FoundMyFitness - #112 How To Slow Biological Aging With a Multivitamin, Vegetables, & Omega-3 | Dr. Steve Horvath

Starting point is 00:00:00 Welcome back to the podcast. Today I'm joined by Dr. Steve Horvath, one of the most influential scientists in the biology of aging and a true legend in the field of longevity science. Steve is best known for pioneering the Horvath epigenetic clock, which is a breakthrough that really helped make biological aging measurable through DNA methylation. Before this work, aging was something mostly described through disease, frailty, organ decline, or simply just the passage of time. Steve's work really helped transform aging into something we could begin to quantify at the molecular level across different tissues, across different disease states, and across interventions. That contribution is hard to overstate. Epigenetic clocks are now

Starting point is 00:00:46 central to some of the biggest questions in aging science, whether we can measure the rate at which someone is aging, whether lifestyle or medical interventions can slow that rate, and whether aspects of cellular age can actually be reversed. In this episode, Steve and I get into all of that. We talk about what biological aging clocks can tell us and what they cannot. This is important because biological age is not just one number. Some epigenetic clocks are more sensitive to inflammation, immune function, metabolic health, smoking history, or long-term stress exposure. others are better at estimating our mortality risk, disease risk, or the current pace at which someone is aging. And once we establish that foundation, we move into the questions that people actually want answered.

Starting point is 00:01:36 We discuss whether lifestyle changes can reverse age acceleration, whether these clocks can predict when someone will die, and why a younger biological age does not necessarily mean you have added years to your life. We also get into some of those more practical and provocative areas of longevity science, including whether caloric restriction can slow the pace of biological aging, whether omega-3s, vitamin, or a daily multivitamin can shift aging clocks. What type of exercise appears most effective for slowing epigenetic aging? Whether vegetables matter more than exercise in some methylation data sets. Whether red meat shows up as an aging signal.

Starting point is 00:02:14 How sleep disruption and social connection appear on biological aging clocks. Whether GLP1 drugs like semaglutide can may reverse epigenetic aging signals. How to interpret consumer biological age tests without overreaching. Why two epigenetic age tests may even give different answers. Whether AI will build better aging clocks. And one of the most fascinating frontiers in the field, partial reprogramming, the possibility that cells may be made biologically younger without losing their identity. We also talk about what aging clocks miss, because even if a clock moves in a favorable direction, that does not mean every single hallmark of aging has been repaired. DNA mutations, telomere attrition,

Starting point is 00:03:01 senescent cells, protein damage, and tissue level decline may somewhat still remain. And that distinction matters. A younger biological clock is not the same thing as complete rejuvenation. So this episode is really about scientific precision. Aging clocks are powerful tools, but they are not crystal balls. They are not death date calculators. And they are not proof that one supplement, diet, or intervention has, quote-unquote, reversed aging. But if used carefully, they may help us understand which aspects of aging are measurable, which are modifiable, and which interventions are most likely to move the biology in a meaningful direction.

Starting point is 00:03:43 Steve Horvath is one of those rare scientists who did not just contribute to the aging field. He helped define it. And I'm very excited to have him back on the podcast today. Before we begin, I want to point out just a couple of things. First, we have show notes for this episode, which you can find at foundmyfitness.com forward slash episodes. We've put together detailed notes for my conversation with Steve, including the major aging clocks we discuss, what each one measures, and how to interpret them without overreaching.

Starting point is 00:04:14 At the bottom of the show notes, you'll also find a brief consumer guide. to biological age testing. This will include what to look for in a test, why it matters which clock is being used, and which test to use if you are interested in mortality prediction, disease prediction, metabolic health, or your rate of aging. Again, you can find all that, including the Consumer Guide, at foundmyfitness.com, forward slash episodes, E P-I-S-O-D-E-S. you can click on the Steve Horvath episode to find all that info.

Starting point is 00:04:51 And lastly, you may have noticed that Found My Fitness is ad-free. We don't run sponsorships or interrupt these episodes with ads because our goal is to keep the science as objective and independent as possible. That is made possible by listeners like you who directly support the show. If you find value in the evidence-based conversations that you listen to you on this podcast, please consider becoming a Found My Fitness premium member. Premium membership directly supports our work, gives you access to exclusive benefits like the Aliquot.

Starting point is 00:05:22 This is our members-only podcast. Also, monthly live and recorded Q&A's with me and our curated science digest that we send out to you twice a month. You can learn more about supporting the show and becoming a Found My Fitness premium member at FoundMyFitness.com forward slash premium. Again, that's FoundMyFitness.com forward slash PRE. E-M-I-U-M premium. Thank you so much for your support.

Starting point is 00:05:51 Now on to the podcast with Dr. Steve Horvath. Just a quick heads-up, the first 20 minutes may be a little technical for a few of you because we have to explain and define these epigenetic aging clocks since they measure different things. But if you stick around, after that we get into all the practical questions that everyone once answered. Hope you enjoy. Welcome back to the podcast.

Starting point is 00:06:13 I am sitting here with Dr. Steve Horvath. Steve, good to see you again. This is the second time you've been on this podcast. You have been incredibly influential in the longevity field. You are the developer of the original Hortha Epigenetic Aging Clock, which is really revolutionized the way the aging field has been able to measure biological aging. So thanks for coming back on the show. Yeah, thank you.

Starting point is 00:06:42 I'm very excited to be here. The science has evolved quite a bit from the last time we spoke. So it's a wonderful opportunity for me to talk to you and your audience. I'm so excited. I mean, the last time we spoke was in 2019. So I would hope that there's been a lot of new, exciting data to discuss. But, you know, maybe this, the way we could start this is for people who might be new to the field, this idea of biological aging. and explaining what biological aging means?

Starting point is 00:07:19 It's a good question. Everyone talks about biologic age, but it has so many different definitions. So for many people, biologic age refers to fertility issues, as an example. Broadly, it relates to this phenomenon that people of the same age have different mortality risks, morbidity risks or people who you know from your high school they look older or younger than you.

Starting point is 00:07:51 All of that is in that concept of biologic age. However, longevity researchers or geroscientists who study aging really conceptualize biological age using measurement technologies. How do you get a number for measuring biological. age. And the field has really exploded over the last 13, 14 years. People have developed biologic age measures based on wearables, step counts, gate speed, which is very exciting. Many imaging data, you can measure your brain age based on imaging, for example. My field is in the realm of molecular markers of aging. So I work on epigenetic marks, and we can talk about it later,

Starting point is 00:08:49 but I just want to give an overview of the field. There are so many so-called genomic technologies for measuring anything from gene expression, proteome, metabolome, glycom, really any ome, and for any readout, people have developed clocks, aging measures. I started with DNA methylation. Back in 2011, we published our very first epigenetic clocks. And why methylation? Because the signal for aging and even mortality is very strong in methylation.

Starting point is 00:09:32 But when you want to measure biologic age, you really need to look at many levels of readouts, molecular, then biochemical readouts, blood biochemistry, various measures of organ function, fibrosis, as an example. And then, of course, above all, functioning measures, V-O-2 max, gate speed, and daily living-living. activities. Frailty. It's so important for people to understand that, like, you know, as we have this chronological age, everyone knows their age, right? This is how long you've been alive since the day you were born. And the interesting thing, you talked about biological aging. You know, you have this, these processes that are happening that affect your daily function. They affect your disease risk. And not everyone has the same disease risk at the same age. And so they're could be this disconnect where some people, perhaps, you know, genetic and also lifestyle factors

Starting point is 00:10:38 contribute to them not aging quite as good. And so they may get cardiovascular disease earlier or cancer earlier, right? And the opposite is true. And that's what people are really interested in. Well, let's say I'm 50 years old, but I want, you know, the organs in my body and the cells in my body to seem like they're 30 years old, right? Yes. To be younger. And so that's why it's exciting to have these tools that do measure function like you mentioned. I think, you know, cardiorespiratory fitness and VO2 max, you know, frailty. There's a lot of different ways that people are measuring function. But then on the molecular level, that's very exciting because it's quantifying this process of aging. So I... Yes. I mean, there is one key word that has to be

Starting point is 00:11:20 mentioned in that context. It's all about prevention, you know. So what motivated my work was to understand aging in people who do everything right. For example, in you. Why do you age, given that you and me, we really take care of ourselves. We try to optimize lifestyle prevention, all of that. But something still changes deep inside of us in our cells. And what is it? What drives aging?

Starting point is 00:11:53 And these methylation clocks that I've developed, they really track damage accumulation on one way or another, you know, because that is something that just happens, you know, and that drives then organ dysfunction many years and decades later, you know, but it's almost unavoidable to age. And what I wanted to accomplish with these methylation clocks is to have a precise tool to allow researchers to actually, identify novel interventions.

Starting point is 00:12:30 How do we truly reverse the ages of individual cells, of organs and the whole organism, you know? You mentioned something that caught my attention. You said these methylation clocks or patterns are able to track the damage that occurs. And that's, to me, always been a question, is it tracking the damage that occurs? and or if you're changing these patterns, does that change the damage?

Starting point is 00:13:01 So because you're globally affecting, you know, the way genes are activated or not activated gene expression, as we call it, then you would imagine, is it like a two-way street, possibly, where you're able to increase, you know, genes that we have that help take care of damage, repair, you know, all these, you know, stress response genes better as well. But I guess we'll get into that. So I think one of the points. confusion I've heard repeatedly, you know, from, from my audience and just from, you know, in general, like out there is that people think these biological aging clocks are just sort of like

Starting point is 00:13:39 one thing. You hear biological age. It's like this one thing. You reverse biological age. It's just this one thing that's happening. But we actually have very, you know, different clocks that seem to be perhaps tracking or have different, you know, strengths and weaknesses and what they're tracking and what they are sensitive to in the context of the aging process. So maybe we can kind of just, can you walk us through some of these clocks and, you know, what their core strength is, like what they are tracking and perhaps even what a common misconception is in terms of what it's tracking? Yes. So maybe we start with the big picture. Aging is, of course, associated with the accumulation of damage on all levels, the proteomic level. And the proteomic level.

Starting point is 00:14:26 metabolomic, intercellular communication, but also damage accumulation surrounding the DNA molecule, these chemical changes to the DNA. There is an accumulation of damage and that impairs than the cell function. For example, certain cell identity genes need to be active in a liver cell, and different genes need to be acting in a brain cell and so on. And so the damage impairs the function of cells and then tissues and then organs. And interestingly, methylation changes can be observed at really millions of locations on the DNA molecule. And many of these changes have actually no consequence.

Starting point is 00:15:19 And by the way, when I talk about changes on the DNA, I talk about gain of methylation at the wrong places, but also loss of methylation at the wrong places. So what is happening with aging is that the methylation landscape really flattens out. And conversely in a young cell, you want to have really peaks of methylation at regions that need to be shut down, and conversely, low methylation at regions that need to be accessible on the DNA. So anyways, these methylation clocks look typically at hundreds of locations on the DNA that are carefully chosen. However, one can really look at tens of millions of locations and people have developed different clocks based on tracking changes at different locations.

Starting point is 00:16:17 And one of the great misconceptions is to expect that all clocks disagree. agree with each other that all clocks give you this one readout. That wouldn't be reasonable, right, because you have millions of locations. So methylation clocks really capture, again, different properties of aging. Some clocks are very good at tracking inflammation. Other clocks are very good at metabolic syndrome. Then these are now second generation clocks, They really relate to inflammation and various stressors, smoking.

Starting point is 00:17:02 But then the earlier generation of clocks, so-called first-generation clocks, had a totally different goal. They just want to measure calendar age, you know. And yeah, so the misconception is that people get disappointed that two different clocks lead to slightly different readouts. But the metaphor I want to use is think of the word of, proteomics. If I told you protein one measures the same as protein two, you would just not believe it. And the same happens in the case of methylation. If you target certain parts of the DNA, they give you

Starting point is 00:17:39 a different readout from other parts. Okay. Yeah, that's really good to kind of clear up. And, you know, I guess if you understand that concept, you wouldn't want all these clocks to be giving you the same readout because then that would be kind of a problem. I think. It would be overly simplistic. Right. And most clocks were tailor-made for blood, for the sake of convenience. But arguably, you would want to develop special clocks for the brain, for the liver, for the kidney.

Starting point is 00:18:13 And the field is moving in that direction. So people develop actually single-cell clocks and organ-specific clocks. Oh, that's cool. So let's talk about some of the main ones that are used. And so we have the one that was, you know, the original Horvath epigenetic aging clock, first generation for chronological age. And then we kind of get into these other clocks, which were first generation, and then they have second generation versions as well. So the DNA pheno age, does that clock lean more towards inflammatory and metabolic function than pure chronological age? Yeah, for sure.

Starting point is 00:18:51 So the so-called pheno-age clock was a giant step forward when it came to mortality risk prediction. This clock was very much constructed to track really biochemical markers and also changes in blood cell composition. These markers measure organ dysfunction one way or another. and the idea was to actually develop a methylation surrogate of these clinical parameters. And we should discuss the pros and cons of that idea, you know. But yes, so this clock was then impressive mortality risk predictor for humans. However, it was then superseded by the Grimm age clock, which was named after the Grim Reaper. It was published also many years ago, 2019, but it continues to be very impressive for mortality risk.

Starting point is 00:19:55 And from a mathematical perspective, these clocks were constructed in very different ways. But overall, they very often agree, you know, when you have an intervention that appears to slow grim age progression. it also slows pheno age progression. So often there is actually agreement to some extent, which is impressive given that these clocks were constructed in very different ways. Can you talk a little bit about the different ways they were constructed? So with the grimage, you know, I think it was my understanding that there's, smoking is somehow embedded in that calculation or, you know, whatever we want to call it.

Starting point is 00:20:43 stress-related proteins, inflammation, but the pheno-age also has some inflammation as well in there? Yes, yes. Yeah, maybe I'll start with a much simpler example. C-reactive protein is a marker of chronic inflammation. It's a very important biochemical readout. And the doctor will measure it when you have certain conditions. But interestingly, you can actually

Starting point is 00:21:13 estimate C-reactive protein levels based on methylation. And I should say the estimate is not very tight for the experts. I will say correlation maybe 0.3 or lower, you know. So it's not a tight correlation. But I want to mention it as an example for this idea of using methylation to estimate a famous marker. But now imagine you actually get these two readouts from the lab. let's say you go to a longevity clinic, they can easily measure both.

