briefly at the end of our last podcast, and I want to come back to it with all of us on this table, because there's so much in what you just said, Matt, that I'm going to lay out a broad question, and then we can start attacking it in different ways. So one of the things I want to address is, do we believe
that it's possible that of the hallmarks of aging, epigenetic change is the most important. Another topic I want to address, do we believe that the epigenetic changes that we observe over time, which are undeniable, are causal in the arrival of other states, everything from the arrival of senescent cells, the increase in inflammation, the reduced function of the organs, which really is the hallmark of aging,
And if so, does that mean that reversing the epigenetic phenotype will undo the phenotype of interest and rich where I'm going that you and I left off was, what about the proteome? What about the metabolism? So you made three statements there.
broad general statements. And I think each of the three deserves careful amendments. Let's do it. To be polite about it. The first test to do with hallmarks of aging, which I think set the field back dramatically. I think when you are officially branded a hallmark of aging by two people sitting alone at their computers and writing a review article, a hallmark of aging. I thought they were walking around a pond when they came up with this. Walk around a pond. Okay, okay.
means that somebody wants it. I'm interested in aging. That's kind of important, isn't it? Let's put it on our list. You can't tell if something is a hallmark of aging. Does that mean it goes up with age? It goes down with age. You can change it in a way that will extend lifespan. You can kill a mouse or a worm by removing it. Basically, it's something that somebody wants that might be of interest to aging.
And the downside of that is once you're officially branded as a hallmark of aging, anyone who wants to write a grant on that doesn't have to prove that they're a fundamental cause and effect model has any merit because it's a hallmark of aging. I don't have to prove it anymore. Someone I don't know who or what grounds has decided it's important. My reviewers know it's important because they've read the hallmark of aging paper.
So I don't have to think about whether it's important. The negative side of that coin is that there are lots of things that didn't make it into the hallmark list. I really think it's premature to close thought off on some of those. It's easy to come up with a dozen.
things that ought to be investigated. But if you want to investigate it, it's not on the hallmarks list. What are you wasting? So deciding which of the hallmarks is the big daddy hallmark or whatever strikes me is not the correct thing to talk about in the hallmarks arena.
So maybe we should talk about that before we go through all of these. I think there's a lot to remember the other ones. If you guys could afford to give me a little piece of paper and a pen to be able to write down. I think the hallmarks is a list, a kind of arbitrary list, not completely arbitrary because they had some reasons for being there. I don't think any of us would say that those 12 things are not involved in aging.
But that's a very little into any of us want to rattle them off being that I'm the only one that's got the list sitting in front of me. We could do a game where we each name one and see who can't see if we get to all 12. Yeah. But certainly in that list, I would not consider epigenetics as the key hallmark. Assuming there are such things, I consider it to be an interesting list. It became.
Biblically sacrosan, almost immediately. And I've never understood why, but for some reason it did. So I'd agree with Rich. So conceptually beautiful. I mean, so I agree completely with Rich and he knows I do because we've talked about this before. I think the flip side is I think the hallmarks have been immensely useful to the field. They are a very.
easy way to communicate this idea of biological aging. And it helps convince some of the scientific community that thought it was all just hocus pocus and snake oil, that there is some mechanistic research happening. We can point to specific things that are aging. So I think that part of the hallmarks has been actually really valuable and has contributed to the popularization of longevity. And at least to the extent the science of longevity has been popularized has contributed to that.
And it has been extremely detrimental to the field. And the way I think about it is it just caused the field to narrow prematurely. And this goes back to what I alluded to before. I don't know if we understand 80% of biological aging or 0.005% of biological aging.
My guess is it's closer to 0.005% and by and large, the funding to look outside of the hallmarks dried up once the hallmarks became the dominant paradigm and people stopped looking and I think we need to go back to more discovery science and thinking outside the box.
I think it's been a double edged sword. Would that happen automatically if we could wave that magic wand and increase funding? It would help. I don't know that it would help enough, but it would help. I mean, you also kind of have to change the mindset about what people call phishing expeditions. That's like a bad word in grant review panels, phishing expedition, meaning you don't really know what you're going to find, but you got to go look before you can figure out what's important. So we have to kind of change that mindset as well.
can usefully concretize this discussion. I imagine that one of this, I don't read these papers because they upset me, but I imagine inflammation is on one or more of this. I'll bet. Chronic inflammation. Okay, good. Chronic inflammation. So what that does, if you say I'm interested in chronic inflammation, so I'm doing good stuff, huh? But what could be happening is this particular set of cytokines might be over expressed by some glial cells and that leads to loss of cognitive function.
Whereas this other overlapping set of cytokines produced by the macrophages in your fat, maybe you're more prone to diabetes or metabolic syndrome. Whereas this particular set of lymphocytes are necessary to repel COVID and that's why you are more susceptible to COVID.
So learning what changes within the extremely broad, generic idea of inflammation, what changes in what cell types, in what people under what pharmacological or genetic changes, how they are interacting with other aspects of pathology, that's marvelous to do. But to say, oh, inflammation, that gets bad when you're old, is a way of avoiding the labor of thinking. And that's why I'm against it.
And I think Matt brought up a really important point and we scientists are to blame is the way that research gets reviewed. For lazy reviewers, having these 12 hallmarks is really helpful. Oh, this has got one of the hallmarks in it. This must be good stuff. I do think reviewers need to be more open to new ideas and new approaches. I mean, everybody knows that NIH grants are approved if they're incremental.
If they're really breakthrough, they don't get approved. In fact, very famous biologist, E.O. Wilson, told me years ago, he said, don't ever include your best ideas in a grant. They won't get funded. Do it standard stuff, save your best ideas for projects that you do on the side. That's one of the reasons I left academia. Throw me nuts. Almost impossible to get the important stuff funded.
The second of your multi-partite question was, does epigenetic change, what are the results of? Is it causal? And the third which we may get to is, can you reverse it and would that be a good thing? So let's talk about the second element here. Is it causal? The problem is what it means. There are
some changes that occur in this particular set of 40 cells in the pineal, and there are other changes that occur in these cells in the bone marrow, and there are other cells that change in the gut and villus lining cells and the crypt cells. So they are all epigenetic in some. They are caused by some things, and we don't really know which, if any of these
Count for aging if someone says i'm gonna prove that an epigenetic change is responsible for aging they haven't begun to come to grips with the nitty gritty people always ask just as you hinted does your drug change epigenetic.
things. And unfortunately, that's where they stop thinking. We're always willing to give people tissues from our drug treated mice if they are keen on epigenetic changes that affect neuron regeneration. Excellent. Their experts will send them the brains and they can do that stuff. It's important. I'm not making fun of it. But the general notion that that's aging vaguely thought of is due to epigenetic change. More vaguely thought of doesn't really get you anywhere. That's my skeptical view.
Is part of the issue that you're saying, well, what's causing the cause? No, it's just that the concept of epigenetic change encompasses thousands of changes in hundreds of cell types under hundreds of influences. Of course, some of that causes other stuff agreeing to that, ascending to that notion that epigenetic change is causal for all sorts of age-related pathologies.
