Navigating Biological Age Testing

Welcome back to the podcast. Today, I'm joined by Dr. Steve Horbath, 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 Horbath 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 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 agent 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. 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 three's, Vitamin D, 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 datasets. whether red meat shows up as an aging signal, how sleep disruption and social connection appear on biological aging clocks? whether GLP one drugs like semiglutide 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, telomeir attrition, 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 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 foundoundmyfitness. com forward slash episodes. We've put together detailed notes for my conversation with Steve, including the major aging clocks we discuss each one measures and how to interpret them without overreaching 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 tasks 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 foundoundmfitness. com Ford slash episodes EP I S O D E S You can click on the Steve Horbath episode to find all that info 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 this 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 on this podcast Please consider becoming a F My Fitness Premium member Premium membership directly supports our work, gives you access to exclusive benefits like the Alquat This is our members only podcast. also monthly live and recorded Q and 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 foundound My Fitness premium member at found myfitness. com forward slash premium. Again, that's foundmyfitness d. com forward slash P R E M I U M. premium Thank you so much for your support. Now ono the podcast with doror Steve Horvath. Just a quick heads up. The first twenty 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 wantce answered. H hope you enjoy Welcome back to the podcast. I am sitting here with Dr. Steve Horaff 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 Corevath epigenetic agent 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. 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 twenty nineteen. so I would hope that there's been a lot of new, exciting data to discuss. But um You know, may 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 That'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 I have u Different mortality risks, morbidity risks People who you know from your high school, they look older or younger than you. all of that is in that concept of biologic age U However, u longevity researchers or geros scientists who study aging really conceptualized biological age using measurement technologies. how do you get a number for measuring biologic age And the field has really exploded over the last thirteen, fourteen years People have developed biologic age measures based on wearables, step counts, gaate speed Just very exciting manyany 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, 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 Proteum, metabolome G like com. really any om and for any readout, people have developed aging measures in. I started with DNA methylation. Back in twenty eleven, we published our very first epigenetic clocks And why methylation? Because the signal for aging and even mortality is very strong in methylation But when you want to measure biologic age, you really need to look at many levels of readouts, molecular biochemical readouts, blood biochemistry, various measures of organ function, fibrosis as an example And then, of course, above all, functioning measures Um VO two max gate speed and daily living activities in. Frailty Fraty of that. It's so important, you know, 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 time the day were born. And the interesting thing, you talked about biological aging you know, you have this 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 there could be this disconnect where some people perhaps you know genetic and also lifestyle factors 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 fifty years old, but I want, you know the organs in my body and the cells in my body to seem like they're thirty years old, right? too 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, cardio respiratory fitness and VO two 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 Yes. is one key word that has to be 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 and we try to optimize lifestyle prevention, all of that But something still changes deep inside of us in ourselellves. And what is it? what drives aging Th these methylation clocks that I've developed, they really track damage accumulation on one way or another, becausecause 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 cool to allow researchers to actually identify novel interventions. How do we truly reverse age 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 and that's to me always been question Is it tracking the damage that occurs And or if you're changing these patterns, does that change the damage So becausecause you're globally affecting 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, jeans 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.s So I think one of the points of confusion I've heard repeatedly, you know from my audience and just from, you know in general, like out there, is that people think these Biological aggeing clocks are just sort of like 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 We actually have very, you know, different clocks that seem to be perhaps tracking or have different You know strengths and weaknesses in 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 in 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 metabolomic interacellular communication, but also damage accumulation Surrounding the DNA molecule, these chemical changes to the DNA. there is an accumulation of damage and that impairs then 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 impaairs 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. 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 Mhal the metethallian 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, you know 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 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 metab metabolic syndrome. Then these so called these are now second generation clocks, you know, they really relate to inflammation and various stressors smoking 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 world 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 a different readout from other parts Okay, yeah, that's 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 read out because then that would be kind of I think it would be overly simplistic. R. And most clocks were tailor made for blood for For the sake of convenience Arguably you would want to develop special clocks for the brain, for the liver, for the kidney. you know, and the field is moving in that direction. So people develop actually single cell clocks and organ specific clocks. Oh, that's cool. Yeah. 