Starting point is 00:21:45 But which one is more informative for you? Now, a medical doctor will always focus on the plasma-based readout. They are trained to look at thresholds and then they diagnose maybe an acute infection. But the surprising finding is that the methylation estimate is actually a better predictor of your mortality risk, far better predictor of your mortality risk than the plasma measure. And that's one famous example that has been validated. I give you now another example, smoking. So you can ask someone, how many cigarettes do you smoke per week,

Starting point is 00:22:28 for how many years have you smoked? And this is known as the smoking pack year estimate of smoking exposure. Interestingly, you can use methylation to estuary. estimate smoking exposure as well. And you can ask the same question. Well, which measure is more predictive of how long you end up living? Is it the self-reported measure or the blood measure? And again, we know the answer from many studies by now.

Starting point is 00:23:00 Again, the methylation estimator is actually superior to self-reported. So I mention it because that then gives rise to an idea. Well, why don't I build a clock that uses these methylation estimators of C-reactive protein, of many other famous proteins, and also the methylation estimator of smoking history, why don't I use these methylation biomarkers in a linear combination? I combine it an optimal way to build a mortality risk predictor. And this idea is underlying the grim age clock, the grim reaper clock. And it just worked beautifully in many validation studies.

Starting point is 00:23:49 We now know this idea worked. But that's really the idea of the grim age clock. And this was developed in your lab, the grim age clock. Yes, by Ake Loo in my lab. Finno age was developed by Morgan Levine when she was a. And Morgan was on our podcast a few years back as well. Yes. So why should methylation patterns be able to predict your mortality?

Starting point is 00:24:16 I mean, that's, and I mean, how accurate is that? I mean, like, what are we talking about, you know? Yeah, the first question, why does methylation relate to mortality? It is a good question, because when I published the very first clocks, I remember, I was extremely nervous about what I had published. I thought maybe these clocks have no use. Maybe they just measure your calendar age, you know. And now I was so relieved that basically six weeks after I had published it,

Starting point is 00:24:52 somebody came to me at UCLA and said, you know, we just applied your clock and it predicts mortality. But anyways, but then by now we know that these methylation clocks very much, predict mortality risk, to the point that certain startups pursue the idea of using methylation clocks for pricing life insurance policies or financial products, you know, and of course, methylation clocks are used in serious randomized controlled trials, you know, so the evidence is very strong and without any debate. But why is that, you know? And it could be that these clocks really track long-term exposures of a stressor. So, for example, smoking again, you know.

Starting point is 00:25:49 So maybe if you just smoke a bit, it doesn't really show up in other biomarkers. But if you have really this prolonged stressor, it really alters the epigenome. Why? Because the epigenome creates a memory, really. Think of the epigenome as a memory of stressors, and it primes the cell to respond. And you can imagine if the cell senses, this onslaught of various stressors, it tries to remodel its regulatory system so that it prepares for future stress. That's maybe one way to conceptualize it. Yeah.

Starting point is 00:26:37 And I mean, we even, I think the, this concept of, you know, the stressor affecting the epigenome, you know, we even know it can affect the epigenome in gonads, right, in sperm and eggs. And that's why certain, we have those studies out of Sweden, where they went through these periods of starvation, like famine, and then there was feasting depending on, you know, the, what food was available at the time. and I know that some researchers had looked at how the epigenome had changed, and that also seemed to affect life expectancy of the offspring as well. So, and then smoking. Yes, I think this is a study from the Netherlands, the so-called Dutch hunger, perhaps.

Starting point is 00:27:15 Yes. I'm not sure whether that's what you meant. Yes. Yeah, that's right. Yeah, very exciting work, you know, that maybe a couple of years of starvation could already change the gonad methalome and that could then lead to changes in the offspring. So I think it's very exciting, but I need to tell you I haven't worked in that space. Yeah.

Starting point is 00:27:36 Well, it's been years since I've looked at those studies, but I think there were like pre-pubescent boys too where it's like if they have gone through these periods of like hunger where they were calorically restricted, it obviously changed their, you know, their gonads, the epigenome in their sperm in a way that was, you know, more permanent. And so they had offspring that were like more resilient against type 2 diabetes and, you know, other age-related diseases as well. So I think they also lived longer, like their grandkids or something. Like it affected their life expectancy as well. But smoking is another one that would also go, it gets, I mean, that's something that goes, you know, deeper, right? And affects the gonads, if I'm correct. I mean, or

Starting point is 00:28:17 Yeah, I need to tell you regarding these findings, I'm usually interested and excited about them, but I want to emphasize to your audience, they are controversial fundamentally. Okay. Very smart people disagree with these findings. Personally, I'm completely neutral, but I just want you to know that. They disagree that the epitina changes? Yeah, so that, no, just to be very precise, that an exposure from your parents, for example, has an effect on you. Again, this brilliant people publish on it, and these studies go through rigorous peer review, but I just want you to be aware that they are strong counter arguments, you know,

Starting point is 00:29:01 so it remains to be seen, I want to say. Because I want to think that if your parents or grandparents went through severe stress I want to think that you still are born with a clean slate, you know, so that you are in certain ways not predisposed or doomed in one way or another, you know. Well, sure, that would be a nice thing to think. Yes. But, I mean, on the bright side of things, even if there is, and I've seen, you know, I've seen evidence that convince me that there's an epigenetic change that does happen. Yes. And in, you know, sperm DNA, for example, like if you have an obese.

Starting point is 00:29:47 male and then they lose weight. You can look at their sperm DNA and it changes from being obese to lean. And epigenetic changes, gene expression changes are happening. But even if it's on the bad side, you know, the good news is that once you're born, you can do things in your life to change things in a positive way too, right? So it's not like, you know, even if you don't have the cleanest slate. Yes. Yeah, what I want to tell you briefly about sperm, that is, yes, they are mainly.

Starting point is 00:30:17 methylation changes and also changes with aging. So the sperm methalome of a 50-year-old is different from that over 20-year-old. However, the changes that occur are at completely different location from the changes that we use in any of our other clocks. Another way to say it is if I take grim age or pheno age or any of my clocks and apply it to sperm, it completely fails. So, for example, what is known as the Horvath pan-tissue clock, you apply to sperm, you get one number, 37 or so. But everybody has the same number, in essence, you know, uninformative. It's just very different locations. The same statement also holds, by the way, for the placenta.

Starting point is 00:31:08 So people have developed clocks applied to placenta to estimate the age of the newborn, meaning gestational. age or also various stressors from the mother. But again, these changes are very different from what we observe in blood or adult tissues. Have there been clocks for sperm? Yes. That would have been developed that are more precise. Yes. Okay.

Starting point is 00:31:35 I have a question about grim age, but it sort of leads us into the next clock that I want to have you discuss, which is the duoden pace, as I say it right? I think it's called Dunedin pace. To need in pace. That's right, to need in pace. So the question I have is, you know, with the DNA grimage, we're talking about this methylation pattern being able to predict mortality and very, you know, pretty, pretty accurately, mortality risk. And it's able to measure, you know, this accumulation of damage that's changed the epigenome in a way.

Starting point is 00:32:07 That's obviously, you know, quantifiable. What if you're 45 years old, you get your DNA grim age test done? It gives you your mortality because you've had all this, you know, lifetime exposures up until the age of 45 of, you know, let's say air pollution. Maybe you smoked a little bit, whatever, alcohol, poor diet, stress, chronic stress, all those sorts of things. But, you know, you change your lifestyle. and it gets better. Does that grimage change? If you had asked me that question two years ago,

Starting point is 00:32:47 I would have humped and hard, you know, and I was always very cautious about that. In certain ways, how reversible are these changes, you know? But the science has really advanced, and now I'm confident in saying that you can reverse grimage to some extent.

Starting point is 00:33:05 The key word is to some extent because these changes appear to be very minor. We can talk about it later, but they have been very rigorous, randomized control tries with supplements and medications. So there's a hopeful message. You can reverse it. So that's what we're going to get into, folks. That's going to be the exciting stuff. So this other clock that's able to measure the pace of aging. Can you talk a little bit about the adenant? Can you say? Yeah. Yeah. So there is another widely used clock, is known as a Dunedin pace clock. It was developed by Dr. Moffitt and Dan Belski.

Starting point is 00:33:46 And it was constructed in a very different logic from other clocks. And the metaphor is it's supposed to be an odometer. It's supposed to measure the speed of aging or what they call the pace of aging, whereas previous clocks really measured in certain ways the accumulation of damage. So the idea is very compelling. Maybe I just review how it was constructed. So the team really looked at rate of change in established physiologic markers and biochemical markers, including also importantly, and we should discuss that, change in body mass index. So, but also measures of ways to hip rates. ratio, also measures of glucose impairment, markers of inflammation, many readouts.

Starting point is 00:34:49 And the study leveraged a unique epidemiologic cohort study in New Zealand, in the city of Dunedin. And so it's a study where they tracked middle-aged people and younger people for many years and assessed these readouts repeatedly. For the experts, it's the longitudinal studies. And by having these longitudinal data, multiple measurements per person, they could really estimate the pace, each person's individual trajectory. So far so good.

Starting point is 00:35:28 So you have these pace measures. But then they went to the next step, which is similar to Grimmish, they said, why don't we use methylation to estimate the pace of aging based on these physiological measures? And I think that's a very good idea. Why?

Starting point is 00:35:47 Because people care about what's my current pace of aging. Actually, it's a good question. I'm not quite sure what people care about. Some people want to know, let me know where I stand right now. Or how an intervention is effect. how they're aging perhaps.

Starting point is 00:36:06 Yes, thank you. Yeah, that's a good point, you know. So if you have an intervention, you want to see, does it really change the pace? Does it affect the odometer, you know? And so therefore people use Dunedin pace along with all the other clocks that I mentioned in, when they study interventions.

Starting point is 00:36:28 That's by now part of the standard repertoire of clocks. When people publish a paper on longevity interventions, they hopefully report about five clocks, I want to say, just in order to give the reader a chance to judge the evidence because the very best intervention will touch on many clocks, you know, that would be a robust rejuvenation of the meth alone. In my experience from reading the literature, that's pretty much what I've seen. I see the main clocks that are being used are the pheno age, grim age, perhaps grimage two. Yes. And I see the duodenian pace that those are at least three of the ones that are they seem to be. And then there's a few others that sometimes are in the mix. But those three stand out to me when I'm reading the literature, maybe because I know them the best.

Starting point is 00:37:24 But those are the ones that stand out. With this disagreement, and you kind of touched on this already, you know, if you're, if you're, you're looking at an intervention, and we're going to get into those in a minute. And you see, you know, your DNA grim age doesn't change. So your mortality, your mortality risk is the same or, you know, determining when you're going to die is the same. And yet your rate of, your rate of aging perhaps slows a little bit. Maybe it's not much. Maybe it's 2%. Some people will look at that and go, oh, these are all like if you're changing your pace of aging, why are you not changing the grim age. And then the question in my mind is, well, how long was the trial?

Starting point is 00:38:07 You know, so if you're changing the pace at which you age by 2%, and the trial was six months, is that going to be reflected in the grim age or, you know, what's the standard deviation here that we're even talking about with grim age, right? Yes, I think you make a very important point. If you have an intervention that has a very strong effect, I would expect the, that most of these clocks will show it. Why? Because these clocks are correlated with each other. And just to throw out a number,

Starting point is 00:38:41 correlation 0.5 after you regress out age, sex, and various variables. But there is still a fairly good agreement. This is the typical glass half full, half empty, is a correlation of 0.5 high on low, you know. To me, it's reasonably high if you have a very strong rejuvenating intervention. Now, when it comes to, I need to tell you, I'm obsessed about the question, which clock is best? And so I... Best for why?

Starting point is 00:39:16 For judging longevity interventions. Yeah, because when it comes to mortality risk prediction, we know the answer right now. after several large studies. There was a study in Scotland, Generation Scotland, 18,000 people were evaluated and Grimmage was best. And then there was a study from Harvard, I want to say 30,000 people were evaluated, Grimmage was best.

Starting point is 00:39:43 So we know which clocks is best for mortality risk prediction. Can I pause you right there? And I just want to make this point because usually when we have these studies, at least observational studies, looking at diet, because you'll never have a randomized controlled trial that's going to last, you know, 30 years or 40 years. So if you have, if you have, if you're looking at observational data and how different lifestyle like effect or diet and lifestyle affect mortality, you're typically

Starting point is 00:40:09 looking at, okay, how much seafood did they eat, how many people died from cardiovascular disease, how many people died from cancer, right? So you get this all cause mortality, right? Number. And what you're saying is that you can actually now, instead of having to just have observational data, looking at that all-cause mortality, you can now have an intervention. We're going to give people, you know, fish or whatever, we're going to do this intervention for a period of time, and you can have the grim age, which is kind of like the surrogate all-cause mortality, but it's very, actually a very good estimate of it. Is that, am I thinking of it a little bit correctly? Yeah, you think of it correctly and that's certainly the ambition but I want to be very precise using the language of the

Starting point is 00:40:56 FDA because I think we should do that. So the dream of the longevity field is to develop what is known as a surrogate endpoint for a clinical trial. In other words, you have a study where you apply let's say multivitamin for two years and then you see a change in any clock. It could be a proteomic clock. It could be a grimage, any other clock. And let's say you see a reversal. Now you would like to, I want to call it, jump to the conclusion that this actually translates into a lower mortality risk. And this, so we would like to think that is the case. But from a regulatory perspective, that hasn't been proven, you know. And, and. And in general, the FDA evaluates biomarkers, you know, why?

Starting point is 00:41:54 They want to give guidance to companies to biotech, where they say, if you show us that your treatment reverses that biomarker, therefore we believe that it actually helps patients, you know. And I just need to tell you and the audience, the biomarker field has not yet developed any biomarker that is credible to the FDA when it comes to this ambition of being an official surrogate endpoint of a clinical trial. Having said this, we just can't wait for this regulatory approval yet. Why?

Starting point is 00:42:36 They are urgent questions, right? People have exciting interventions. So we need to make assumptions. And for the longest time, I've been very cold. cautious when it comes to this claim, do methylation clock meet this high standard, you know. And I'm coming around, you know, just because I see increasing evidence, you know, that these changes track what I call validated interventions, you know, where we know the intervention has a benefit for human mortality risk. And then I see that it also,

Starting point is 00:43:17 touches methylation clock in the expected direction. It gives me confidence, you know, that the clock does what it's supposed to do, you know. So that's where I'm at, you know. What have you, what's the most robust intervention or it doesn't have to, you don't tell me what the intervention is or you could, but what's the most robust data that you've seen in terms of, you know, reversing biological. age by some of these clocks, grim age, pheno age. What's like?