Everyone can agree to that, but it's meaningless because what counts is to say this specific change is really important in this disease. Here's an epigenetic alteration or this specific broad spectrum change in multiple tissues causes something good or bad. You have to define what it is before you can test it. So let's use a specific example.
When you look at a patient with type 1 diabetes and you look at their beta cells in their pancreas, they look different epigenetically than the beta cells of an age matched person without type 1 diabetes. And we also know that their beta cells don't function. So they've lost function. So let's ask that question as a specific example. What do you believe or what confidence would you assign to the notion
that the epigenetic change on the beta cells of the type 1 diabetic are indeed causal to the loss of function of the beta cell. My last exposure to the causes of type 1 diabetes was an isometical school, which is more than five years ago. But if I vaguely remember it was an autoimmune disease, right? So if your poor little helpless beta cells are being attacked by antibodies and macrophages and things,
Those stressors reactions are going to cause epigenetic change. And whether those epigenetic changes contribute to some extent to the ill fate of the beta cells is possible. And if I were an expert on diabetes pathogenesis, I'd really want to know that. It doesn't have anything to do with aging, but it's an interesting question. But it's a way to address causality. Yeah. But you might equally say, no, no, it's my decondry that have changed. They're a hallmark of diabetes. Yeah, or it's the glycated proteins.
There's a ton of things and there's no reason in the world at this stage, I think, to actually give epigenetics primacy over anything else. And then it's a nice hypothesis. It's a hypothesis. You can formulate these questions because a lot is known about type 1 diabetes. And I understand 0.05% of the biology of age. 0.05. Yeah. I was giving... You're off by an order of magnitude. I'm tenfold on raising you by a lot. Yeah, I thought you were one log off.
Formulating the questions in exactly the way Steve did makes it clear how difficult it is to evaluate the concept that epigenetic change contributes to pathogenesis and type 1 diabetes. And we know more or less what is going on. We don't know what's going on in aging. We don't even know what part of that body is going on or parts more likely of the body.
I at least internally reframe it a little bit and say, what would the experiment be? What would you need to do to convince yourself that either broadly speaking epigenetic dysregulation causes aging, whatever that means, or this specific epigenetic change that is associated with chronological age causes aging? And so that's an easier way for me to think about it because I feel like it's all a fascinating conversation, but we're never going to get to the answer until somebody actually does the experiment.
or decides that it can't be formulated because it's too complicated. It gives up. Yeah, that's right. But people are trying to do both of those things. I mean, people are using partial or transient epigenetic reprogramming and asking, can that have effects on biological aging? I'm actually cautiously optimistic it can. I don't think it's going to be a game changer, but I think you can modulate aspects of biological aging. The technologies are being developed for targeted epigenetic modifications. So if we think this particular epigenetic mark
at this particular location in the genome controls aging. And I don't think it's going to be that simple, but let's say it is, you could go in, you could modify that and then see, do you reduce disease? Do you increase lifespan? Do you improve health span? So those are the kinds of experiments that I think would get us to where we can have a lot of confidence.
If it's the case, if somebody, let's say at Altos, publishes a paper three years from now that they have made a mouse live six years by multiple rounds of transient epigenetic reprogramming, I'll be like their biggest fan. They moved the needle. That convinces me that that strategy modulates biological aging. Nobody's done that yet.
What about something far less impressive, but still worthwhile? So consider if we could get to the point where we could locally deliver vectors that would epigenetically change chondrocytes so that you could take osteoarthritis in the knee and just regenerate cartilage, regenerate cartilage by changing the epigenome. But is that biological aging?
I wouldn't be convinced that's modulating the biological aging process. I would be convinced that's a clinically useful strategy for people who benefit from that therapy. I guess it kind of depends on why we think an individual would be experiencing osteoarthritis. How much of that is senescence? How much of that is inflammation before we cut out that?
Is it the S word? Yeah, yeah, let's talk about sedescence. If you think osteoarthritis of the knee requires a knee joint replacement and that's going to help your patient, you are not rejuvenating. It's perfectly possible to do great things with technology, including condrosite regeneration without having to decide that that's related to aging. People don't age because they fail to have titanium knee joints or something.
One way I think about this, and again, this may be completely wrong, but it's a useful way for me to think about it, is I think about age-related disease as the downstream effect of biological aging. For most diseases, there becomes a point where the pathology of that disease mechanistically is no longer the same as biological aging, in which case- It's very good. You should listen to them. One of the implications of that is the interventions that slow biological aging may not work.
Once you get past that point, but things that do work for that disease may have nothing to do with biological aging. Does that make sense? Yeah, go deeper on that idea, though. Let's use the example. I mean, what's your favorite disease?
My favorite disease. Let's talk about cancer. Cancer is an easy one. We know with cancer, in many cancers, the process is you have one or more mutations, which then often lead to additional mutations. You get genome instability. Eventually, you get an oncogene that gets activated and that leads to uncontrolled cell division. There are more tumor suppressor gene that gets deactivated. Yeah, right.
If we accept that immune surveillance is one important anti-cancer mechanism, we know that immune surveillance declines with age. Early on, we're clearing a lot of our cancers. As our immune system declines, these cancers are going to escape immune surveillance. They're going to accumulate all these mutations. They're eventually going to go into uncontrolled cell division. That uncontrolled cell division, at that point,
You can treat the cancer, but uncontrolled cell division is not biological aging. It's not a part of the normative aging process. So the treatment there, so the mechanism now is fundamentally different from normative aging. And the treatment, let's just say the treatment in this case is chemotherapy might benefit the cancer, but it's not going to be a normal aging. Yeah, right. Yeah. And I think rapamycin is a good example here where I think we all believe that rapamycin and inhibiting mTOR slows biological aging.
At least in up to mice, hopefully in people. It's a fundamental node in the network. That's the way I think about the hallmarks of aging. It's a node in the network that underlies the hallmarks of aging. We can manipulate mTOR with rapamycin, slow aging. Rapamycin is a pretty good anti-cancer drug.
until the cancers have evolved to ignore the mTOR break, then rapamycin doesn't work anymore. We know rapamycin doesn't work for most cancers. That's an example. That's been tested. We know that. Yeah, absolutely. It's because the cancers evolve to bypass the mTOR break or to bypass the ability of rapamycin to inhibit mTOR.
That's a really good point that we all take for granted that I think is worth noting. Rapamycin can be unsuccessful as a chemotherapeutic agent and can yet be very successful as a cancer preventive agent. Absolutely. And it's exactly for that reason. And I think this also illustrates why traditional disease based medicine is not about the biology of aging. It's about something of the biology of aging.
is distinct and it needs to be investigated in a different way. And we know that in the aging field, but the people in the cancer field, in the cardiology field, in the neurology field, I don't think they understand that. This gets to, if I were health czar, this is what I would do because it comes back to what Rich said at the outset, which is, why is this a zero sum game?
I mean, you didn't ask it that way, but that's effectively the problem you're dealing with, which is why can't we study cardiology, oncology, and neurology, and aging without everybody feeling like a team. So my way of saying that in Peter terms is we need to have medicine 2.0 and medicine 3.0 in parallel.