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 or vath epigenetic agent clog first generation for chronological age And then we kind of get into these other clocks, which were're first generation, and then they have second generation versions as well. But so the DNA pheno age Does that clock lean more towards inflammatory and metabolic function than pure chronological age Yeah, for sure, you know, 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 Um 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. U But yes, so this clock was then impressive mortality risk predictor for humans, you know However, it was then superseded by the Grim Age Cock, which was named after the Grim Reaper. It was published also many years ago, twenty nineteen But it continues to be very impressive for mortality risk And from a From mathematical perspective, these clocks were constructed in very different ways 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 you 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 with the grim age you know, I think it was my understanding that there's smoking is somehow embedded in that in that calculation or you know whatever you want to call it stress related proteins, inflammation, but the phenoge also has some inflammation as well in there Yeah, maybe I'll start with a much simpler example C reactive protein U is a marker of chronic inflammation. It's a very important biochemical readout and just u The doctor will measure it when you have certain conditions But interestingly, you can actually estimate C reactive protein levels based on methylation. And I should say the estimate is not very tight For the experts, they will say correlation may bezo point three 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 But which one is more informative for you Now, A medical doctor will always focus on the plasma based readout 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? 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 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. 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 estimate of smoking history. why don't I use these methylation biomarkers? In a linear combination, I combine it in an optimal way to build a mortality risk predictor and This idea is undernderlying the Gim Hge clock, the Grim Reaper clock And it just worked. beautifully in many validation studies. We now know this idea worked. But that's really the idea of the Grim H clock. And this was from this was developed in your lab, the Grim H by Ake Lu in my lab. you know phheno H was developed by Morgan Levine when she was a start in my lab. Morgan was on our podcast a few years back as well. Yes. So why should methylation patterns be able to predict your mortality. I mean, that's And I mean, how accurate is that? I mean, like, what's What are we talking about, you know Yeah, um 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, and And now I was so relieved Basically six weeks after I had published it, 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 these methylation clocks very much predict mortality risk. point that certain startups pursue the idea of using methylation clocks for pricing life insurance policies or financial products Um, and Of course, methylation clocks are used in serious randomized controlled trials, 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 For example, smoking again, you know, so Maybe 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 And 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. and I mean, we even, I think 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 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 the life expectancy of the offspring as well So and then I think this is a study from the Netherlands, the so called Dutch hunger, perhaps Yeah I'm not sure whether' what you mean Nethers. Yeah, that's right Yeah, very exciting work. you know that maybe a couple of years of starvation could already change Gonad methylone 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. 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, they're going as this epigenome and their sperm in a way that was, you know, more permanent. And so they had offspring that were like more resilient against type two diabetes and you know, other age related diseases as well. So I I think they also live 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 Gon NAads if I'm me 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. Very smart people disagree with these findings Personally, I'm complepletely neutral. I But I just want you to know they disag that the changes Yeah, so that no, just to be very precise 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, so It remains to be seen, I want to say. because Um I want to think that if you're parents or grandparents Um went through severe stresses. I want to think that you still 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, so Well sure. that would be a nice thing to think.. But I mean, on the bright side of things, even if there there is and I've seen, you know, the I've seen evidence that convinced me that there's an epigenetic change that does happen. And in you know, sperm DNA, for example, like if you have an obese male and then they lose weight, like you can look at their sperm DNA and it changes from being obese to le. And epigenetic changes, gene expression changes are happening. So But if 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 even if you don't have the cleanest slate. Yes Yeah, what I want to tell you briefly about sperm is yes, their are methylation changes and also changes with aging. So the sperm methylome of a fifty year old is different from that of a twenty year old However, the changes that occur are at completely different locations from the changes that we use in any of our other clocks you 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 Horwas pan tissue clock, you apply to sperm, you get one number, thirty seven 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. So people have developed clocks apppplly to placenta to estimate the age of the newborn, meaning gestational age were also various stressors from the mother. But again, these changes are very different from what we observe in blood O adult tissue thing. Have there been clocks for sperm? Yes have been developed that are more precise? Yes. I have a question about grrim age, but it this sort of leads us into the next clock that I want to have you discuss, which is the do it paste, as I say right? I think it's called Dun andast. needen paste. That's D paste. So the question I have is, you know with the DNA grimmage, 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 that's obviously you know, quantifiable What if your forty five years old. you get your DNA grimge test done, it gives you your mortality because you've had all this you know Lifetime exposures up until the age of forty five of, you know Let's say air pollution, mayaybe you smoked a little bit, whatever alcohol Poor diet, stress, chronic stress all those sorts of things. You know, you change your lifestyle and it gets better that Does that grimage change If you had asked me that question two years ago, I would have hummed and heart, you know and I was always very cautious about that In certain ways, how reversible are these changes?? But the science has really advanced and now I'm confident in saying that you can reverse grimage to some extent The keyword is to some extent because these changes appear to be very minor. We can talk about it later, but there have been very rigorous randomized controll trials with supplements and medications. so There's a hopeful message. you can reverse it. So that's what we're gonna get into folks. That's gonna to be the exciting stuff this this this other clock that's able to measure ase of aging. Can you talk a little bit about the? Yeah. Do can you say Yeah yeah. There is another widely used clock which is known as a Junedan pace clock. It was developed by Dr. Moffitt and Dan Belsky. 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 whereereas 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 and established physiologic markers and biochemical markers includluding also importantly, and we should discuss that change in body mass index So but also measures of waist to hip ratio or u also measures of ose impairment, markers of inflammation, many readouts And the study leveraged a unique epidemiologic cohort study in New Zealand in the city of Duneden 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 a longitudinal studies. And by having these longitudinal data, multiple measurements per person They could really U estimate pace each person's individual trajectory So far, so good. 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 pace of aging based on these physiological measures And I think that's a very good idea. Why? Because people care about What's my current pase 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's affecting how theyre. Exactly. Yes, Thankk you. ye. 