Starting point is 00:43:53 Yeah, I will start with interventions that are in certain ways boring to you and me. Why boring to you? You and I, we are hopefully healthy people and we want to optimize our health. But I want to start with people who have a condition to answer your question. HIV positive people exhibit epigenetic age acceleration. It's actually a pronounced pro-aging effect, maybe five to seven years in blood. And sure enough, if they stick to their antiretroviral therapy, that will reverse their epigenetic age.

Starting point is 00:44:34 And I mention it because that... For how much? Several years. Several years. Several years. to give you a number four or five years. Four or five years? Is it happened pretty immediately after taking the drug?

Starting point is 00:44:46 Yes. Probably several weeks or months, you know. But there have been many studies all over the world that have shown it, you know. So it's very well established. And yeah, so that's one application. I mentioned it. I trusted 100%, but many people are not HIV positive, you know. So therefore I say do not take antiretroviral.

Starting point is 00:45:11 therapy, you know, it's just not. So the other intervention that has very strong evidence is anti-TNF alpha therapy, really anti-inflammatory drugs. For people who have autoimmune disease, again, that just makes sense, you know, but, yes. And metformin is an interesting intervention to many of us. The problem is, and I'm coming. around to believing that metformin affects epigenetic age. There have been a couple of studies that suggested, but I need to emphasize the effect

Starting point is 00:45:50 is way weaker than the above. So these are really medical interventions, and in general, as you can expect, a medical intervention has a much stronger effect than a supplement. When it comes to supplements, we do have some answer. Omega-3 has a beneficial effect, apparently vitamin, multivitamins have an effect. The problem is that these supplements have much weaker effects. Suddenly we talk about a couple of months of rejuvenation. And we're going to talk about those more in depth and what that means.

Starting point is 00:46:30 But I want to kind of, this gets me into the controversies and hype because you're talking about these really robust effects if someone has HIV, which is obviously devastating for you. your body and then they take the antivirals and that's really kind of it does have a pretty robust effect on obviously their life expectancy you know many different features of health as well as epigenetic aging so that makes sense but i've heard people out there talk about reversing their biological age by seven years in sorry they reverse their their biological age by five years in seven months by doing lifestyle or interventions Is that something that you think could be a real biologic effect?

Starting point is 00:47:15 Do you think that could be noise? Do you think it could be cherry-picking the best clock to get whatever outcome that they're wanting? Or, I mean, how do you feel about that statement? Yes. So it's a very good question. I think the first thing I would ask, what was their BMI before they started? and many other clinical readouts. So if you start with a person who was obese, had inflammation, diabetes,

Starting point is 00:47:49 many of these stressors in their lives, and they really changed everything. And they take their GLP-1 receptor, you know, they suddenly go to the gym, and they do everything right, then it would perhaps be possible. But there are many pitfalls. and I can discuss them later. But I don't think it's not possible when you start with this baseline. So you're very unhealthy.

Starting point is 00:48:19 You're very unhealthy. All the things. And above all, you actually start with an epigenetic age measure, let's say grim age, that shows you are eight years older than you should be. You see, you're in this highest percentile of risk. So then maybe you can go back to the average, you know. However, now let's talk about the opposite case, a biohacker, obsessed about healthy lifestyle, and now they say I changed my diet and now I reversed my age by five years, I would have the

Starting point is 00:48:57 hardest time believing it, you know. And by the way, this is something we see over and over again with various rejuvenating interventions. They seem to work in people whose epigenetic age is already accelerated, you know, but not in the people who are very healthy, you know, so. But yeah, so anyways, I would be very skeptical, but I'm open-minded. I'm strictly data-driven, you know, so I would have a long conversation with that person, you know. Yeah, well, you make a really good point, and that is, you know, people that are already accelerating, they're aging at a faster rate. So they have this age acceleration, right?

Starting point is 00:49:40 Their grimace is already, you know, they're going to, it's higher than it's supposed to. Is that correct? Yes. Higher. Higher than it's supposed to be, you know, their biological age or pheno age is higher. Their pace of aging is higher. So they're already age acceleration for whatever reason.

Starting point is 00:49:56 They're sedentary. They're obese. They're sedentary and obese and they smoke. Or perhaps they're. They have vitamin deficiencies. That's another one I've seen, like vitamin D deficiency has been shown to be, you know, associated with age acceleration. And if you correct those problems by losing weight, by getting physically active, by quitting smoking,

Starting point is 00:50:13 you know, by eating healthy, by getting your micronutrients and filling the gap so you're not deficient, then you see a more robust effect. And that is also a recurring theme that I've seen from reading the scientific literature where it's like, okay, if you already have enough vitamin D, and we'll talk about this, like, you know, If you're already sufficient, taking a vitamin D supplements not going to slow your aging. Exactly. The thing you're doing, you're already doing it. You're avoiding deficiency.

Starting point is 00:50:39 And that's the key, right? You're trying to stop things that cause the acceleration of aging seem to be easy, more responsive. Exactly. Yeah. The other question I wanted to ask you, it goes back to something that you mentioned earlier when you were talking about these insurance companies being able to predict your mortality risk pretty accurately. Using the DNA grim age, I've also heard people say that you can take this DNA grimage test and predict the day you're going to die like within a month. No, no, no, that's not true.

Starting point is 00:51:11 Okay, now why is that not true? Yeah. So I want to start out by commenting on insurance companies. They are in the business of predicting how long you live. If they make an error, it will cost them a fortune. And they are superb at that. And just to emphasize, they look at so much. So they will, above all, look at very traditional readouts, such as what's your blood pressure, what's your medical history, prior history of cancer, you know, substance abuse.

Starting point is 00:51:45 So they will look at all of the above because all of these variables I mention are very strong predictors of mortality risk. And the question is, does grimage add something, or grimage or another methylation? That's really the question for these companies. And scientifically speaking, I can say, yes, it adds something, but not that much, you know. Clearly the life insurance companies have done very well without having a methylation readout. But the exciting thing is methylation adds something. But then these companies have to weigh the costs, you know, because, these tests are not cheap. They cost several hundred dollars, or is it worth it to measure?

Starting point is 00:52:28 And by the way, that's the same question for any consumer. Is it really worth it to you to measure it, you know? Sorry, the other part of the, you had a second part of the question. Yeah, the question is, I guess I can word it a different way. If I were to go out and get a DNA grimage test. Yes. And it said that I was going to die when I was age age. am I actually going to die at age 80? How reliable is that number? How accurate is that number? Or am I going to die at perhaps age 85? Yes.

Starting point is 00:53:03 I want to tell you that grim age could lead to a prediction of when you die. Let's say age 85. It could. And we know, though, that this estimate is accompanied by a large error. plus minus six years. I'm just making it up. So let's say you are a 50-year-old, you measure your grim age, and we apply the math, the mathematical algorithm,

Starting point is 00:53:35 which, by the way, is very complicated, you know, for estimating your age at death. But the error rate is substantial. And this makes sense because human beings are so complex, you know. Think how many things. can happen even in the next year. You can go through a divorce, you get hit by a car, you get depressed, you start smoking, you stop smoking, you know.

Starting point is 00:54:02 So these, it would be unethical to report literally the age and death to a person. Therefore, we have decided to only ever give people an age estimate, right? We will say your grim age is 50. and what I want to really explain to anyone who listens is that please do not translate that age estimate in your mind into an estimate when you will die. In other words, if your grim age is 10 years younger than your calendar age, it does not mean you will now live 10 years longer than the average person. You see, you cannot compare this differential into a lifespan differential. Then what does it mean? Yes.

Starting point is 00:54:57 So what does Grimmage really measure in a mathematical sense? What does it measure? It really measures the instantaneous hazard that you drop dead. I always say to people, it's your risk that you will die in the next year. That's how you need to think of it. compared to a person of the same age and the same sex. So let's start with the 50-year-old, and let's say the grim age is 58,

Starting point is 00:55:29 eight years older than expected. Then their risk of dropping debt in the next year is more than twice that of the average 50-year-old of the same sex. Does that make sense? So it's really, mathematically speaking, it's a hazard ratio. And the hazard ratio measures instantaneous mortality risk. Now, you can translate that then into an estimate of your lifespan. It's easy to do.

Starting point is 00:56:02 But it's a very complicated formula, certainly highly non-linear. And, as I mentioned, associated with a strong arrow bar. Are there companies that have consumers, available test doing that, where they're measuring the grim age and then doing that translation to when you will die? Is that something you've seen? No, I have not seen that. And I'm glad, because I would have a problem with that. On two grounds, I find it on some level perhaps unethical, but I believe in freedom. So if people want to do something, I'm okay with it. My concern is it's scientifically unsound. It really is, you know,

Starting point is 00:56:43 for the reasons I mentioned, there's a strong error bar, you know. Right. If you're talking five or six years either way, that's a pretty big error bar for when you're going to die. But it seems like people are using it more to estimate their biological age, right, in a way. Right. And that's typically what people are usually.

Starting point is 00:57:01 We use grimage, of course, to understand the effect of various stressors. And I'm a longevity researcher. I'm very excited about finding interventions that reverse it in humans and, of course, in animal models. So that's how I use it, you know. For these clocks, when we're looking at the like aging process as a whole, you know, we're talking about damage. You know, there's the insult that is the initial insult. And then you have perhaps the damage response, maybe the amplification of that damage. with inflammation, then you start to have tissue breakdown, right?

Starting point is 00:57:46 Stem cell exhaustion, like things that are more downstream of the damage and amplification of that damage. Do these aging clocks, where do they sit on that? Yes, we have gained a lot of insights into aging in general, by the way. and also which aging hallmarks really affect epigenetic clocks, you know. So 10 years ago, we barely knew anything about mechanism. Epigenetic clocks were rightly criticized as black box readouts, but after really 10, 12 years of research by the very best labs in the world,

Starting point is 00:58:33 you know, we really have characterized these changes. Maybe for the biologists, they are these hallmarks of aging. And we know that clocks relate to mitochondrial dysfunction, the energetics. They relate also to stem cell changes, very much so, stem cell biology. They relate to metabolic changes, nutrient sensing, to some extent as well. And also aspects of DNA repair, you know, so that is part of the biology, they clearly relate also to changes in what is known as cell composition. So in blood we have many different blood cells.

Starting point is 00:59:26 And some cells are aged, so-called stressed memory T-cells, cytotoxic T cells that are exhausted. This is actually a technical term, exhausted T cells from aging. And conversely, they're these naive T cells, you know. So we understand that epigenetic clocks also relate to inflammation and that biology. So epigenetic clocks should be conceptualized really as integrators

Starting point is 01:00:02 of many different stressors. but not all. They don't capture everything. And the most striking blind spot I want to highlight, which is frustrating to me, but I want to emphasize it. People in the aging field have heard of senescent cells, xenolytics, very exciting intervention.

Starting point is 01:00:25 I'm very much following that literature. However, epigenetic clocks really don't capture that well. know. So let me give you the prime example. You have cells growing in a dish. You radiate them, any radiation. You induce senescence. The cells can no longer proliferate. And by the way, radiation leads to double strand breaks. It really very much stresses the cells. And wouldn't it be nice if methylation clocks pick that up? But they don't, you know. So, So radiation damage, at least for cells. They don't pick up double-stranded breaks even?

Starting point is 01:01:10 Yes, at least when you induce it by radiation, you know. So we know radiation is very bad for you, but methylation changes do not result directly, you know. And so, and I give you the converse of that when it comes to senescence. Many of many people have heard of telomeres. In theory, you want reasons. long telomeres at the ends of your DNA. And for many years, people have thought aging is about telomere attrition. Now we know better, it's not.

Starting point is 01:01:45 But anyways, it's a famous hallmark of aging, telomere shortening. However, many of the clocks have only a weak correlation with telomere biology. It's a frustrating aspect. And 20 years ago, people had an exciting idea. overexpress a part of telomerase, the turd, overexpress turd. And there were companies that pursued that as a rejuvenating intervention. And at least in our hands, we did not see a beneficial effect, at least in vitro. So although I like epigenetic clocks for many studies, but they don't capture the totality

Starting point is 01:02:34 of aging, you know. So you really want to complement epigenetic clocks with other readouts. That's interesting that they're not, because you mentioned that they do track with the DNA repair process, but not. To some extent. I know I'm giving conflicting messages, but that's the biology. So there's certain experiment that show that some aspects of DNA repair relate to epigenetic aging,

Starting point is 01:03:07 but others don't. It's just not a tight story, you know. So I think the field really needs to nail that down. Yeah, I mean, well, there's a lot of things that lead to aging. You know, it's a very complicated, you know, multifactorial process. Yes. When you actually are able to perhaps reverse, you know, biological aging or I guess there's two ways of thinking about it you're slowing age

Starting point is 01:03:39 acceleration right if you're taking away something that's negatively accelerating aging or negatively affecting your health but then also let's say you're if you can actually somehow slow the aging process at least on the readout the clock is showing that you're younger after doing something where do you think do you think that's like inflammation like these processes that are that you described that are sort of tracking with these clocks are being affected so the you know mitochondrial function inflammation those processes are improving and the clocks are sort of picking that up um yes and no i mean so epigenetic clocks such as grimage and do need and pace and pheno age they do track inflammation to some extent no question so yes if you

Starting point is 01:04:29 reverse that, these clocks will pick it up. But it would be a grave error to assume that the clocks only measure that biology. It's really not true, you know. The clocks very much relate also to stem cell functioning, you know, and other aspects, you know. So again, they're integrators. And so there there will be interventions that actually don't even touch the inflammation in one way or another, but they could have a very strong effect on reversing your epigenetic age. And the prime example would be therapies that, for example, completely rejuvenate your hematopoetic stem cells.

Starting point is 01:05:15 Just assume you have an intervention where you really replace your bone marrow, you know, the hematopoetic stem cells that produce all of these blood cells. And you just get hematopoetic stem cells with an epigenetic age of zero. That would very much rejuvenate your blood drastically, you know. We know that from mouse studies but also human studies. You know, the epigenetic age in a bone marrow transplant recipient often reflects the age of the donor, you know. So do you see there various interventions that could have a very strong effect, but they just don't touch on that biology you mentioned. If it's rejuvenating the blood,

Starting point is 01:06:04 is it also perhaps rejuvenating other organs? That's a great hope, you know. So my responses assume not, because wouldn't it be nice? What have animal studies shown? Have they looked at that? Yes, there have been animal studies, I want to say, in the lab from Vadim Gladyshev at Harvard, and the studies, my reading of the studies is that they have been disappointing. They didn't rejuvenate other organs. If anything, there was a disappointing result that after X number of months, actually the stem cells had aged. So the body has the memory of the old body.