Because the tools of the medicine 2.0 scientist and physician, which we see on display today, are putting the stent in, giving the chemotherapy, lowering the cholesterol, all of these things. The medicine 3.0 toolkit looks different. Different science, you're going to use rapamycin here. You're not going to use it over here because it's too late. Instead of saying one or the other, why isn't it both?
Why wouldn't we want both of these running in parallel? Well, we would. But of course, zero sum game is a pretty good analogy for what's actually going on. The amount of research dollars at least available to NIH is not infinitely expandable. It's set by a complex political process. And then there's a separate downstream process that allocates it amongst institutions. So saying that it would be a good idea to have more funds. I agree with you. I'll bet these two guys do as well.
But it's not easy to do. Yeah, I think I misspoke. It will be a portfolio of geolocation. But it will be worthwhile because the burden of this disease will be lower. So in other words, it's sort of like saying, right now I spend $100,000 a year on the barrier to my house to prevent anybody from breaking in. And I spend $100 a year patrolling the neighborhood to make sure there aren't too many bad guys in the neighborhood.
There's a scenario where if your total budget is $100,000 and $100, maybe you could spend $80,000 in total by spending more money patrolling the neighborhood. I think we generally agree with you that having a greater proportion of available research dollars, both private and public going into the biology of aging and its impact on late life health would be a good thing. I don't think you're going to get an argument here.
But I also think you're going to get a huge argument from anybody in the cardiology field, the neurology field or Alzheimer's. Alzheimer's field. It's their money. But wouldn't some of those people as the funding dollars move towards the aging side also want to move and say, look, I'm going to study this through the aging lens. I was on the council for the National Aging Institute for three years.
And if at any point i can swear to this from personal testimony somebody would say something like i wonder if maybe a few percent of the alzheimer's budget might instead go to studying how slow aging models would have an impact on late life nor degenerative disease the next day the director of the aging institute.
would get a call from two or three Congress people who are on the Appropriations Committee stating that this will not be happening because there was an Alzheimer's Association person who got the call from the NIA staff member in charge of Alzheimer's saying, tell the Congressman to call the Director and let's put a stop to that reckless idea. They're tied in to the political process in ways that those of us who are not. Well, we just need to go maybe one step further because those Congress people have a boss.
They report to somebody too. Would that be at the stage? Yeah, no. I mean, come on. Maybe it's because the public doesn't understand this. Those people answer to the public. That's a good example. These are our dollars that are going to work. But Alzheimer's Association, I mean, that's a patient advocacy group. That is the public.
Yes, although let's ask the question, what have they done for those patients lately? Well, that's a different question, but I mean, I'm just reinforcing what you said. I think part of this is educating people. If you know somebody who's suffering from Alzheimer's disease, you know very well that the only thing we've got going for us right now is prevention. We don't have too many silver bullets in the treatment gun. Despite
massive spending. I was once in Congress trying to lobby with about six people from the Alzheimer's Association in the same room. I was totally ignored by staffers that were in there. I agree with all of this. I agree with all of this. I think, again, though, we should be careful not to demonize people for wanting
to cure Alzheimer. It's a good thing. It's a good goal. I think the communication piece is about the fact that it's going to be much more efficient and effective to keep people from getting it in the first place. This goes back to the idea that once you've outpaced the biology of aging with the pathology of the disease, it gets a lot harder, a lot harder to do anything about it. So I think that communication part, honestly, I don't know why we've been so unsuccessful because I think a lot of us have been out there
trying to communicate this message for a long time, but it's starting to permeate. We're at that moment, I think, where people are starting to get it, that biological aging is a thing. It's malleable.
We don't really know for sure what works in people and what doesn't work yet, but we're getting there. It's going to take a little while, but there's reason to be optimistic. And there's also the private sector is another reason I think to be optimistic. So let's go on record right now. I think when we, if we defeat Alzheimer's disease, it's going to be because of the biology of aging. It's not going to be because of the drugs that get rid of. Absolutely. Yep. Probably cancer.
Probably heart disease, although I think Peter's more optimistic we can prevent heart disease. If you took the tools of medicine 2.0 and just applied them 30 years earlier, we wouldn't have a CVD. That's the one place where it's where. But again, that's because the mechanism of action is so well understood with a CVD compared to Alzheimer's and cancer. A lot of infectious disease.
A lot of liver disease, a lot of kidney disease, all of those things can be improved dramatically by targeting the biology of aging. If I were to write my book again, I would add a fifth horseman, because I talked about these four horsemen of ASCVD, cancer, neurodegenerative and defending diseases and metabolic disease, but I would actually add a fifth hallmark. It's not really a hallmark of disease, but it's the fifth thing that brings life to a bad close, which is immune dysfunction.
And I don't think I gave that enough attention in the book because, of course, as you said, it factors in very heavily to oncogenesis. But also, as COVID showed us, what a risk factor it was to be old. And, you know, I'm reminded of this when I see people my age get brutal pneumonias.
And like two months later, they're okay. And you realize, two of my patients actually in the past six months have had really bad pneumonias, where you're looking at the CT of their chest, and you cannot believe they're alive. But of course, they're fine. Three months later, four courses of antibiotics later, they're fine. And you realize, you do that to a 75-year-old, it's over.
And it simply comes down to how their B cells and T cells work. That, to me, is an area where I'd love to see more attention, which is what would it take to rejuvenate the immune system as a proactive statement? That's part of the X price health span challenge, of course. I think that that's a perfect example. Influenza pneumonia has never fallen out of the top 10 causes of death in the US. It used to be number two, but still now it's number eight or nine, but it's always there because
You can't really do anything about the late life immune dysfunction. Just to follow this up, if magically you become in charge and you're able to double the amount of research being done on the biology of aging fundamentally, then we can afford to do. Let's give some mice to start with a batch of anti-aging drugs and see if it makes them more resistant to infectious illnesses, including pneumonias, but viral infections as well and many others.
I'd love to know the answer to that, and no one has actually really looked in a serious way, because the ITP has enough money to just measure lifespan, and then we're hoping that everybody else is now going to look at the brain and the lungs and the infection, the sensory systems. That really ought to be done, and it's not being done because of a lack of money.
You said something a while ago, Rich, that I think is timely now, which is with each generation of these drugs, they get more efficacious and less toxic. Not yet, but that's the hope. Well, no, no, but I'm going to use another example. The GLP ones are the best example of this, right? So you go back to the very, very first generation of GLP one agonists, barely lost any weight, horrible side effects.
Generation 2, about 10 years ago. A little bit better weight loss, side effects so-so. Fast forward to semaglutide. Quite a bit better efficacy, still really bad side effects. Next generation, tricepatide. Better efficacy, side effects are almost gone.
Now, why haven't we been able to do that with these geoprotective drugs? So we have this one study using Everolomus that gives us a hint that says, hey, this might actually enhance immune function in people in their mid 60s. But we need the follow up study, the follow up drug. Imagine what the fourth generation of that drug can do, where it's tuned to get the
better and better. Strong commercial motivations. You know, you're going to sell a lot of the obesity drugs. They're very strong commercial motivations to do those studies over and over and over again until you find one that works better. And they're good preclinical models that you can use that you're not wasting too much of your time on clinical trials.