Starting point is 01:06:49 mouse and that then aged the blood really. So did these mice get a hematopoetic stem cell graft? Yes. They did. Okay. Vadim carried out really an elegant set of experiments, various transplantation experiments. And the scientific question is the following. Okay.

Starting point is 01:07:14 If I replace, let's say, the blood by that of a very young mouse, Or take other organs, by the way, should we replace the kidney? Should, you know, so anyway, or the heart or any other organ. Would the rejuvenation of one organ translate to a body-wide rejuvenation? And my current reading of the literature is that we haven't found any such organ as a target, you know. I thought there were some evidence that if you did some of these transplants where you take young blood, and put it into older mice that rejuvenated the brain, for example. Or am I, I mean, that's, I don't know if they were measuring, using clocks,

Starting point is 01:08:00 but they were doing cognitive function and a battery of tests and the cognitive function improved and things like that. No, for sure, you know. So maybe to remind the audience this idea of heterochronic paribiosis, for example, where you really connect the circulation of an old, with a young mouse. And this is really a phenomenal paradigm of rejuvenation, arguably one of the best ones we have,

Starting point is 01:08:29 along with caloric restriction. And so, yes, we know that when an old mouse is exposed to the circulation of a young mouse, it has multiple benefits, cognitive benefits, also muscle benefits. so. And also, importantly, epigenetic clocks get rejuvenated, many organs. So we know that again from several studies, including from Vadim Bladischoff's lab, but others have found that too. So yes, young circulation rejuvenates the liver, the kidney, all of that, you know, on the methylation level. But there's a problem. You disconnect these mice, so they are no longer connected. they're no longer exposed to the young circulation.

Starting point is 01:09:20 Then the things bounce back. The epigenetic age bounces back to that of the recipient mouse. It's very frustrating to all of us who work into the longevity field because that is a very common story. You have a powerful intervention. It actually rejuvenates the organ. The problem is it's transient, you know. But yes.

Starting point is 01:09:41 It's kind of like the probiotics flow through. You have to keep taking them to have a benefit. and the gut as soon as you stop taking them, because they don't stick there, right? Yes. They're not taking residence there. Yes. Well, let's talk about caloric restrictions since you just mentioned that as a rejuvenating

Starting point is 01:09:56 therapy. I mean, at least many animal studies have shown that. And I don't know that anyone wants to be calorie restricted for the rest of their life, but although GLP1 receptor agonists are kind of doing that in a way, there was a very recent trial, the calorie trial. And I'd love for you to talk about this was a two-year randomized controlled trial where individuals were basically eating 25% fewer calories than they otherwise would, or they were eating their normal, you know, daily food intake as usual.

Starting point is 01:10:26 And I wanted to ask you, was this, were the participants overweight in this trial, or were they normal weight? Do you know? I don't remember. I know it's a U.S. population, so assume that they are on the chubby side for sure, you know. Okay. Yeah. Yeah.

Starting point is 01:10:44 So in this, in this trial. It was a two-year randomized clinical trial, and it seemed there was many clocks that were measured, and it seemed like they had different readouts. Do you want to talk a little bit about the findings? I mean, I think. Yeah, I have a lot to say about weight loss. We should discuss it, you know. But the calorie study is a very famous study. U.S. population, very rigorous study, many, many readouts.

Starting point is 01:11:12 But I want to acknowledge something. And the experts know it. The adherence was not good. So there was an ambition that these people would lose more weight than they did. But as everyone knows, it's so hard to adhere to a diet. So the age reduction was on some level very weak, I would say. I apologize, I don't know the number, but I remember it was weak. I mention it because later we should talk about GLP1 receptor agonist,

Starting point is 01:11:44 where the weight loss can be pronounced, and there's discrepant findings, actually. But anyways, back to the calorie study. Again, there were multiple blood draws from these people, and so one could evaluate which methylation clocks pick up a beneficial effect. And I was disappointed that grim age and pheno age did not pick up an effect,

Starting point is 01:12:13 but this new clock, a new clock at the time, Dunedin pace, really picked up an effect, which was reassuring, you know, that reassuring because everything I know about the biology of methylation clocks tells me that they should pick up a reduction in weight if it's strong enough, you know. How much weight did they lose, do you remember? It was pretty, like not very much.

Starting point is 01:12:41 Yeah, it was not impressive to me, at least. So the clock that did pick up the do a dineid and pace. And in hindsight, let's discuss why it picked up the effect. Well, it was like a 2 to 3% slowing of the rate of aging over the two years. That's true. Yeah. So it picked it up. And it makes mathematical sense to me because Dunedin Pace again was trained.

Starting point is 01:13:07 That's the lingo of machine learning. But it was developed to track changes in B.M. So yes, it picked it up. By contrast, Grimmage was never trained to look at weight loss. It was trained on mortality. So yes, Dunedin Pace worked. And my reading of Dunedin Pace is that it is good at that biology. People losing weight, it will pick it up.

Starting point is 01:13:36 And now the question is, why didn't the other clocks pick it up? And there could be several explanations, you know, But my view is if there had been a larger sample size, if the people had adhered to the protocol, I'm as sure as you can be that the other clocks would have picked it up. It's a sample size issue. Or conversely, small effect size. What I can tell you is there was a very exciting study

Starting point is 01:14:04 that involved actually obese people, BMI 30 and higher, who had been put on a GLP1 receptor agonist treatment semi-glutide. And these people really lost a lot of weight over 33 weeks. And by the way, this study was published in Met Archive. It's a pre-print, so take it with caution. It was Michael Corley's group in San Diego. But a very beautiful study, very rigorous. again and a large sample size, so credible.

Starting point is 01:14:45 And they looked at all methylation clocks, and suddenly all methylation clocks picked it up, really all, you know. And so that's my thinking, you know, if you have a strong weight loss intervention, you have really a strong reduction in fat, lipolisus, you know, this inflammatory signal is reduced. I think all methylation clocks will pick up. it up. Right. And I think it goes back to this concept that we were discussing earlier, where if your

Starting point is 01:15:17 baseline is unhealthy, if you are obese, you are accelerating your aging, right? You're in age acceleration mode, right? So you need to slow it down. And with any clinical trial, it's always, you always get a better signal when you're starting with something that's on a population that's either deficient or unhealthy. And then you're giving something to improve. that deficiency or negate it or to, you know, improve their health and you get a more dramatic effect. So we know obesity accelerates aging. We know, you know, you know, that it's associated with, you know, decrease in life expectancy, you know, increase in cardiovascular disease, type two diabetes, cancer, right? All these diseases of aging. So it's not surprising that you would give someone

Starting point is 01:16:02 a drug that does cause rapid weight loss in a short amount of time. So you're going to get a much more robust signal. Right. And you're obviously picking that up with the aging clocks. With a calorie trial, you know, again, I didn't know what the adherence was, but also, as you mentioned, these clocks are trained with different, there's different specialties of them, so to speak, right? And being trained on BMI, wow, that's going to make you sensitive to weight loss for sure.

Starting point is 01:16:30 Yes. And so the, you know, the duodenin pace clock, which is measuring the pace aging, you would imagine would be more sensitive than something that would. But, you know, my question as a longevity researcher is, which clock should a clinician use, you know? If we could briefly talk about multivitamins, this study. Interestingly, here, Grimm-age fountain effect, pheno-age found an effect based on multivitamin use,

Starting point is 01:17:01 but do need and pace failed. It was not significant, you know. So, and you can ask this question now for many interventions, what should be the go-to clock? And, you know, I even, I want to stay clear of this debate because we will never agree, you know. Therefore, I just love it that the field by now simply reports at least five clocks, you know, so the reader can just look at it and be the judge. Let's talk about the multivitamin.

Starting point is 01:17:31 So this was the Cosmos trial. I've talked a lot about the Cosmos trial in the context of brain aging. So the larger, there's, you know, the larger trial. And there was three randomized controlled trials where these older adults were given a standard Centrum silver multivitamin a day, every day. And it was, what was it, about 3.6 years for this trial. And they were looking at, I mean, there's a lot of endpoints of this trial, but one of them was cognitive function in brain aging.

Starting point is 01:18:00 And at the end of the trial, the people that were given, the multivitamin, had slowed their brain aging by 2.1 years. And there was the battery of tests that were done there. And I'm not sure if, in fact, some clocks were used as well. But I know that the global brain aging was slowed by 2.1 years. And they're episodic brain aging. So episodic memory is a kind of memory where you're remembering experiences, people, right? Like those sorts of things.

Starting point is 01:18:26 That was slowed by almost five years compared to the placebo group, which is quite significant. And they did better on a battery of cognition tests. And so that was very, that's very encouraging, you know, and it's something that I do talk about a lot because they feel like it's a very easy, safe intervention that people can take a standard multivitamin. These have a variety of vitamins and minerals, trace elements that people are not getting from their diets. And so they're kind of filling that nutritional gap.

Starting point is 01:18:53 And so, you know, who doesn't want their parents and grandparents to have better brain aging? So my parents are on a multivitamin, right? When it comes to looking at these epigenetic aging clocks, the pheno-age and grimaceing age clocks were the ones that stood out to me. As you mentioned, there was a battery of clocks that were looked at, but it seemed as though they were slowing, or at least, I'm not exactly sure all the calculations that go into this, but 2.7 months to five months, right? Like they were basically, they're slowing the aging by roughly that amount. Yes. Which to me is, if you think about, now, this trial that was done with the aging clocks, I think it was like a subset of it.

Starting point is 01:19:38 of the larger trial? Was it two years or did they do the 3.6 years for that? Do you? Yeah, I think it was two years. Two years, yeah. And so to me, the question is, now this wasn't, you said

Starting point is 01:19:51 the duodenin paste didn't change. No, it changed in the right direction. It just wasn't statistically significant. Oh, I see. No, in the right direction, you know. Maybe a larger sample size would have led to a significant finding. It was definitely in the right direction.

Starting point is 01:20:08 Well, the question I have for you is if you're changing it by, you know, three to five months within that two-year range, according to the grim age and pheno age clocks, and you're to keep doing that, you know, for years. So now we're talking not just two years. We're talking 20. We're talking 30, 40 years. Yes. How do you think that, do you think that you get this accumulative effect? Yes, I think so. I think so. I maybe to step back. if you tell an 80-year-old that a multivitamin will reduce his or her age by three months, they will roll their eyes. They will say, give me something that reverses my age by 30 years, you know. So fair enough.

Starting point is 01:20:55 The effect, we just need to acknowledge the effect is very minor, you know. However, I like the way you conceptualize it. If you really use it for 30 years, right? you're 50 year old and you use it until you age 80, my expectation is that suddenly these three months benefit, they accumulate and suddenly you have a benefit of maybe two and a half years. It's still not great, you know, but there is a benefit, you know. But think of the effort you have to put into just taking a multivitamin, right?

Starting point is 01:21:34 I think it's pretty great for that. of effort, you know, if you're, if you're just having to take one vitamin supplement, and it's going to delay your brain aging, you know, by 2.1 years just after, you know, in that trial, it was 3.6 year trial. But, you know, that's pretty robust. Five years delaying brain, episodic brain aging. And now we're talking about, like, globally, like, biological aging. If it's, if it's slowing it by, let's say, on the high end, five months after two years, I don't know. That seems like a pretty great effect. if you're just taking a vitamin supplement for two years

Starting point is 01:22:09 that's doing that, well, let's continue on and then combine other things, and we'll get into some of the other trials that do show synergy. But I think it's interesting. The other question is that, and this is where, you know, the cosmos trials, people, they're looking at everything, right?

Starting point is 01:22:24 Cancer mortality, cardiovascular mortality, all cause mortality. And those didn't really seem to change, at least within the timeframe that was looked at. And so, you know, we see these epigenotic clocks giving us a signal. We see the brain aging effects. And the question is, why are those showing up before?

Starting point is 01:22:43 Yeah, I tell you my reading of it. And to me, this whole study was one triumph for epigenetic clocks. And I explained to you why. Assume you knew nothing about multivitamins, you would think that there is a benefit, you know. Clearly, vitamins are important. It's a trivial totology. Avoiding deficiencies are important. So you would say, okay, I administer that to the U.S. population, I would hope to see an effect.

Starting point is 01:23:18 And that, of course, is the reason why these large-scale studies were even initiated. Think about how difficult it is to raise the funding for such a large-scale study. Clearly, there must be very compelling reasons. Okay, but there's a problem now. these heart endpoints, mortality, cardiovascular disease, they didn't detect an effect. It deeply frustrating. Oh, is there a trend? It wasn't statistically significant.

Starting point is 01:23:48 Yeah, I let you summarize it. But to me, you know, I just looked at it from the point of view as a consumer. Five years ago, you know, I wouldn't take a multivitamin. I looked at the literature, no benefit. I won't take it, you know. Now, so a person can now make their own judgment, you know, so what does it mean? To me, I take it as a wonderful triumph of epigenetic clocks that they did pick up the signal. And I call this testing the test.

Starting point is 01:24:24 You have an intervention where you really think it's got to move the needle, you know. And then if a readout doesn't show it, one interpretation is, well, maybe the readout is too crude. Maybe all-cause mortality is a real, I mean, I like it as a readout. I used it for grimage. Don't get me wrong. I like that it's hard and definitive. You can't argue with it. However, people die for a hundred different reasons, you know, that may really not relate to the biology of aging, you know.

Starting point is 01:25:01 And so now that we have actually biomarkers that did pick up that signal, even though it's very weak, is to me really reassuring. Yeah. And I think it's reassuring in combination with the brain aging signal that it picked up. And just knowing that, you know, so many globally people are not getting enough of these important vitamins and minerals and trace elements and essential fatty acids from their diet, then it's kind of. of like an insurance, like, okay, I'm going to fill some of these nutritional gaps. They won't all get filled because you can't stuff everything in one pill. I mean, you can only get a little bit of some things in there, right? Yes. But I do think that it's, it's, again, I agree with you. I think it is a triumph, and it's something that I do think that is safe. I mean, it's really been shown to be safe.

Starting point is 01:25:54 And so maybe you pee a little bit more, but out. So what? It seems to be doing something beneficial for the brain and at least for, you know, looking at these aging clocks, it seems like for the way you're aging as well. Yes. Yeah, so what have you got to lose, you know? Yeah. Let's go back to maybe some of these other vitamins. There's other, I guess, lifestyle interventions as well that I wanted to cover.

Starting point is 01:26:19 But since we're on the vitamin train, the big one is omega-3, right? I mean, that I've seen, at least in literature. And this is something that isn't surprising to me. because going back to this theme that we've been talking about, if you're starting out with a deficiency, if you're starting out at an unhealthy point, and you improve that, improve that, you fill that deficiency gap,

Starting point is 01:26:44 or you improve your health, lose weight, whatever, then you're going to have a stronger signal, right? Yes. 90% of Americans don't get enough omega-3 fatty acids. Nobody's eating seafood in the U.S. It's just, you know, so you're starting with the pop. population that's already, you know, I don't want to say deficient, but they're not getting

Starting point is 01:27:05 a sufficient amount of omega-3 fatty acids. And so I think it's probably why it's easy to keep getting this stronger signal because if you start out with someone who's already getting enough omega-3, maybe you go to Japan and do the study. I don't know. It would be interesting to see. Yes. Perhaps it just keeps improving inflammation and then, you know, you'll keep seeing an effect. But it seems like many, many studies have shown that omega-3 fatty acid, whether it's from food, supplementation, a combination of both, seem to slow epigenetic aging by different clocks. Yes, there has been quite some literature. It started with observational studies that you cannot trust. But last year, we published a study, which was very really.

Starting point is 01:27:57 This was a study conducted by a Swiss professor, Haika Bischo Ferrari, who looked at 780 people and followed again the most rigorous design, randomized controlled trial, placebo control trial. In a population that I was very interested in, people 71 years or older, really older people, reasonably healthy. average age, I want to say 75, I think was 73. So older people. And she evaluated famous interventions, number one, omega-3, 1 gram, vitamin D. And we should talk about the intervention about vitamin D was tricky. It was high vitamin D versus low vitamin D. It wasn't vitamin D versus no vitamin D.

Starting point is 01:28:52 That's a key distinction. What was the low? I know the high vitamin D was 2,000 IUs. Yes, and the low was 800 IUs. Oh, so it was only double kind of. Yeah, exactly. And that's a limitation because the results for vitamin D were disappointing, no effect on epigenetic clocks. But that's why I hasten to add. Yeah, but we have other randomized control trials showing the opposite if you start with the deficiency in add it. And we can talk about that.

Starting point is 01:29:19 Okay, so vitamin D. But there was also another disappointing, if you look at the. The exercise. Yeah, we need to talk about exercise. So, yeah. So this was called a home exercise intervention. Now, to remind you, these are people in their 70s and think in terms of ethics approval, you cannot stress these people too much.

Starting point is 01:29:40 So this home exercise intervention was very modest, okay. It was resistance training, right, three times a week. Yes, yeah. But it was, I'm telling you, it was a mom. Mild, mild, mild redistricting, you know. But because, because no effect. Right. I was very disappointed.

Starting point is 01:30:00 Did you read that the, the starting population, 88, like around 88% of them already identified as being physically active? Exactly. I mean, which is, if you were to get a U.S. population, not a chance. Yes. Like that, there's no way you would have had that many people physically active. But anyway, so that's another. No, these are people in Switzerland.

Starting point is 01:30:17 Hopefully they hike in the mountains. They're walking everywhere. Exactly. No, but that was interesting to me because I'm very interested in, in that. population, people who already do a lot of good things, what can they do to improve, you know, their outcomes? Great, yes. Great framing of it. Yeah. And yeah, so I think we already discussed the result. The most credible result

Starting point is 01:30:39 was Omega-3 on epigenetic clocks. A couple of epigenetic clocks picked it up, Grimmage version two, pheno-age, Dunedon Pace also worked very well in that context. So, nice result. for omega-3. The other interventions disappointed. By themselves. By themselves. By themselves. But yes, there was this one treatment arm

Starting point is 01:31:04 where people actually did, used all three beneficial interventions, high-doseage vitamin D, omega-3, plus exercise. And according to pheno-age, that treatment arm did the best. So that's the finding that we would have liked to see, you know, for all clocks. But it's just the pheno-age picked it.

Starting point is 01:31:29 Well, I think there was even a dose dependent where there was the group that just got the omega-3 and vitamin D. And that also improved more than the omega-3 alone. Yes. And then all three improved the most. So you see this nice dose-dependent effect with adding in these healthy lifestyle interventions, even in an already presumably healthy population. Yes. Which is exciting. Yes. And I have the numbers here. I think it was 3.8 months, the pheno age delayed, the biological aging was delayed by 3.8 months. Yeah, over three years. Over three years. Right. And that doesn't sound like a lot again, but they also correlated with some other outcomes, right? So I think there was in all three interventions, yes, it was 3.8

Starting point is 01:32:13 months. It delayed the biological aging, but also that was associated with outcomes that were important. Sixty-one percent reduced chance of getting metastatic cancer. It was like a 20% reduction in pre-frailty, which is also nice to see these outcomes correlated with this as well, right? I agree with that. And I can tell you the same study looked at a new concept in the field called intrinsic capacity, which looks at various domains of functioning, frailty, cognition, psychology. Anyways, also intrinsic capacity was improved in that population. Oh, okay.

Starting point is 01:32:52 So it's not just the molecular readout, yes. I think for me, the take-home, again, is something that you mentioned when you have this already, you know, healthy. They have to be a healthy population of 88% with them physically active, right? So, and you take that healthy population, you can still improve, right? You still improve things. Do you, again, this comes down to the compounding factor, right? So this is three years. And then let's say, okay, well, they're going to start doing this for the rest of their lives, you know, decades.

Starting point is 01:33:22 we're talking, well, in this case, they're a little bit older, but people listening to this podcast maybe in their 30s, maybe in their 20s, their 40s. It's like, okay, well, I'm going to start training, getting, making sure I'm not vitamin D deficient, getting my omega-3, and then you have, like, how is that going to compound over time? And I know it's speculation, but it makes sense. That's the way I think about it. I think of it the same way. I wish I could go back in time and tell myself to stop eating chocolates, which really messed me up. So, yeah, good health behaviors, you know, and supplements included, I think will have benefit, major benefits.

Starting point is 01:34:00 When it comes to vitamin D, that's the one that, I mean, this one study was a bit disappointing, but as you mentioned, I mean, comparing 800 IUs to 2,000 IUs, I wouldn't imagine to see a big difference there because you're already feeling the gap. Exactly. And most of the participants had no insufficiency in vitamin D. They really started at normal levels. And we know there have been, in my opinion, so many studies that I've come across and read over the years

Starting point is 01:34:32 showing that vitamin D deficiency causes age acceleration, in some cases severe, like three years. And if you correct that deficiency, it'll slow age acceleration, where then you say, you know, reversed aging by, you know, four years or whatever. I mean, so I think my take home, and I know the one that I like, the most recent one was the base to the Berlin study.

Starting point is 01:34:59 Yes. Where they took, which was the thing that was nice about that was they had a deficient population and then a sufficient population and gave them vitamin D. Yes, and this was a study in Berlin and they followed people for seven years, which was also impressive, was a large. population. And you can imagine Berlin is of course not blessed by sunshine, so they start out deficient, you know. So it all made sense, you know. Yeah. Reverse aging. If you're, if you're deficient and fill that sufficiency, but the people that were not deficient, actually, there was no

Starting point is 01:35:35 effect, which is, again, what you expect. It's not about this is a magic supplement that's slowing aging. It's not doing that. It's helping people that are deficient correct their deficiency. And that's why there's so much even in the scientific literature with vitamin D, for example, if you're looking at outcomes. It's the same thing. Yes. You know, and it drives me nuts when studies don't measure their baseline levels or if they only measure 10% of the population and then use that to extrapolate and like everyone else. They're like, you can't do that. Yes.

Starting point is 01:36:04 There's so many, you know, and there's gene snips that are affecting vitamin D. There's other micronutrients. Magnesium really affects vitamin D. You need magnesium to convert vitamin D3 into, you know. you know, the steroid hormone. So there's so many different things that are affecting your vitamin D. If you don't measure it before and after, it's hard to really make a statement that it did what it did or didn't do what it was supposed to. Yes.

Starting point is 01:36:28 Okay. So I want to... We should talk about exercise. Yeah, we can go into exercise. Oh, no, but I follow your script. Sorry. Oh, no, no. We were talking about calorie restriction and I just wanted to mention dietary patterns in general, you know, because you mentioned weight loss.

Starting point is 01:36:45 and we've talked a little bit about it with the JLP one. Obviously, if you lose weight, it's probably a big confounder with some of these dietary pattern trials, right? Like if you're getting someone who's overweight and these participants are overweight and you're putting them on a healthy diet or a Mediterranean diet or something like this and they lose weight on all the diets, then how much of what you're seeing is due to that weight loss, right? Exactly. So do you want to talk about that? It was like the direct trial. Is that what it was called? Yeah, I need to tell you.

Starting point is 01:37:19 I don't know too much about it. But I want to explain some properties of Grimm age that I'm aware of. So Grimm age very much correlates with what is known as carotenoid levels in the blood. So what are those? So, you know, let's maybe back off and think of nutritional studies. many people have so-called food questionnaires where they evaluate the diet of participants. And from all I know from analyzing data is that these food questionnaires often don't reflect reality. I don't remember what I ate for breakfast.

Starting point is 01:37:59 Well, I didn't eat breakfast today, but. Yeah, I mean, and people always know what they should answer, you know, so that may bias their memory. They will say, oh, yeah, I ate X servings of broccoli, but it just doesn't. reflect reality. But fortunately, there are blood tests. You can measure the so-called carotenoid levels in the blood and have an objective readout of fruit, vegetable consumption. And the striking finding in post-menopausal women from the Women's Health Initiative was that this measure of vegetable intake has a strong correlation with grimage and other epigenetic clocks. Strong means, maybe minus 0.3.

Starting point is 01:38:45 So it's to me a very strong effect, which really changed my behavior. By now, I really eat a lot of vegetables. Can you translate that to like months? Like what would minus 0.3? Yeah, sorry. I could translate it, but... Just an estimate.

Starting point is 01:39:03 Yeah, no, let me put it this way. Smoking has a correlation of 0.4. So if you smoke a lot, it increases your age. vegetable consumption minus 0.3. So it's actually... Wow. Yeah, I was very surprised. Sorry, I add one more statistic.

Starting point is 01:39:19 Exercise. The correlation would be 0.1. So do you see, so vegetable intake has a much stronger effect. I mean, orders of magnitude, stronger effect on grim age and these methylation clocks than, for example, exercise. And you think it might come down to even the cron. or just the vitamins and minerals and everything in the vegetables kind of compounding. Yeah, you know, I never looked into that, but I feel that would be such a worthwhile research study. What I can tell you is this vegetable association is 100% accurate, but now teasing

Starting point is 01:39:59 it apart. What is it, you know, to be seeing? Probably so many things. I mean, you've got the fiber matrix, you're getting like vegetables, especially greens. And if you're talking about carotenoids, you know, lutein, zanthin, these are carotenoids that are in greens. And interesting, there's been a lot of studies coming out, looking at blood levels of lutein and ziazanthan. People usually associate them with eye health. They accumulate in the eye. There have been randomized controlled trials showing they can help prevent age-related macular degeneration. They also accumulate in the brain. And they're associated with improved cognitive function, crystallize intelligence, improved brain aging in general.

Starting point is 01:40:43 All right. And there's other carotenoids, beta carotene is probably what most people are familiar with, lycopene and tomatoes. So there's a variety of these carotenoids, which are very powerful at basically, I would say, buffering oxidative stress and singlet oxygen, for example, if you're talking about in the eye. Yes. But it's interesting that vegetable intake can have such a profound effect. Yes.

Starting point is 01:41:09 And there was a vegan trial too. I think also there was a trial looking at people that are eating a lot of vegetables versus like an healthy omnivore trial. And I think the vegan trial, they also had slow their epigenetic aging more. But there's always weight loss as a confounding factor because they were eating fewer calories. But that's really interesting that there's a minus point three. That is pretty strong. You gave me that reference point of smoking being, you said,

Starting point is 01:41:34 It was, wait, smoking was point four. Okay, smoking, point four, maybe point four, five. So it's increased correlation. Exercise, point one. Okay. So, and we can talk later about exercise, but very weak effect. In order to see an effect of exercise, you really need to study many thousands of people. With vegetable intake, the effect is so strong.

Starting point is 01:41:59 You probably see an effect when you analyze a couple of hundred people, you know. So, but regarding the question, vegan versus carnivores, you know, I honestly have not seen convincing data. Omnivore, omnivore. Or omnivore, yeah. Carnivore would be the extreme opposite. That's true. Yeah, let me rephrase it. So I have not seen any evidence that people who, let's say, eat a lot of red meat, age much fast.

Starting point is 01:42:32 than people who are vegans. And we looked again in the women's health initiative. I mean, there was a hint, I want to say, when we analyzed 3,000 women. And then women who ate red meat, it was barely noticeable that red meat was ever so slightly increasing epigenetic age. But it was truly negligible, you know. So what I can tell you is I eat so much meat. Hopefully it's not bad for me. vegetables.

Starting point is 01:43:02 I eat meat and vegetables. I try to be easy on the carbs. I eat carbs, but I try to reduce them. Well, we, vegetables are carbohydrates. They're just complex carbohydrates, not simple. So you're not eating the simple carbohydrates. Yeah, exactly. Yeah.

Starting point is 01:43:19 That vegetable stuff is interesting. There's so much in vegetables with the micronutrients and the phytochemicals, right? That's another thing in them. The fiber, I mean, there's a lot of things going on here. Yeah. Somebody should really tease that apart. What kind of vegetables should be eaten, you know, and dosages, yeah. Lots of exciting PhD dissertations could be written on that topic.

Starting point is 01:43:44 Exercise. Yes. So let's talk about that. So you're, you know, there's a trial that you sent me that was pretty convincing and it was kind of, it was a new one in 2025, showing that six months of cycling, it seemed to slow epigenetic aging or grim age, right? Grim age by 7.4 months? Yes, maybe I'll frame it like that. So there have been very nice studies on the effect of exercise on grimage and pheno age and other clocks. And so what do I mean by nice? Studies where they use

Starting point is 01:44:21 one way or another a wearable to really measure your step count and activity. So it's a very very rigorous readout of your physical activity. And the studies were also convincing because they were large-scale studies, many thousands of people, and in different countries, Japan, Germany, US. And the finding is the following. Yes, if you move more, yes, your epigenetic clocks pick up a small effect. And I mentioned earlier correlation minus point one. What it means, you need to study 3,000 people, then you see a statistically significant effect of step count as an example.