That could be done for anti-aging drugs as well, although testing anti-aging drugs in people is a whole separate set of tangle of difficulties. I don't want to talk about that right now, but I'm saying it won't be quite as easy as it was for anti-OBC medications, but no one's doing even the first level of research to find the optimal compounds for efficacy without side effects or even
To begin to see if they have desirable effects on aging rate indicators in people, that's kind of a cheap and easy study and no one has really tackled that yet. Well, I just heard that there are over 80 senolytic studies in early clinical trials.
It was a joke. It's a joke. It's a joke. It's a joke. We have to come back to it. Are any of them are any of them powered for anything other than safety? This is, I think, the problem is one. Yeah, exactly. So they're underpowered. They're almost useless, in my opinion. Well, until they get to phase two, phase three. How many years have we been having phase one analytic trials now? I don't know. At least a decade. God, has it been that long? First one, I remember was 2017. So yeah, a decade easily, because I probably wasn't paying attention in 2014, 2015.
There's lots of complicated issues here. I think endpoints for clinical trials are really challenging, but solvable. There are two places I wanted to go next, and I'm going to let Rich decide, because he's going to have the strongest point of view. Can we talk about senescence? Or can we talk about what biomarkers would be necessary to help us study aging in humans as we translate from your work and Matt's work? I know what I want to talk about, and it's the second of those two.
I don't want to spend the next three or four hours explaining why senescence is silly and anti-synolytics are untested at best. There's no way we're not talking about that. Let's go on to item number two. And I think the most important thing is to make a clear distinction between biomarkers and aging rate indicators.
Please explain the difference to people, please. Okay, I'll do my best. So a biomarker allegedly, and in real life, is something that changes with age. So if you have some drug that slows aging, the biomarkers, many of them in the different cell types and in the blood will change more slowly. They are a good way of looking at whether you're slowing and you'll work in the dogs.
Long live dogs and short live dogs will have differences in the rate of change of biomarkers, a very established part of the literature and valuable. But you have to wait till somebody's old, whether it's a dog or a mouse or a person, because only when they're old has the biomarker of aging, the surrogate marker for biological aging changed very much. So in a clinical trial, certainly in a human situation, no one wants to wait 20 years to see whether the biomarkers have changed.
And a one year is such a tiny fraction of a human lifespan that you don't really anticipate detectable change with a appropriately powered study. It's like aging rate indicators, which are much less well studied and much less well established in principle are things you can measure that tell you whether in a slow aging state or a normal state. Can I just make a point for the listeners so they understand the challenge of what we're talking about?
When we study blood pressure drugs or cholesterol drugs, the biomarkers change so rapidly. And we know the relationship between the biomarker and the disease state. So if your blood pressure is 145 over 90 on average before I give you this ACE inhibitor and three months later, six months later, nine months later, a year later, your blood pressure is averaging 119 over 74.
I know I've done something well. Now I will still probably in the phase 3, in fact I will in the phase 3, have to make sure that I also reduce some event in you. But generally by the phase 2, I know that this drug is not toxic and that it's predictably lowering your blood pressure, that's really really
A biomarker generically is something that's easy to measure that is informative about something that's hard to measure. A classical example, a famous example is you want to know how many cigarettes somebody smokes a day, they'll lie to you. But if you measure cotenine in their blood, that's a byproduct of nicotine, you don't have to ask them, you can find out how many cigarettes they had in the last couple of days by measuring blood. That's a biomarker of cigarette consumption.
Is it a marker of nicotine or carbon monoxide? I don't know the answer to this. I wasn't sure. In principle, a biomarker of aging is there many of them and they are measuring biological aging processes and they're useful in that regard, but they don't tell you how fast you're aging. The analogy I love to use is an odometer is like a biomarker of aging of your car. It tells you how many miles your car has gone, but it doesn't tell you how fast the car is going.
The speedometer tells you how fast your car is going and so what we need and what I think we're just beginning now to document is things like the speedometer aging rate indicators that reliably discriminate slow aging my sore people from regular old my sore people.
We have now a dozen or so things that change in the fat, in the blood, in the liver, in the brain, and in the muscle that are always changed in any slow aging mouse, whether it's drug A, drug B, drug C, calistriction diet, or single gene mutations. We've looked now at five different single gene mutations. And this whole set of 12 or roughly 12 aging rate indicators always changes in every slow aging mouse. And it does so in youth, which is the key point.
So if it does so quickly after an anti-aging drug is administered, that's the transition. That's the bridge you need for clinical studies in people. If you want to know whether metformin or conagloflosen or something slows aging in people and you don't want to wait 20 years, but you've got things that tell you whether they're in a slow aging state, how fast they are aging versus normal. And that's a big if we don't yet have evidence we can do that. We just have hope we can do that.
then that allows you quickly, quickly being within six months to a year to know whether your anti-aging manipulation, alleged anti-aging manipulation, has moved them to a physiological status, which is associated with slower aging. A lot of that can be done in mice with drugs, with mutants.
And are these all proteins rich? No. Some of them are changes in the fat of different classes of macrophages. The pro-inflammatory macrophages, the bad ones, go away. The anti-inflammatory macrophages, the good ones, go up. UCP1, I recall. UCP1 goes up in every one of our 10 different kinds, 11 now, slow aging months.
up in any of the mice that did not receive a successful drug.
and then make those comparisons a really important thing to prove. So far, our only control has been untreated mice. At some point in this, I had to bring this up. But let's imagine that Rich is incredibly successful at finding these things.
That is a very, very long way from assuming that it's going to be the same in people. Most things that clinically work in mice do not work in people. It might be, and that would be wonderful, but I think ultimately we're going to have to find this for people. And my thought is the kind of evaluation that you do routinely of your patients.
If we took a group of 65 year olds and we gave them a drug that we thought was an anti-aging drug and followed them the next five or six years doing these evaluations, I think you could probably safely say, this is slowing aging or not slowing aging. So I don't think that it's going to be that easy to jump from ice to people in this. I've always wondered if in people the easiest way to do it.
would be to take the most obvious thing that we know is going to reduce the rate of aging. So it'd be an interesting experiment, but you find someone who is overweight, diabetic, and smokes and has hypertension. You get hundreds of these folks. You put half of them on a to be ethical, a plan where you try to get them to stop and presumably many don't.
In the other group, you pull out all the stops and you don't care because you're interested not in testing the hypothesis, does this thing help you? You're interested in getting them to lose weight, not have diabetes, stop smoking, exercise like crazy. The greatest division between two groups of individuals where we would, I think, be able to agree that this group is now aging slower, the group that we've
reconcile their diabetes, quit the smoking, et cetera, et cetera. And then I'd love to see Rich's 12 line up in that population. That would be great. Let me just say that I think that people that study animals, myself included, always underestimate how well we can evaluate health in people with a very, very thorough evaluation, because we don't do that.
Why do you think that is, Steve? Why is it? Because I was going to ask about parabiosis later on in the discussion. We might as well talk about it now, right? Parabiosis seems to actually kind of work in certain mouse models. Do we have any reason to believe it's going to work in humans? And if not, why not?
Why are mice so different from people? Well, wait a minute. I wouldn't say that just because we don't have evidence that it works in humans means mice are different from people. First of all, when it comes to parabiosis, that's a different discussion. But I agree that if you look at the attempts to cure cancer or other diseases in mice and translation to people, most have failed. I actually think that's because those are artificial mouse models where they tried to give young mice an age-related disease. I'm more optimistic, I don't know this.
Rich doesn't have those mice. Yeah. I know. I'm more optimistic that biological aging or normative aging is going to be much more likely to translate to people, both interventions and biomarkers than the specific disease interventions. I might be wrong. I don't know the answer. We would hope that's the case.
That's fair. I don't think we should rule out the mice as a useful model. In fact, I think there's reason to be optimistic that it will. I actually am kind of bullish on parabiosis as I think it will work to some extent in people. It's not a pragmatic approach for population, gerotherapeutics. But I'm just wondering why it wouldn't be as efficacious.
This is something that, I mean, aren't there six or eight clinical trials going on right now? Different variants of that. Yeah. Yeah. I haven't seen them. I've seen the one that's looking at, it's not really a parabiosis study, but it's looking at plasma for recess for Alzheimer's. I consider that a little bit different, but fair enough. Okay. Because they're just using albumin, I think, aren't they? Right. But there's also studies going on of young blood.
Yeah, okay, okay. But if you think of parabiosis as both taking away the bad stuff that accumulates with age and adding in the good stuff that's in young, some sort of plasma exchange hits at least half that equation. Okay, I'm going to come back to this, but my question was why the difference? You're saying that the difference is probably amplified in disease specific cases like heart disease, cancer, and Alzheimer's disease, probably less relevant when you're talking about aging because even a flawed mouse model still ages. In fact, it's designed to age in a certain way.
Yeah. And I mean, I think normative aging looks very similar. Again, if we look from mice to dogs to people, just broadly speaking, the process looks pretty similar. So I'm cautiously optimistic that these things are going to translate. Not to pay too much attention to Steve's pessimism on this point, although he's completely right. Of course, most things that do have an important effect in mice fail in human clinical trials. And it's for a variety of reasons. Sometimes humans are different from mice. Sometimes the drug has side effects.
that are tolerable in mice, not tolerable in people, et cetera. But I always like to look at the other side of the coin. That is, if your goal is to develop a drug that blunts pain in people and you screen 40 or 50 drugs and you find a couple that inhibit pain in mice, that's a really good start. It doesn't guarantee they're going to work in people, but it gives you this category of snail-based neurotoxins.
Let's make 40 of those from 40 different snails. We'll find one that actually in people works can be made by a scalable process and doesn't produce serious side effects. So it's not a one to one mapping. It works in mice. It doesn't. It works in people, but it's an important critical first step, which usually succeeds in finding a set of drugs of related families or with related targets at least.
There are efficacious in people, most drugs that are used in people had useful rodent-based research somewhere in their pedigree. Absolutely agree with that, Rich. Nobody's saying that 100% of things that work in mice do not work. But I think there's a critical difference for aging research, which takes four years.
to do one of these and mice. And so if we have to do 40 to find one or two, that's why I like aging rate indicators, speed things up. I'm stepping on your toes, Peter, but the question I always come back to, I agree, we need these aging rate indicators. How do we get to the point where we're confident that they actually work in people? And maybe more importantly, how do we get to the point that FDA is confident that they work? That's the only way you're going to be able to use them in a clinical trial. I don't see a path in the short term.
Well, I don't know that we need that to tell you the truth. So I went to the FDA to try to get them to approve a trial of metformin. And we didn't couch it in aging because you're right. As soon as you mention aging, their eyes glaze over and they're not interested anymore. But we did it in terms of multi-morbidity and they were fine. They were fine with that.
different end point. That's not a biomarker. My right to your question is that you've merged two different difficult problems. Problem A, can we find drugs that slow aging in people? Problem B, can we surmount the legal and political barriers to getting them to work? That's not what I was asking. I was asking how do we get to the point?
Okay. What I'm saying is that you were focused on something I don't have any answers to, basically, which is how do we get the FDA to develop and approve clinical trials? I was more interested in a step before that. It'd be nice to have some drugs that actually do work to slow aging in people.
But you have to trust the biomarker of aging rate before you can be confident that the drug that moves the biomarker of aging rate works in people. That's fundamentally what I'm asking. How do we get to the point where let's just take FD out of the equation? The four of us would sit and look at the data and I'll be like, yeah, well, that's sort of my work experiment. I would have to take an example in humans that is so egregious that nobody with a straight face could say one group isn't now aging slower than the others. Sure. Would that convince you though? So let's say we do that.
Well, it would make me worry. It would only show you the positive signal. It would show you the specificity and not the sensitivity of the test. That's the problem. You might miss the signal. If you found a proteomic genomic, like if you found a multimodal signal that detected a difference in rate of aging between those two very extreme sets, you might miss it with a gyroprotective drug, which wouldn't be as dramatic as that change. So what if I told you that there are people who claim
There are epigenetic signatures that do that, that correlate quite well. They claim with health outcomes, 10-year mortality, five-year mortality, three-year mortality in people, and are measuring the rate of biological aging.
Because it's out there. I mean, it's in the literature. I mean, this is not perfect, but it would be one thing I would immediately think of, which is I would take a really good bio bank that would have enough samples that I could sample a bunch of human stuff and use an unbiased sample and a bias sample. So I would determine an algorithm based on one and see how well it predicted on another based on enough samples.
That would have to be true at a minimum. Yeah, I think it is. I mean, again, at least it depends on how much faith you put in these research studies, but I mean, people have published epigenetic algorithms. Dunedin PACE is the one that most people are going to talk about that correlate seemingly pretty well, at least with mortality and with metrics of health span for lack of a better way of framing it. So that exists. Dunedin PACE is using something besides epigenetic or is it only epigenetic? I think it uses something else. It was trained off of
other biomarkers. And then they found epigenetic marks that correlate with those other biomarkers. So it's a correlation to a correlation, but there's still a correlation. What do you think, Rich? Well, I wanted to go back to the example you gave where you took a lot of people and gave them intense exercises and dietary changes to improve their health, likely health outcomes. And that's a good place to start a discussion because you said every sensible person would see
the treated group as aging or slowly. I would want to ask before I agreed to that, do they also have improved cognition? How are they doing in cataracts? How are they doing in hearing? What happens when you give them a flu shot? Do they have a great flu shot? The things you point to are really important for both overall health and for cardiovascular risk and the things linked to that. So it's nice to know. But to convince me that you now have a slow aging group of people,
You need to go beyond the risk factors for specific common human diseases. If you could show that then for the first time I would be convinced you had an effective anti-aging manipulation in people. Currently I don't know that there is any effective anti-aging manipulation in people. If your approach got there that would be a terrific research model.
Well, but now we're getting into the definition of aging a little bit, which is, would you agree that the approach I'm describing would produce a longer life? It's easy to produce a longer life. If you happen to have a clinical condition where you're tied to a railroad track and there's a train coming, you can extend that woman's life enormously by simply giving her a knife and cutting the bonds and letting her walk away from the track.