Starting point is 01:45:04 But I've been deeply dissatisfied with that finding because we all know exercises what they call the polypill. You know, it touches so many systems and it's very beneficial. So I would have loved to see a strong effect on blood methylation, but the literature shows weak effect. And what about muscle methylation? Yeah, so people have built clocks for muscle. So literally human muscle biopsies. I don't know what to tell you. All right.

Starting point is 01:45:39 Yeah. Some people claim they see in effect, you know, but I just am not yet convinced. It is disappointing. So I would say it's disappointing. So then there's this study that was published by first author I can remember. Van Dam, I think differently spelled from the actor, but anyways. And this intervention was very different because it didn't look at step count or what we discussed earlier than home exercise intervention.

Starting point is 01:46:10 That was the next level intervention. It was putting people on a bicycle and they now bicycled four and a half hours a week. Now, for the health nuts out there, that's not much, but to me this is daunting, you know. So if you forced me to bicycle four and a half hour a week, I would struggle with that. Why, we are all busy people, you know. But anyways, the people who adhered to that trial, they had strong effects on VO2 max. 20%. And many other readouts, you know, so they didn't fake it, you know.

Starting point is 01:46:50 So they really saw physiologic benficiary. benefits. And then, sure enough, suddenly the clocks worked, you know. So PC grimage as an example. We keep talking about PC. PC means principal component-based grimage. That's a version of grimage that's even more robust than the original, robust in the sense of test, retest variability. It's a very reproducible measure. So anyways, it picked up a seven-month reduction. in grimage, which again dwarfs everything we just discussed, you know. So, and that was a six-month intervention. These people were younger, though.

Starting point is 01:47:34 I want to say they were between 30 and 65, basically a population that you can put under such as stringent regimen, you know. Well, they're young and middle-aged, but I would, I mean, so I would argue, Steve, that this is 10,000 steps. Like, that stuff is like, it's. okay, it's better than nothing, but if you really want to move the aging, I mean, like, you got to go more than that. And this is the kind of stuff, I mean, that we talk about on the podcast. I mean, I've had Ben Levine on. He is a rock star in the cardiovascular exercise physiology

Starting point is 01:48:11 world, and he's done multiple randomized controlled trials, but he did one that was a two-year-old in 50-year-olds. They were about 50-year-olds, and they had never been physically active, but they didn't have any other diseases. Put them on a two-year trial where they were working out, exercising about five, on average, five hours a week, doing a lot of cycling. They were doing some high-intensity interval training in there, a little bit of resistance training, but a lot of it was aerobic, and they improved their VO-2 max. And their heart structure, so he looks like the structural aging of the heart. So as we age, our heart gets smaller with age, it gets stiffer. and they improved the structure of their hearts by, it was like, if you, basically, it looked like

Starting point is 01:48:56 they reversed aging by about 20 years. Their hearts, you know, got bigger and they were more flexible. And it looked more like a 30-year-old, even though they were 52 at the end of the trial. Right. And so I would argue that, you know, doing, really taking time to exercise every day, something and more than just walking, you know, is very powerful. for longevity and for, you know, slowing age acceleration. Yes.

Starting point is 01:49:23 And so it is really nice to see this new trial because I have also been very disappointed in, you know, some of the data. But no one's really doing these kinds of studies where they're saying, hey, again, it's like getting a stronger signal. Let's not just walk. Let's not just do 10,000 steps. Let's push them to improve their VO2 max by 20%, like, and see what that does to their aging clocks, right? Yes. Now we know. You know, I mean, the study didn't have a control arm. We should mention that, you know. So, but it, I certainly was impressed by that. And it's hard to argue against exercise, you know. So. Yeah. I mean, there's so many studies showing it improves outcomes, right? Cancer mortality, cardiovascular mortality, all cause mortality. It improves brain aging. Alzheimer's disease risk is lowered. Everything, like all these age-related diseases. Frailty, you know, you're stronger, you're more capable, you're healthier, your heart's working better, your lungs are working better, it's improving organ function. So we know it's good for aging, for sure.

Starting point is 01:50:27 And so it's nice to see that, I mean, there might be a real threshold to pick it up with this epigenetic clocks where you have to kind of put in the effort. Exactly. And so are you going to put in more effort now? I mean. Yeah, I will try. Yeah, definitely. You know, it's hopefully there will be more studies. as these epigenetic clocks become more available for researchers as tools, it's something they can add to other things that they're looking at, you know, because I want to see a 10-minute hit, hit, you know, every day.

Starting point is 01:50:59 Like, how is intensity affecting it? How is volume, duration? I mean, there's so many things to look at. You know, we need to develop exercise in a pill for people who have lost mobility. It's never going to happen. What do you tell someone who is in a week? wheelchair, what do you tell to an 85-year-old? You know, so we need to develop interventions that still rejuvenate them.

Starting point is 01:51:25 It's low aging, but... I would say for people that are disabled in a wheelchair, we do have deliberate heat exposure that mimics moderate intensity cardiovascular exercise. I've never seen anyone looked at an epigenetic ageing clock. But so you can get in like a hot tub or a hot sauna, your heart rate starts to elevate, you know, a lot of the same physiologic. mechanisms that are happening during moderate intensity exercise. There's been head-to-head comparisons with like getting on a stationary bike and, you know, doing about 100 watts. So you're

Starting point is 01:51:57 for 20 minutes. And then comparing that to like a 20-minute sauna and you get a lot of the similar benefits. You get improvements in blood pressure, improvements in your resting heart rate. You get, you know, again, you're sweating, your core bi temperatures going up. So that we do have some interventions that may mimic it. The pill, there's so many things that change. change, you know, Steve, like, I don't, I mean, maybe we'll get that, but it's, it seems like. Yeah, I'm joking. Yeah, I know. It seems like a moonshot.

Starting point is 01:52:29 I want to briefly comment on body temperature. There has been a very elegant study in mice. So it turns out if you stimulate certain neurons in the brain, the pre-optic nerve, I think, you can actually lower the body temperature of a mouse. And there was a team in Harvard, Sinisa Varatin, who did just that in the mice. And he lowered the body temperature of the mice, I want to say by three degrees Celsius,

Starting point is 01:53:00 or of magnitude. And then he just looked at their methylation clocks, multiple organs, and guess what? Very strong effect. So the mice whose body temperature was lowered, they really aged substantially more slowly than a control mass, you know. To me that was very interesting. Well, their metabolism is probably slowed.

Starting point is 01:53:24 Inflammation, because you be going colder, vasoconstriction also happens, I would assume. Yes. That maybe, I mean, so inflammation maybe. It's interesting, you know, so I just want to mention it. So the benefits of sauna and all of that are undisputed, you know, but I just, just want to mention that maybe lowering your core body temperature by a degree or so could be beneficial. Who knows? During hibernation, animals that hibernate? Yeah, same thing. There have been a couple of studies that suggest that there's a slowing of aging. We did such a study at UCLA. We looked at

Starting point is 01:54:08 marmots in Colorado, I think. And sure enough, during hibernation, the methylation clocks didn't advance. Yeah. So interesting. It is. It's interesting. I think things kind of just, you know, just, I think people need to realize that just normal metabolism, normal neuro, you know, fear firing of, you know, cognitive function

Starting point is 01:54:32 and, you know, neurotransmitter firing away, all this stuff is producing damage, you know. So if you're just in this slow everything down, I say cold, I associate the cold with slowing it down, but at least in the hibernation state for sure, everything slow down. And so that would kind of make sense that you're kind of just slowing the whole process. Yeah, makes sense. So sleep is something that you and I were discussing off camera where there's just not a lot of evidence. We all know sleep is good for us. We'd like to see more evidence. I mean, there may be some observational studies, but there were lots of confounders there.

Starting point is 01:55:10 Yes, so I worked with a team at UCLA, Judith Carroll, and she looked at sleep disturbances in the Women's Health Initiative and other cohorts. And sure enough, people who report severe sleep disruptions, these people exhibited increased epigenetic age. No surprise here. I mean, it was an observational study. I know that people are looking at that, you know, especially now we have these wonderful tools for tracking sleeping. So I hope somebody will do the obvious study, you know, correlate the hours of deep sleep, the hours of REM sleep with epigenetic aging measures. I think it will be exciting. But I'm just not aware of any study at the moment.

Starting point is 01:56:01 Yeah, I think we know that. sleep deprivation, chronic sleep deprivation, increases inflammation, changes your appetite, people gain weight too. I mean, so there's all the reasons why it would accelerate aging, and that would make sense. But yeah, I don't know that there's enough evidence looking at the specific stages of sleep, and there's a lot to tease apart there and, you know, a lot more research to be done in that area. Yes. But another area that's very exciting has to do with our mental health and our social relationships. Yes. Right. I mean, that's, This was the biggest surprise to me in the last six months, perhaps.

Starting point is 01:56:38 So I need to tell you I'm not a social scientist. I don't study behavior. I really am not. So anyways, there was a researcher at Harvard. Laura Kaczynski, I butcher her last name, but she is a very rigorous scientist, and she wanted to evaluate what she calls, I think a social cumulative advantage, which is a measure of how connected you are in the community,

Starting point is 01:57:12 your social behavior, your friends, your community. Anyways, how does that affect biologic aging? And this is similar to the vitamin study we just said. It's got to have an effect, right? I mean, so we all know loneliness is the big killer in the elderly, at the level of smoking, right? You don't want to be lonely and socially deprived. So anyways, she did a very rigorous study, large sample size,

Starting point is 01:57:44 and she evaluated everything a researcher would evaluate. So what am I talking about? You want to evaluate cortisol levels, various hormones, that measure stress. You want to measure inflammatory markers, you know, IL-6 and various other readouts of inflammation. But fortunately, she had enough research funding, apparently, to measure methylation. Because I say that, because if I had been a researcher, I would have focused on urine and blood for measuring hormones and inflammation. And for methylation, I would have, I would have advised that don't even measure it.

Starting point is 01:58:27 because I just don't think you pick that up. And why do I say that? Why would your connectivity, your friends, your relationship with your spouse and your family, why would that translate to changes on the DNA molecule in blood? You know, think about the mechanism. It's so far removed. But anyways, Fortunately, she did do this study, and the great surprise to me was the methylation redoubt dwarfed the other redouts.

Starting point is 01:59:07 If anything, the other redouts didn't work. So Grimmage, again, picked it up. People who are blessed, really, by having wonderful family relations, community, just this social advantage, you know. Sure enough, their grim age was reduced. It really taught me something. Do you know how much it was reduced? Do you remember? No, you know, my problem is I only ever look at P values.

Starting point is 01:59:37 I'm a statistician. I know everyone always wants to know how many months, but I just go by P value. You know, there's a lot of things here. I had Arthur Brooks on and he talks about the science of happiness. He's amazing, by the way, if you don't follow him on X, you showed. He's got really great science out there. But, and Richard Davidson's coming on the podcast. He's at Harvard, and he's been involved with the Harvard Health Study looking at how social relationships and happiness really do correlate with longevity and why.

Starting point is 02:00:05 Yes. But, you know, if you think about the flip side of that, the loneliness and not having those social relationships, there's also the possibility that the relationships were unhealthy. And so people separated from that. You know, there's, so there's stress. Probably that's involved in that equation, too. loneliness itself has been shown to increase stress, you know, as was picked up on this study and others. But there's a lot of, I think, nuance there with respect to, you know, if you're someone

Starting point is 02:00:35 that has a lot of social relationships versus someone that doesn't, and like a lot of times you look at the people that don't, there's usually some trauma too, right? And that definitely would cause a stressor. That's a stressor. Oh, I couldn't agree more. if you're in a toxic relationship, get out. Of course, you know. Right.

Starting point is 02:00:54 Don't tolerate abuse. I mean, just for sure, you know. But those things probably leave their mark on the epigenome that stress. Yeah. I need to tell you, I always like studies that actually show the opposite from what I report. I want studies that show that people who are terribly stressed and depressed and don't sleep well, that they don't age too fast, you know. Have you seen that study?

Starting point is 02:01:18 So I'm always happy when a sleep study shows only a weak effect, you know, and so because I'm rooting for these people, you know. But I'm not sure. Let me say something about the elderly. Again, loan needle is the big killer in old age. And unfortunately, geriatric patients are often isolated, you know, many of their friends have died. and what to do about it. And there have been very nice studies in Japan, of course, where they deploy various robots, you know, to entertain people.

Starting point is 02:01:58 The robots are coming. The robots are coming, the companions, you know, and maybe to a Western audience, this is culturally a little bit alienating. But I look at it as an opportunity, because maybe this AI revolution, you know, And then upcoming robotics will give us companions, at least, to fill this urgent need to engage a geriatric patient. I just think it's better if they interact with something as opposed to just sitting in a chair, you know. Yeah.

Starting point is 02:02:34 Ideally, their kids would come visit them, but I guess, you know, that's not always the case. It's just not realistic. You know, many of these jobs that deal with geriatric. patients are underpaid. There's a shortage, you know, so we need to think of creative ways of addressing really this need, you know. Well, let's talk about, I want to talk about, you know, we're talking a lot about these diet, lifestyle, healthy, unhealthy patterns of living that affect the way we age, and now we have a tool that we can use to kind of give us a concrete number to give us more data and more of an understanding of how we're living and how that is

Starting point is 02:03:19 affecting the way we age, right? And this is obviously used at the level of research quite nicely, but it's also that's something that's available to the consumer. And I think a lot of people that are listening to this, we do have researchers listening, but we also have just people interested in their health and interested in living healthy. And everyone's coming from a different starting point. Some people are overweight and obese. And the thing they have to focus on is weight loss. That's like, focus on that and then everything else can come after, right? Some people are smokers and they need to focus on quitting smoking. Some people are not sleeping and they need to sleep. Some people are not exercising and they need to exercise, right?

Starting point is 02:03:56 Vitamins, minerals, all these things come into the equation. Some people want to do all of it. They want to do everything they can. They really want to feel as good as they can, age as good as they can and give themselves the potential that they have to age the best way they can. And I'm definitely one of those people. I know a lot of listeners are in that category. And so I think the excitement for them is they want to go out and perhaps try to experiment with some of these tools that are available to them and get a baseline test of their DNA grim age or something and see what their biological age is. And do they have room for improvement? And can they start to improve things and then see that improvement? What would, what would you?