Longevity promoting interventions. 80% of people died as a result of trains on train tracks. That might be a worthwhile example. But given that 80% of people die from these four chronic diseases. I'm all in favor of protecting people against chronic diseases. That's a good thing. I'm glad that people are doing that. No question about it. Now, talking about the biology of aging, there are all sorts of things that also happen when you get older that are not part of those chronic diseases.
And to make a case that you've got an anti-aging manipulation, you need to show that those are changed. But do all of them have to change or just most of them? Don't enough have to change that you increase the length and quality of your life. And if you still get a cataract at the same rate, I'm not sure that should be disqualifying.
Right, but the important thing I think about what Rich said is all the stuff that he pointed out could be easily done in humans. Wouldn't be hard to measure hearing. The nice thing about the dog examples, we've got well-known, famous, long and slow aging dog breeds, and it's true for horses too. It's certainly true for mice.
is that more or less everything slows down together, the tiny dogs that are very long lived. It's not just that they have a delay of cancer, they have a delay in neurodegenerative disease, a delay in digestive diseases, in joint diseases, aging has been slowed in those dogs.
and if the dogs did your way. We might not have an intervention that does that to your point, Rich. I'm saying we might not have a non-pharmacologic method that does that. It's not clear that even though exercise clearly extends lifespan, it's not clear that it's doing so by slowing aging. Those are two different things to your point.
It's not clear, but it's an interesting question. Do you believe exercise slows aging, exercise healthy diet sleep? I have no idea. I think so. My intuition is I think so, but I can't point to the evidence that tells me so. Well, there's evidence to support it. The question, does it rise to the level of evidence that would convince rich? I believe it probably does too, but I'm not going to say up with 100% certainty.
i think here's where we get back into health span versus life span effect of exercise on longevity is pretty small it's a fact on quality of life is enormous somewhat depends on where you start. I've always found these to be a little bit problematic because i don't think that.
Defining it by the input is as valuable as defining it by the output. In other words, to say you exercise this many minutes a week versus that many minutes a week is a little dirty because intensity matters. What you do matters. Sometimes the output is what matters more. How strong you are, how high your VO2 max is. Those tend to be more predictive because that's the integral of the work that's been done. But your point is it's well taken. The impact on health span is what I tell my patients. If this amount of exercise didn't make you live one day longer,
The quality in which your life would improve would justify. Now, fortunately, we can move past the semantic discussions because there's no molecular ways of checking this exercises. I'll bet all of you know, increases an enzyme called GPLD1 in the blood of exercise people and in mice.
And so vietas lab has shown that if you elevate gpld one, it does great things to your brain more neurogenesis and more brain derived protective factors brain drive notropic factors. I recent also goes up in humans and in mice after exercise, it does great things for your fat as does cloth.
Let's leave that for a moment. Oh boy. Oh boy. I'm striking all the nerves here today. All right. You may be quite right. I wanted to stick with the GPLD1 and I reason to make the point that they also go up in all of the slow aging mice. That is all the anti-aging drugs, the calistrictor diet, the isolucine-restricted diet, and five different single gene mutants that extend lyspanin mice. They all elevate GPLD1. 17-alpha estradiol.
Yes. Can I go flows in both sexes. Well, this is the key question. I reason is sex specific GPLD one is in both sexes. This is how one begins to answer that question. This is the exact kind of question one has to ask. So if you are.
interested in the idea that exercise regimes have a benefit beyond the obvious exercise linked physiological declines at age. Do they improve cognition? And if so, how these molecular changes are the things you need to begin to investigate. The anti-aging studies in mice show that the anti-aging drugs, at least the ones we've looked at so far, increase the same things that exercise does.
Rich, have you done this experiment with an ITP cohort where you run in addition to a drug parallel? Nope. You know what I'm going to ask? Well, you're going to ask if we exercise our mice. Yes. Yeah, we've never done that. So you haven't done a sedentary versus exercise? You have not done that. You haven't done a obesogenic versus fasted.
We never use obesity, genetic diets. It's worth doing it. The IDP doesn't do it. We don't have the resources. We have enough resources to test about five drugs a year, but if we wanted to test them in exercise versus non-exercise. We got to get you a budget increase because that will now get to this question because now we could look at the solution. Maybe it would. Maybe it wouldn't in mice.
I'm very agnostic about what we can learn from exercising mice because mice are basically kept in a jail cell, something the size of a jail cell their entire life. If you took a bunch of people and put an exercise wheel in a jail cell that would use it, would that be the same? Would that substitute for people that walk around to go inside, they go outside, they go to the gym? That do this substitute for all of it. No question. So to me, it's a very low level of exercise. If you didn't see anything from it,
then you wouldn't rule it out. Right. So the testable molecular hypotheses that link the biology of aging to anti-aging drugs and to exercise and teasing out how those are interrelated and which of your exercise regimes increase irison, increase GPLD1 and increase neurogenesis,
That's a research agenda that could be very valuable. Then if you want to screen drugs in people to see which ones deserve expensive long-term testing, the ones that raise GPLD1, IRISAN, and some aspect of a neurological function, in addition to the good stuff they're doing for the muscles.
That's an approach agree completely and this gets back to what we were talking about before with the epigenetic changes is if you had a mechanistic connection which is what rich is drawing there. Not only this is correlated with this outcome but here's why we all feel a lot more confident that this is real that it's important and especially if that mechanistic connection is preserved in people.
Do any of you believe that GLP1 agonists are gero protective? I'm super interested in that question. I don't know. We need to find that out. They look good. I think there's two parts though. Are they gero protective from a caloric restriction effect, or are there caloric independent effects that could potentially be gero protective? I'm actually asking the second question. I'm taking the first as a given.
Yeah, that's a different question. Is chronic caloric restriction beneficial in normal weight people? But most people taking GLP1 agonist aren't normal. Yes, yes, yes. And I think it's impossible at this point because the studies are all done in obese and patients with type 2 diabetes that we can't disentangle them. So we will just say that for that patient population, the caloric restriction appears to be geroprotective. But yes, you're right. I'm technically asking the second question, which is, in an individual who is metabolically healthy but overweight,
where there's actually no evidence that weight loss per se is necessary. Outside of maybe some edge cases in orthopedic stuff, is there a zero protective nature to this? And where it's most talked about is in dementia prevention right now. That's where it's at least most complicated to tease that out. So what do you guys think? And it clearly has neurological effects as effects on addiction. The dementia connection is not- It's crossing the blood brain barrier.
I mean, Rich, this is one for you to test. Why hasn't the ITP tested this yet, Rich? Is it because the oral ones are just not strong enough and we want to... Can you break your protocol and do an ITP with an injection? No. Why? Because it's enormously laborious to do weekly... That sounds like an I need more money problem. And also you need a separate control group. That sounds like a I need more money problem. Because you get shame injections and are... Yes, if you increase our budget dramatically, I think it's a worthwhile experiment, but what we're waiting for
is oral drugs that work, that you don't have to do injections of drugs. There is an oral semaglutide formulation that's taken daily. We submitted to us this year. The detailed protocol, however, is, again, technically very laborious. Each mouse has to be food deprived for six hours, then the material is administered, and then they have to have a change in their water balance for the next two hours.
It is technically not an injection, but it is not any less laborious. And in addition, you have to have your own separate control group that gets all of those different manipulations with a sham injection. Could you do three instead of five next year and make that one of them?
Reallocate some funding. Well, I'm not in charge. It's a heavy lift. I'd vote against it. I would vote for waiting about a year until somebody comes up with a pill that you can just mix into mouse food or water and give it to the mice and it'll work. And these are going to be mice that are an incredible amount of stress from all the handling the injection. Yeah, that's why the control group is necessary. But the companies are putting so much money into this. They understand why people don't like to inject themselves. I'm reasonably sure. I mean, I know nothing about it.
But I'm reasonably sure that in a year or two, there'll be some agent that works when you put it in the food of a mouse or pop it as a pill as a person. Those would be enormously important to test. Do we know if there's appetite, for instance, if we're given to people of normal body weight, do they also lose 15% of their body weight?
I have not seen the data on that. I can tell you anecdotally having seen patients, it's going to be dose dependent. So as you know, that drug is dosed from as low as two and a half milligrams weekly to as much as 15 milligrams weekly. Usually people who don't need to lose much weight, someone who says, look, I just want to lose this last 10 pounds. And I've done all the exercising and dieting I can do.
They typically just lose that 10 pounds and they take a very low dose. Now, to your point, if they took the 15 milligrams, would they become sarcopenic? I don't know. I think this conversation points out, again, how constraining lack of resources are. I mean, there are... We can sit here in 20.
And I mean, every time I hear Rich talk about this stuff, it just pisses me off because there's a bunch of stuff that should be tested, should have been tested by now, that hasn't been tested, not because it's not a good idea, but because there just isn't any resources to do it.
Well, I think what's really frustrating as well is that these are the types of experiments that would allow us to actually start to economically model the impact of these drugs outside of just kind of a disease state. For example, if drugs like these are indeed your protective
And people can work three years longer, five years longer because they're healthier. Think of the impact on that over at OMB. What does that mean to tax take? What does that mean to delaying Medicare? What does that mean to reduced healthcare spending at the time when it is most expensive? So last estimate I saw was 38 trillion a year for every year of health span. Wow. That was a Mackenzie report.
38. I'll send you the link. Not 3.8? No, 38. That's analysis by Andrew Scott, his British economist. That's bigger than I would have guessed. Wow.
Can we just, because I'm in the mood to see you get spicy, can we just talk about senescence for a minute? Senescent cells, he means rich, you know, the things that drive aging. What do you mean? Do you want me to talk about senescent cells? Okay, yes, I'll be glad to do that. It's a terrible historical accident. Leonard Hayflick way back found that human cells would only divide 50 times and stop one of his colleagues, a guy named Victoria defending made a joke at lunch and said to him, Hey, Len, maybe they're getting old.
And then did not understand it was a joke. He thought it was a serious scientific hypothesis. It's clearly nuts because we don't get old in a way that is modeled by having embryonic lung fiber blasts. Stop growing. But at the time, the hottest technique in modern medicine was you could grow cells in culture. I was really so cool. You could do stuff with them. So all the cell biologists who really wanted to use the coolest new toys.
wanted to have a way of studying aging without all these messy mice and rats and having to wait and stuff. They could do it in vitro because this is in vitro aging. This is in vitro senescence and the field to skip 30 or 40 years. The field went ahead with this metaphor without ever questioning it. It's now such an industry that the people who review these grants and papers and advise billionaires and advise startup companies
They all were trained in labs that just do senescence for a living so they never stop to question. One of the most famous and best scientists in serious women in duty camp easy recently passed away last year she and i were assistant professors together boss university. She and i were going to send a program project with a third person barber bill crest.
I was going to study immunity and aging. Barbara was going to study skin cells. We talked, Judy, you want to study cells in essence. So she read the literature, she came back to us and she said, it has nothing to do with aging. I mean, it's good cell biology. It's good about cancer biology, but of course, there's nothing to do with aging. And we told Judy, of course, it has nothing to do with aging. We understand that. But the reviewers think it is aging. So if you can just keep a straight face for the three hours of the site visit, pretend you think it has to do with aging.
You'll get a great score. And that's what happened. She got a great score. We got the program project when she moved to Berkeley. She took her grant with her. And after a year or two, she had apparently convinced herself that it was aging. It was close enough to aging. So the notion that aging is due to senescent cell accumulation is bad for two reasons. It's a grotesque oversimplification. The evidence for this is awful.
But even worse, it again cuts off productive thinking. There almost certainly are changes that occur in some glial cells in the brain. So as you get older, they start making bad cytokines as bad for your brain. There probably are changes in some bone cells or some cells in the lineage that leads to the beta cells in the pancreas that lose the ability to divide.
And that's bad for you. And finding out how it happens is really important. But once you've convinced yourself, that's all the same thing. This cytokine, this sort of proliferation, this change in ability to make specific fibers connective tissue, let's call that senescence. It's the same thing.
You've lost what you need to think of good, careful, well-defined experiments with well-defined endpoints. If you say that there is a thing called a senescent cell, the thing that's happening in this glia and in this marrow cell and this pancreas, it's due to the senescent cell.
Accumulating, you blocked off productive generation of research hypotheses. The last point I'll mention in this rant has to do with senolytic drugs. So the ITP was asked to test an allegedly senolytic drug called Fysetin.
It was given to us by someone who is using this now for clinical trials as a company that's interested in senolytic drugs. So we gave it to mice that had no beneficial effect whatsoever. What's the mechanism of this drug's action? It has no action.
has no action or it had no effect. It had no effect. What is it supposed to do? It's supposed to kill senescent cells or something. So we told this guy, sorry, it had no effect. He said, well, let's prove that whether it had any change in senescent cells. So we gave him blind tissues from each of the treated and untreated mice. And he tried to test and there were no changes in senescent cells by his marker. He tried six different markers. There were no changes in senescent cells.
So then he said, well, send the brain and the liver and the muscle. Maybe the senescent cells have been changed in the brain. So we send blind samples to a colleague of his. There were no changes in senescent cells by any of the markers that these folks looked at. So this drug, which is now being marketed in clinical trials, and you can buy it, I'm sure.
It's a natural product. It's a natural supplement. There's no evidence, as far as I know, that it either has an anti-aging effect or removes senescent cells. But once you've got a commercial company pushing the stuff and your whole brand, your whole lab, your whole program project, and all the people who are reviewing you are convinced senescent cells exist, their bad and drugs can kill them. It's a snowball rolling downhill and a rant of the sort of just delivered has no impact on the field.
So can I give a, yeah, I want to tell you an example, because there's good experimental data that these things can be at least partially eliminated. And when you do that, there's an improvement in health. And this has been done both in a genetic treatment, which genetically, which they prime these cells to be genetically killed. And it's also been done with drugs, not with ficetin, I hasten to say.
So I think there's strong evidence that getting rid of these P-16 positive cells, which is really what it's all based on, can have an improvement in health and in longevity. This is the Van Derson paper you're talking about in which they were allegedly depleted. Yeah, yeah, yeah, yeah. Let me tell you about that, because I was on the program project.