Starting point is 02:04:35 you say to those people like in terms of like first of all finding a reliable test do they have to go out and do a couple of tests to make sure you're getting the same age at baseline to make sure it's a reliable test at first and and is something is it something that you think people can use let's say they find a reliable test they established that they got the same close to the same age a couple of times then can they perhaps start doing the cycling for six months and improving their VO2 max and then also, in addition to measuring their, either they measure their VO2 max or they measure an estimation of that, which is probably a lot more accessible to people. They can go out and do a 12-minute run test on a flat track and do the equation, get an estimation. It's kind of what your Apple Watch

Starting point is 02:05:20 does and a lot of wearable devices. But also add this DNA grimage and other perhaps, you know, test of these epigenetic aging clocks in there. Yeah. Well, I would say several things. First of all, unfortunately these tests are expensive they cost several hundred dollars and I always say you don't need to measure anything on yourself to know that you should stop smoking and exercise and eat vegetables you know but interestingly longevity doctors always tell me that an epigenetic clock measure leads to better adherence because I you know I go to conference and then longevity doctors approach me and they thank me for developing epigenetic clocks

Starting point is 02:06:10 and I ask them, well, what are they good for in your practice? And that's what they say is number one use case that people who measure it, they are better motivated to stick to various regiments. It's important to, again, highlight the costs because companies are trying to develop cheaper reasons. which I very much applaud. I just want a $50 test.

Starting point is 02:06:40 And what I can tell you is technologically, this is fully possible. It's just nobody has really put their mind to it, you know, to really offer that, I think, you know. But I mention it because companies will work on that. And what it then leads to is a different clock. So when you go out there and you look at different providers, they may offer clocks that have been less characterized in the literature. I'm not saying these clocks are worse in any way. It's just there's not the same level of literature. We discussed earlier today there are these five clocks that everyone uses, why they all use a particular technology, the so-called Illumina array.

Starting point is 02:07:30 and also do need and pace. Everyone uses that technology, and therefore we can leverage legacy data that have been collected over the last 10 years, you know, to see, well, what is the effect of eating vegetables or exercise? Whereas if you lower the cost, you don't have these legacy data, so less characterized. Where should someone, if someone wants to get one of these tests done, perhaps they have the money and they can afford it, and they want the motivation. because I absolutely agree that data does motivate you. What should they look for in terms of the, they want to make sure it's one of those tests that use the Illumina array. They want to make sure it's the reliable.

Starting point is 02:08:11 Does it have to say like DNA grim age, does it have to say pheno age, the duoden and pace? Like how does someone navigate that world and try to find the most reliable test to use? Yeah, I want to tell you that overall my reading of the, community is that there are several good providers of tests, really, you know, because the beauty of this Illumina array is that it follows a very standardized protocol, you know, and many years of research went into how to pre-process the data, how to optimize the signal versus technical

Starting point is 02:08:52 noise, you know, so that has been standardized. So I think as long as you go to a lab that has experience with generating this data, you're in really good shape, you know. And why would people not want to go out and use the Horevath epigenetic agent clock for their biological age? No, you know, when you use an Illumina array, they give you the Hormat clock. They give you, or they give you, they will give you a hundred readouts. If anything, you may get traumatized by what they give you. Remember, I started discussing various protein markers.

Starting point is 02:09:29 CRP or famous markers like plasminogen activator inhibitor 1 or anyways, various famous proteins also get estimated with methylation, you know. And maybe if I want to mention a very important innovation in the last year, really, people use methylation to estimate the ages of different organs, you know. So it's a blood measure, but they will say your kidney is older or you're a little. lung, you know. So that's where the field is at, developing organ-specific methylation markers. And those are consumer available as well? That's already available to the consumer. You know, so you may end up with a report 50 pages,

Starting point is 02:10:15 100 pages. You may be overwhelmed by it, you know. But you don't need to obsess too much about who does the analysis, because as long as you have access to the data, you could then apply these latest tools that are being developed to analyze it. How would you do that? You know, there are web pages. You upload the data to a webpage and it outputs the results. Like what webpage? Yeah. I started a non-profit foundation. It's called Epigenetic Clock Foundation. I know they have a calculator where people upload data and they get an output. But I just want to emphasize there are many other outlets, you know, so you can do some Google searches on who offers that. Well, I've kind of not, I think based on our last conversation and my skepticism on, you know, using these clocks on the individual level and then trusting what's consumer available.

Starting point is 02:11:19 I haven't really experimented with them since it's been years. And so now we were talking a couple of weeks ago and I was going to, I'm going to do some. experiments, but we didn't have enough time for two weeks to do all this and come on the pockets and talk about it. But I'm now interested because of all the progress that's been done in the field and including the consumer available tests that are out there in, you know, seeing what I get from my data and see what room for improvement I have and whether or not it does get picked up because, again, I'm already healthy and I do take a lot of supplements already. I want to briefly mention the most obvious medical use case, perhaps.

Starting point is 02:12:02 It's really finding people who age faster and then thinking about what to do about it. And we talked about various interventions. The problem with you and me is we probably already optimized, you know. Let's, I would be surprised if you learn anything new, you know. But maybe you start a completely different regimen, and then it would be interesting. How does it affect your methylation readouts? Right. And then probably presumably don't want to measure it when you're sick or...

Starting point is 02:12:38 Yeah, maybe let's talk a little bit about variability, because they have also been major insights that surprised me. I'll start maybe with the background. So we talked about these principal component-based versions of clocks such as PC. Grimmage that was used in the cosmos multivitamin study. Anyway, these are very reproducible. And to give you a number, let's say you measured that marker two days apart. You measure PC grimage on Monday and then another measure on Wednesday and nothing has happened.

Starting point is 02:13:20 I would expect a technical variation of maybe four or five months perhaps. or two months. It's a few months, you know. And so this is just technical variance, you know. But, and, and, but other clocks do need and pace is slightly less robust, but also very high technical reproducibility. However, if you use different types of clocks, you will get different measures.

Starting point is 02:13:55 So if you take grimage and then compared to what people call Horvath pan tissue clock, you may get very discrepant results because they measure different aspects of biology. The Horvath pan tissue clock is very good for stem cell biology, hematopoetic stem cells, precursors of leukemia, that type of biology, just not good for mortality risk, you know. Yeah, I think that raises another question in my mind, especially for people and consumers that are interested in maybe measuring some of these clocks and seeing where they're where they're at and if they're going to do any interventions where they're at after the intervention. But, you know, which clock is best?

Starting point is 02:14:43 So are we talking about like if you're wanting to look at the duodenin pace and the pace of your aging versus your DNA grim age, right? I mean, what is, maybe you kind of need both almost. Absolutely. I would look at both, you know. I really would. It's a bit like the example of a biochemical test when you go to a doctor, you know, do you focus on hemoglobin A1C?

Starting point is 02:15:10 Do you focus on cystatin C? Give me all, you know, let me look at it. Because they do give you different lenses at the changes in the methanol. But you would predict, and this is something that, again, with some of these trials, we're seeing the duoden pace is picked up, but then the grimage is not, or vice versa. And it's like the question then becomes how these clocks were, I don't know, trained and developed and what they're more sensitive to. And that's another thing. So if you are someone that loses a lot of weight, then you would, you know, both would pick it up, pick it up.

Starting point is 02:15:48 But presumably the one that's trained more on BMI. would be more sensitive. Yes. Remember the exercise study that we discussed four and a half hours of bicycling. Grimmage was better than do need and pace, you know. And so we- Inflammation, right? Does grimage pick up inflammation?

Starting point is 02:16:06 Yes. Yes. But, you know, we are really learning about these clocks, you know, because all of them were built with AI machine learning models. And we are trying to understand. what perturbs them, you know, what kind of interventions touch them. And ultimately, what the field needs to develop is what we discussed earlier, surrogate endpoints for a clinical trial.

Starting point is 02:16:32 Because when you do a clinical trial, you need to tell the regulator, what is the primary readout? You can tell them, I look at 10 clocks, you know. So, and the very fortunate situation is that, um, There is a biomarker consortium, biomarker of aging consortium, that really rigorously evaluates all of these clocks. And also substantial research funding goes into that field. There was an announcement by ARPA-H to study interventions,

Starting point is 02:17:08 but also to develop then biomarkers for tracking longevity interventions. And so I'm very hopeful, actually, that the science will advance. that next time you and I talk, you know, I can tell you this clock is the primary readout. How do you think AI might change, you know, these clocks and development and the, you know, progress in them as well? Like, are you hopeful that using AI technology will help you make them better? Yes, absolutely. And maybe to give you some perspective. So, Akelu in the lab, published Grimmage 2019.

Starting point is 02:17:50 way before chat GPT, before anything. And now it's 2026, and Grimmage still seems to be the best mortality predictor. To me, that's deeply frustrating because I want to see step changes in these biomarkers. And I'm sure it can be achieved. Now, the good news is people have already published new clocks based on AI. You know, they do use large language models. One person, Lucas, published what he called Grimmage Version 3, but their new clock systems age, then there's OMIC-M-H.

Starting point is 02:18:34 So these clocks have all come out in the last few months. And the reason why I don't talk much about them is because they haven't gone through this extensive review by the community. But fingers crossed, you know, that any of these newer clocks are, way better than grim age. Why? Because we need even better clocks for clinical trials.

Starting point is 02:18:57 Yeah. I think since we're talking about new technology and, you know, it's something that I'm super interested in, as you know,

Starting point is 02:19:08 that is, and it's just this concept that goes back to the Yamanaka factors and basically the birth of these induced proepotent stem cells,

Starting point is 02:19:20 Right? I mean, Chinya Yamanaka won the Nobel Prize and was it 2006 for discovering you could add four transcription factor proteins. These for people listening are a type of protein that can, you know, change the way several different genes are expressed, activated, deactivated. And he could add them to any cell, old cell, a skin cell from an 80-year-old, and revert that cell to a, you know, pluripotent stem cell state, which is, you know, pluripotent stem cell state, which is, so cool and fascinating. And you could just sit there and think about that for hours and all the things that it means and how it happens and, you know, I'm just on and on. So, you know, the, and I think we talked a little bit about this in our last conversation, which is, you know, what happens to the epigenome when you reset it from like an older, more differentiated type of cell like the skin to a stem cell. And it seems like the epigenome changes, right? For sure, you know. So back in 2013, I published the pan-tissue clock. Figure 5 in that paper showed Yamanaka factors reversed the age to a prenatal state.

Starting point is 02:20:36 So you take a skin cell from a 50-year-old and the epigenetic age of an induced pluripotent stem cells is a negative number, meaning prenatal, you know. And of course, so many people have worked on the idea then to apply these Yamanaka factors briefly and briefly interrupted reprogramming. There are many names in that field, Juan Carlos Belmonte, Manuel Serrano, but so many more have worked on David Sinclair famously, who now has a clinical trial for optic nerve regeneration based on that idea.

Starting point is 02:21:21 Yeah, but the idea being, so apply these factors or a subset of these factors to rejuvenate organs. And why inter-rejuvenate but keep their identity. They're not going to become a stem cell. Exactly, because you don't ever want that skin cell forgets that it's a skin cell or a liver cell, that it's a liver cell. And why is that dangerous? Cancer. That's a great danger. And there have been substantial developments. So on the one hand, I mentioned the study from David Sinclair, where he now administers adeno-associated virus and AIV to the eye of people who

Starting point is 02:22:07 really need to regrow optic nerve or end. And the study apparently will start this year, 26. So the longevity field is waiting with a baited breath. Will that succeed? It would be a triumph for the whole field. There have been extensive characterizations in mice. So which kind of organs benefit if you target them and also in vitro. So we understand quite a lot.

Starting point is 02:22:39 but what companies struggle with is where exactly do you deploy it for what kind of condition, always keeping in mind to ensure safety. Yeah. And there's questions in my mind that are even more mechanistic, you know, just because that interest me, which is, you know, if you are, if you're taking an old cell that has these hallmarks of aging, there's like 12 of them now, right? You're talking about mitochondrial dysfunction, you know, inflammation is now even a hallmark. It used to be just this amplifier that still is an amplifier, but, you know, you have proteostasis isn't working right.

Starting point is 02:23:23 So your proteins are not folding properly and they're also being not degraded properly. You've got DNA damage, nuclear damage, genome instability, all these things that happen with age and older cells. and if you're going to change, if you're basically just going to change the way the gene expression pattern is and the epigenome, so to speak. Yes. Like, how does that get rid of all this damage? And what doesn't it get rid of?

Starting point is 02:23:55 Yeah, apparently it doesn't get rid of all types of damage. And the obvious damage is, of course, various somatic mutations in the DNA. you just don't touch it. The impressive part is how many hallmarks do get reset, you know. I seem to remember one aspect that wasn't restored was telomere length. Right, you imagine that. So that wasn't.

Starting point is 02:24:22 And also, even when it comes to the epigenome, there are vestiges that don't seem to be touched by that, you know. So certain cytosines that do not get, completely reversed, you know. It's so interesting. Do mitochondria get healthier? Yes. So mitochondria oxidative phosphorylation.

Starting point is 02:24:46 What about mitochondrial DNA? Yeah, sorry. I forgot. So mitochondria get healthier. Yes. Stem cells, stem cells get rejuvenated? Or do they just start working better? I mean, what?

Starting point is 02:25:03 I want to draw on attention, because most of our conversation was about epigenetic clocks, and now we talk about other readers. Yes. It's important to distinguish because methylation clocks do detect a benefit of interrupted reprogramming in certain organs, but not all. I just want to alert people. Which organs do they not, or which do they do detect?

Starting point is 02:25:28 I know I remember, I'm trying to think of old publications, but I remember in skin there was a strong effect. I want to say also muscle, you know. It's just not all organs. And now I'm talking about interrupted reprogramming because, as we said, if you go all the way, you will find an effect, you know. But I mention it because when it comes to that intervention, you really want to measure many readouts that we discussed, you know. So above all organ function test, you know, so depending. on the target organ, you need to really establish that it works well.

Starting point is 02:26:09 As an example, if you study the liver, really measure their liver functioning or kidney, that just show functional restoration. On a molecular level, there have been very detailed functions of gene transcription that indicate that the gene expression reverses, reverts back to a more useful, profile. But there's a problem with that statement that many people may not appreciate, which is it's actually very difficult to build clocks based on gene expression. So what does it mean that gene expression is rejuvenated? And the field has struggled with that for many, many years, you know. But I can mention, so people look at so-called mesenchymal marker.

Starting point is 02:27:05 So some of you may have heard epithelial mesenchymal transition. So cells change their phenotype as we age, in part due to inflammatory signals. So an epithelial cell forgets that it's an epithelial cells. It thinks it's a mesenchymal cell. But anyway, so that's a readout, inflammatory markers, we mentioned oxidative phosphorylation, so various readouts that convince a researcher, okay, the cell seems to be younger. If we talk about the extreme case of making an induced pluripotent stem cell, do the somatic mutations persist in that as well? Yes. That's disappointing. Because you cannot touch it, right? It's that DNA is changed.

Starting point is 02:27:57 Yeah, I mean, it's just, we've got to solve that problem. No, but you need to ask a different question, perhaps, that has a hopeful answer, perhaps, which is do somatic mutations actually matter? That's a, and now, to be clear, cancer is often due to somatic mutations. So if you say, does cancer matter? Of course it does. But what happens as we age, all cells in your body accumulate somatic mutations. They really do.

Starting point is 02:28:31 And the question is, does that actually translate to biologic aging? Doesn't it depend where the mutations are? Of course. And you already ask the right question. Because most of these somatic mutations have zero consequence. And I love that, actually. By the way, the same statement holds for methylation. As I mentioned, millions of changes, but fortunately, many of them don't matter.

Starting point is 02:29:00 But same with somatic mutations, you know. And when you ask aging researchers, how important are somatic mutations for true blue aging, you know, you will get different answers. Some people will say it's hugely important, and then there are other people who will say it's negligible. the field is really split on that question. Yeah, I mean, if you're getting somatic mutations in regulatory parts of the genes or even, you know, parts that are promoter or whatever, I mean, you'd think that you start to have dysfunction and level the proteins, right? Things aren't going to work properly. But again, if is the key word, if you get them in those regions. So you would think the more, I mean, obviously if you get more and more of these mutations, then the,

Starting point is 02:29:50 chance of you having it in a part that matters goes up, right? For sure. I mean, just to be clear, we don't want it. The question is, how bad are they? Let me turn it around and ask a question to you and the audience. Imagine you had a way to completely stop somatic mutation. You have the perfect therapy. Would you stop aging?

Starting point is 02:30:12 I mean, can't we use CRISPR to sort of, I mean, if there was a way you could, every time you got a mutation, just use CRISPR to change. Yeah, and also coming back to DNA repair, right? So if you, let's say you have ways to improve DNA repair. I'm asking the question because my answer is the following. I think if you stopped all sorts of, if you completely stopped somatic mutations, I think you would still age. I don't have definitive proof, but I, that's,

Starting point is 02:30:49 where I'm at, you know. For me, a lot of aging. Would you age slower? Yeah, no question. It has a benefit. You would still age. You would still age, you would still age for sure. It's not, no. But you would. Because aging happens at all levels. We mentioned the epigenome today a lot, but also the transcriptome and the proteome, right? Proteins aggregate, and that protein aggregation may have nothing to do with somatic mutations or even methylation, you know. And so, I mean, damage accumulation happens at so many levels. And the debate is in certain ways which, how much do we gain if we clean up damage at a certain level, you know?

Starting point is 02:31:33 All the damage. So there's 12 hallmarks, right? That's why, I mean, obviously genome stability is just one. So if you take care of that, you're still got 11 more to take care of. You're still going to be aging. But so if you were to clean up all 12, I mean, there's no doubt you have a benefit. Then what happens?

Starting point is 02:31:52 I mean. But you know, I liked our earlier discussion about, let's say, organ transplantation because I'm looking for a miracle intervention. I'm making something up. Imagine somebody has a pill that really prevents sarcopenia. You keep your muscle strength. Could it be that this benefits so many organs and suddenly we increase health? health span by five years, you know. Or we have another pill that really preserves your kidney function,

Starting point is 02:32:23 you know, how much do you gain? So I like these silver bullet dreams. You have one intervention, you really improve one organ, and it has massive benefits. Well, we know that. We know resistance training absolutely helps you not only maintain but increase your muscle mass, and that's hugely important for life expectancy and quality of life. So, I mean, I would imagine if you just improved muscle function with age that you would have an effect on... I'm with you on that, you know. Yeah. But let's now again talk about the 85 year old. So let's say we have such a pill. We give them this intervention and you really even restore muscle functioning. Will they suddenly live five years longer? I see.

Starting point is 02:33:11 I hope they will, but I'm just saying these are the interventions. But what about their cardiovascular disease risk? I mean, if it's true that people's organs age at different rates and there is individual variation there, so maybe my heart is aging faster than yours, maybe you are more susceptible to your brain aging more. I don't know. Like, if that is true, I mean. It is true.

Starting point is 02:33:40 It is, right? It is, right? We know that even from methylation clocks, yeah. That even within a person and, you know, obviously their diet and their lifestyle, everything's like, should be the same, affecting the same organs, the same, but it doesn't, right? Yes. Either it doesn't or there's other things that are happening that we don't quite understand. But where was I going with this? Yeah, that basically, if our organs are aging at different rates, then, you know, obviously the muscle would only affect. the people that are going to die from their falls or whatever, you know, I don't know.

Starting point is 02:34:15 Yes. I think it's the, it's an interesting, it's an interesting question in terms of like, what organs are aging faster in you? And, you know, there's biomarkers that can help you understand that risk, but the aging clocks, that is something that people can now go and test, right? Yes, that's where the field is at. So, and now I'm talking about the biomarker field in general. So people have developed protein markers of various organs, which is the obvious thing, you know, organs secrete various proteins or measure them.

Starting point is 02:34:51 The exciting aspect is that the same has happened at the level of methylation. So people have methylation readouts of different organs. I'm not saying they are optimized. There's room for improvement, perhaps, to be seen. but that's how I envision really medicine 2.0, preventative medicine. You measure many readouts of organ function. You diagnose something is going the wrong way, and then you target it, you restore it, you know, precision medicine, really.

Starting point is 02:35:26 I even, you know, I've done my gene array before and looked at, there's like all these different companies that are able to go. go and look at your SNPs or even your whole genome. And even those tests, when you get the raw data back and sort of look at them, you'll have genes that say, oh, you're predisposed to coronary heart disease or, you know, so they're already sort of targeting organs or neurodegenergeneer disease like Alzheimer's disease. So we know there are even genes that are involved in predisposing you to certain diseases that are based on your organs. And so it makes sense that the methylation patterns would also play a role in that because they play a role. And, you know, it was a

Starting point is 02:36:06 to briefly comment on that because I used to be a human geneticist, actually, at some point I studied genetics. And you're entirely correct. Of course, there are these SNPs and also polygenic risk scores for various disorders. But I would like that people know these associations are absolutely minute, more often than not. I mean, they're famous association, apoi4 for Alzheimer's. they're a strong association. But I just want you to know that if you have a genetic risk for a certain cardiovascular disease, these effects are absolutely minute and they are dwarfed by you just walking your

Starting point is 02:36:48 10,000 sticks. Yes, yes, yes, I agree. However, interestingly, methylation is a far stronger signal than SNPs. So epigenetics, order of magnitude, more informative than genital. than genetics, you know. So looking at the epigenetic, organ-specific epigenetic clocks even. Yes, it's just you can't compare it, you know. I'm a health nut.

Starting point is 02:37:15 I spent many hundreds of dollars on various tests. Many tests have no use. But I haven't spent money on a G-WOS test. I mean, I did for ancestry. I just want you to know that it doesn't inform me personally, you know. So I just think we have better readouts. We mentioned proteomics clocks, you know, and above all, just your regular biochemical markers, you know, just go with what the doctor orders. There's a reason why your medical doctor doesn't order a genetic test for you.

Starting point is 02:37:50 You know, it's less informative. Right, yes. You're not doomed if you have a bad prognosis based on genetics, you know. Exactly, absolutely not. I mean, there's a lot of people that have APOE4, that do not have Alzheimer's. Alzheimer's disease and there's a lot of people with Alzheimer's disease that do not have an APOE4 allele. So it's not, it's not a hopeful message. Yeah, diet and lifestyle matter.

Starting point is 02:38:12 And that's kind of the point of the conversation that we had. We were talking about these epigenetic clocks as a, you know, biomarker readout that is a little bit, you know, more comprehensive than just getting a C-reactive protein or HBA1C or even, you know, looking at your lipid levels. because it can actually look at your biological age, right? And that's so cool. So thank you so much for coming on. Is there anything else that we need to discuss that we didn't get to so much? No, I think we covered everything.

Starting point is 02:38:49 That was a real pleasure. Have you done any of these biological tests on yourself? Yes, for sure. Do you like the results? Yeah, I do. you know so I remember a pheno age result a couple of maybe half a year ago was 13 years younger if I remember that I like that so I'm actually doing well on various biologic tests how old are you I'm 58 right now oh you're 58 wow you look great yeah I don't I look horrible thank you but I look horrible have you done the organ specific one not yet you know so yeah okay I am Again, I'm trying all sorts of health behaviors. I actually don't need any readouts, you know, for motivation.

Starting point is 02:39:37 I'm a bit of a health nut, so I don't need that. So what's your routine? What do you eat? What, like, what's your health nut routine, your supplements? I go with validated interventions. We talk about omega-3, multivitamin, creatine, I take a lot. By the way, I love your podcast. I learn a lot from you.

Starting point is 02:39:58 Thank you. Yeah. I started multivitamin. vitamin after you started talking about it. That motivated me. From you, I learned the importance of having a cooling mattress for sleeping. So I implemented that advice from you. Are you sleeping better? Do you sleep better? I think so. Yeah. But by the way, I love placebo effects. They always work. I love placebo effects. Nothing wrong with that, you know. I don't like nocebo effects, but I love placebo effects. That's right. Yeah. So the reason why I mention it, I,

Starting point is 02:40:30 I do, I think it worked, you know, but I don't have hard data on that. Do you take vitamin D? Yes. Vitamin D. And you do a lot of vegetables. Exercise, how does that come in? Yeah, I do. Every day, 30 minutes, you know, not too much.

Starting point is 02:40:46 That's good. No, that's great. I follow routines. Yeah. I mean, exercise needs to be a routine. It needs to be part of your personal hygiene. Yes. I also take medications against high glucose.

Starting point is 02:40:59 I'm actually a pre-diabetic because of my decades of eating hundreds of grams of chocolate each day. So I – yeah, so I take something called acarbos, you know, to – but also I take – Does that have any effect on aging? A-carbos? I have no idea, you know, so I just – yeah, so anyways, I take statins. I take isatamip, you know, so various interventions. where there's very credible evidence, you know, that they move the needle. I'm always impressed by people who swallow 120 pills, but it's not me.

Starting point is 02:41:38 No. I take a lot, but not 120. Do you take ubiquinol if you're taking a statin? You might want to think about that because statins target the melvonite pathway, which is HMG-CoA, important for cholesterol synthesis. That's why it's most widely prescribed drug for lowering LDL cholesterol, but also that pathway is important for making COQ10 in your mitochondria. And so that's something to consider as well.

Starting point is 02:42:06 So taking COQ10, I say ubiquinol. It's the reduced form ubiquinone also does the trick. But you might want to look into that as well. Thanks. I know I would learn something from visiting you. Well, do. Well, Steve, thank you so much for all your contributions to the aging field. Thank you.

Starting point is 02:42:23 The ones that you continue to make. people can look up your publications and many many many publications where else you're on x what you're what you're i have a handle prof underscore horvath h-or v a t h my twitter account is all about epigenetic clocks and and longevity interventions but yeah i want to thank you i think you really do a great service to the public to educate them. All I can say is I follow you, I listen to you. I think it's awesome. Thank you.

Starting point is 02:43:02 Thank you so much, Steve. I really appreciate that. Is there anywhere else you want to direct people to you besides your Twitter and your publications? No, stay young. Try not to be stressed too much, you know, and, yeah, enjoy life. Enjoy life. I think that's good. Try not to stress too much because at the end of the

Starting point is 02:43:22 the day, your deadline, doesn't really matter, right? I need to tell you, so the hopeful message about stress is that short-term stress does not seem to affect epigenetic clocks, psychological stress. So I always love that. But repeat it. Short-term, is that repeatedly or just like? So there is some literature that really severe psychological stress, we're talking now, childhood, sexual abuse, perhaps even PTSD, that affects you.

Starting point is 02:43:52 epigenetic age. But I always like it that these short-term stresses don't seem to touch you, which is a hopeful message for everyone who is terribly stressed. Like being worried about a podcast. That's right. I have never seen. Grant deadlines. Exactly. So I've never seen evidence that this has a strong effect, you know. Well, don't stress too hard. That's the bottom line. Thank you so much for this conversation. Thank you. It's a pleasure. I want to thank Dr. Steve Horvath for joining me today and for giving us such a clear, rigorous, and nuanced tour through one of the most important frontiers in aging science. Steve is one of those rare scientists whose work did not just contribute to a field.

Starting point is 02:44:32 He helped define it. If you haven't already, you should follow Dr. Horvath on X, formerly Twitter. His handle is at P-R-O-F- underscore H-O-R-V-A-T-H. That's at Prof underscore Horvath. He regularly posts interesting papers, updates, and insights on aging. biology, epigenetic clocks, rejuvenation, and where the field is heading. Highly suggest you follow him. And for everyone listening, we've also put together detailed show notes for this episode. You can find them at foundmyfitness.com forward slash episodes, E P-I-S-O-D-E-S. At the bottom of

Starting point is 02:45:10 the show notes, we've included a brief consumer guide on biological age testing. That includes what to look for, why the clock that you're using matters, and which clock you should use if you're interested in things like mortality risk versus disease risk versus metabolic health versus the rate of aging. I also just want to take a brief moment to thank you for supporting this show. Found My Fitness is ad-free. That means we don't take any sponsorships. We don't interrupt these conversations with ads and we don't shape our content around commercial interest. The goal is to keep the episodes as evidence-based, as rigorous, and as independent as possible. And that independence is only possible because of listeners like you and your support.

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Starting point is 02:46:23 and you'll get sent a curated Science Digest twice a month. Your support helps us continue producing ad-free, unbiased, evidence-based content on health, fitness, and aging, and it directly sustains the research and production that go into every single episode. There are hundreds of hours that go into this. You can help us support the show and sign up to become a pre-reaching, me a member at foundmyfitness.com forward slash premium. Again, that's foundmyfitness.com forward slash premium, P-R-E-M-I-U-M. Thank you so much for listening and thank you for

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FoundMyFitness - #112 How To Slow Biological Aging With a Multivitamin, Vegetables, & Omega-3 | Dr. Steve Horvath

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