The two papers, okay, one was with the short live mice. Yes. Okay, so don't talk about the one that is not the short live mice. There's a paper, a famous paper by Van Derson, Kirkland, and several other colleagues, Darren Baker. Are these the guys at Mayo? Yes, they will. I remember this.
They've left, two of them have left, but yes, they allege that they could remove senescent cells by taking genetically modified mice, giving them a drug, all the senescent cells would go away, and the mice lived longer, according to the paper. It was in the cover of Nature. It was on the cover of Nature. I remember this one. I was a part of the program project, so was Judy Kempese, and my job was to do the lifespan experiment.
We got the mice from Kirkland and Venderson. We got Campeses mice. We got the drugs from them, and we gave the drugs to the mice at 18 months. And, you know, they had no effect on senescent cells. Not one. We tried seven times to show depletion of senescent cells in their mice using their drug and went zero for seven.
We then took the tissues, blinded, and sent them to Judy's lab, Judy Campese's lab, so she could measure p16 cells. But she didn't know which ones were from treated and which ones were untreated. When we undid the code, there was no effect on senescent cells whatsoever.
So I remain somewhat skeptical. I asked Venderson, had he measured the number of senescent cells in his treated mice? No, we're planning to do that. But what was the phenotypic change in the mice when you did this experiment? Oh, when I didn't want to do an expensive lifespan experiment,
with an alleged anti-synolytic drug until I knew that it was depleting senescence. So how long did you treat for? I used their protocol and I asked them, I asked Darren Baker, what is the dose? How long do you treat the mice? And how long after you add the drug should you wait before you detect the removal of senescent cells? And his answer astonishingly was, we don't know. We've never looked at that. But the nature mice were treated for how long?
They were a long time. They're a long time. They were treated. I think they started treatment in middle age. In the published papers, they do show a reduction in P16 positive cells, and you're saying you couldn't replicate that in your lab. We're conflating a bunch of different issues here. We're conflating the genetic model with the drugs, and do so in essence, cells even exist. I think Rich's skepticism is valid in many ways, and there's actually a large body of evidence that
Whether we agree on the definition of senescence, what people are calling senescent cells do accumulate in multiple tissues with age in mice and people. And if you get rid of them, you can see some health benefits. Am I convinced they have big effects on lifespan? No, I'm not because the data is mixed. And even that genetic model, other people haven't been able to reproduce. So it's messy.
But I think partly maybe start with what is the definition of a senescent cell, because that's where a lot of this confusion comes from. That's what I was saying, that there is no satisfactory definition. Satisfactory to you. I mean, is your issue rich that we talk about it like it's one cell? That's a big part of it. You can't think about it clearly if you imagine that these many, many different kinds of cell intrinsic changes with potential pathological impacts are all aspects of the same phenomenon.
But we do that with other things with mitochondrial dysfunction. There's lots of different ways to get to mitochondrial dysfunction. So the NIH has just put about $600 million into a network of researchers to study cells and essence. And I'm on the advisory group for that. And to the extent that Rich is saying, these are many, many different things, all pretending to be the same thing.
That's clearly true, but they're coming up with bigger and bigger and broader definitions of what a senescent cell is. But on the other hand, they're also coming up with more and more interesting things that those senescent cells do, either in tissue culture, which I don't put much or in mice. I don't think the NIH would put that kind of money into something if they didn't feel there was a valid basis.
I think part of this is we're calling it senescence. And I think none of us, to me, that's stolen a really good word out of the vocabulary because senescence just means aging. And it used to be, you could talk about calendar aging, you could talk about senescence, which is what we now think of as aging. Now you can't use this anymore because anytime you do, they think you're talking about these cells.
Is this what they call the zombie cell? I keep trying to purge this for my hypothesis. The most common definition, I think, is just an irreversibly arrested cell that doesn't die and typically gives off a pattern of inflammatory cytokines and other factors.
which is a catch-all for a lot of different ways to get there and a lot of different states that these irreversibly arrested cells can exist in. Yeah, but even neurons, they're not considering senescent neurons and neurons are post mitotic. They don't always give off this pattern of signals, right? No, that's right. This is part of the problem, as you mentioned, P16. I think even at the molecular level, the catalog of markers that people are using to define a senescent cell is changing and it seems to change. Broadening, yeah.
I agree with much of what you're saying. I just don't think we should throw the baby out with the bathwater here and say there's nothing to this. I think there is something to it. And I think there's lots of evidence that, are there enough similarities between all the different classes of senescent cells that people are studying now that they should be categorized as one thing? I think that's a valid conversation to have. It's a good discussion point. I don't think we know the answer. And they discussed this a lot in the Cenect.
because even the sasp, even these things that are oozing out of the cells, varies quite a bit depending on the nature of the cell. That's the problem, of course. You referred to it as almost anyone would, as the sasp, the set of senescence-associated proteins, secretory proteins,
And once you think of it as the SAS, you've lost. Because the key point is not to do that. The key point is, here's a set of cytokines that this cell's begun to make. That's really interesting. Here's another set, overlapping probably. They make it when you've made them stop dividing for a separate reason. That's interesting. We should study that. But to think you've proven something about this cell type when you've actually been looking at this cell type because of the SAS.
has been changed. But do you think it's possible that a drug such as rapamycin has part of its effect on aging through a broad inhibition of a subset of the sasps? I think it's very likely that rapamycin changes cytokine production by
many different cell types, and that some of those changes would probably have health benefits. I would like to know what it does to the cytokine production from the macrophages in the fat and the glial cells in the brain and cells that are in charge of protecting you from viral infections. But the mistake is to say, yes, it's affecting the sass. It's easy to see an analogy. If I said, here's a drug and it helps you because it affects neurons.
You'd laugh at me because what you really want to know is, is it motor neurons, sympathetic neurons, parasympathetic neurons, neurons in your hypothalamus, what part of the hypothalamus, the ones that control appetite? And I said, no, no, no, it affects neurons.
I've got a drug that affects neurons. But I mean, people are aware of these complications and are studying these complications. Now it seems to me that it's the terminology that you object to and I can appreciate that. It's thinking that I object to you. The terminology is problematic because it makes people stop thinking about the important details and start imagining that they've had a thought when they say, I have a drug that removes senescent cells. The problem is that the words trap you into patterns of thought that are in this case non-productive and misleading.
Maybe inefficient, but the field is making, I would say, quite a bit of progress. And I think the way you learn about the complexities, you start with a simple model, you study it, and then your model gets more complicated. So I totally get the frustration, Rich, because I get as frustrated as you are about senescent cells, about other things.
I think this is also part of the natural process here, and I think what Steve said is really important. The fraction of the NIH budget that goes to study the biology of aging through NIA has remained tiny, but senescent cells are actually a really good example of how a bunch of people in other institutes are studying aging, and they don't even know it. They're studying senescence in cancer, or senescence in Alzheimer's, or senescence in kidney disease.
So it actually has had an impact in broadening the appeal and scope of the field outside of NIA in ways that I certainly didn't anticipate. Do you think that going back to the meta problem at the beginning of our discussion, do you think that's maybe a better way to think about allocating funds? So for example, the NCI obviously receives the most funding within NIH. Maybe some of the NCI funding goes to the NCI to study cancer prevention through gyro protection.