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 u, So therefore, people use Duned and Pace along with all the other clocks that I mentioned in when they study interventions, that's by now part of the standard repertoire 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 a rejuvenation of the methylone 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 grrim age two. Yeahes. And I see the Duedenian pace that those are 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 those three stand out to me when I'm reading the literature, maybe because I know them the best. But those are the ones that stand out. with this disagreement and we kind of you kind of touched on this already. you know, if you're if you're looking at and 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 when your mortality risk is the same or, you know, determining when you're going to die is the same And yetate your rate of aging perhaps slows a little bit. Maybe it's not much. Maybe it's two percent 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 You know, so if you're changing pace at which you age by two percent and the trial was six months Is that going to be reflected in the Gim age or, you know, what's the standard deviation here that we're even talking about with Grimage, right? Yes, I think you make a very important point. If you have an intervention that has a very strong effect, I would expect most of these clocks will show it. Why? Because these clocks are correlated with each other. and just to throw out a number, correlation point five after you regress out age, sex and various variables, but they still Fairly good agreement. This is the typical glass half full, half empty. It is a correlation of zero point five 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 for judging longevity interventions um, Yeah, becausecause when it comes to mortality risk prediction, we know the answer right now after several large studies. There was a study in Scotland, generenation Scotland. eighteen thousand people were evaluated and Grimage was best And there was a study from Harvard. I want to say thirty thousand people were evaluated. Grimmage was best. So we know which clocks is best for mortality, right pusey right there. And I just want to make this point because usually when we have these studies at least observational studies looking at because you'll never have a randomized controlled trial that's going to last, you know thirty years or forty 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 effffect, mortality, you're typically 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, you know, fish or whatever, we're going to do this intervention a period of time and you can have the grrimge, 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 or Yeah, you think of it correctly and that's certainly the ambition. But I want to be very precise using the language of the 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 a lower mortality risk. And u This so we We would like to think that is the case, but from a regulatory perspective, that hasn't been proven, you And in general, the FDA evaluates biomarkers, you know, whyy? 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. And I just need to tell you and the audience 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. whyy? They are urgent questions, right? People have exciting interventions. So we need to make assumptions, you And for the longest time, I've been very 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 in a way we know the intervention has a benefit for human mortality risk. And then I see that it also touches a 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 What? Have you, what's the most robust intervention or It doesn't have to be of to 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 biologic age by some of these clocks, grrim age, pheno age What's like 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 too answer your question. HIV positive people exhibit epigenetic age acceleration. It's actually pronounced P aging effect, maybe five to seven years in blood And sure enough, if they stick to their anti retroviral therapy that will reverse their epigenetic age And that And I mentioned it because how much Sal years, you know several years to give you a name. And is it four or five years? Four or five years. Is it happened pretty immediately after taking the drug? 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 trust it one hundred percent, but many people are not HIV positive, you know So therefore, I say do not take antiroviral 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 an autoimmune disease Again That just makes sense, you know, But yes And u M Foreman 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 suggest it, but I need to emphasize the effect is way weaker then So these are really medical interventions. and in general, as you can expect, a medical intervention has a much stronger effect than a supplement Yeah, When it comes to supplements do have some answers u Omega three has a beneficial effect. Aarently vitamin, m vitamins have an effect. problem is that these supplements have M weaker effects. Suddenly we talk about a couple of months of rejuvenation So yeah. And we're going to talk about go more in depth than what that means. But yes I want to I want to kind of, this gets me into the controversies and hype because you're talking about like these really robust effects if someone has HIV which is obviously devastating for 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 there talk about reversing their biologic age biological age by seven years. in sorry. They reverse their biological age by five years in seven months by doing lifestyle interventions. Is that something that you think could be a real biologic effect? 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 many of these stressors in their lives And they really changed everything. And they take their GLP one receptor agonness, they 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. I don't think it's U possible when you start with this baseline. So you're very unhealthy. You're very unhealthy 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 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 reversse my age by five years, I would have the 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 but not in the people who are very healthy, 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, I 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? Their groom age is already, you know, they're going higher than that it's supposed to is that correct Is it?es.. Higher than it's supposed to be. you know, their biological age, their pheno age is higher, their pace of aging is higher. So they're already age acceleration for whatever reason. They're sedentary, they're obese, they're sedentary and obese and they smoke or perhaps they have vitamin deficiencies. That's another one I've seen, like vitamin D deficiency has been shown to be know associated with age acceleration. And if you correct those problems by losing weight, by getting physically active, by quitting smoking, you know, by eating healthy, by getting your micronutrients and filling the gaps, 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. You know, if you're if you're already sufficient, taking a vitamin D supplement is not going to slow your aging. thing the thing you're doing, you're already doing it. You're avoiding deficiency. and that's the key, right? you're trying to stop that acceler things that cause the acceleration of aging. seem to be easy, more responsive. Exactly The other question I wanted to ask you 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 grimge test predict the day you're going to die like within a month. No No that's not true. 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. They will look at all of the above because all of these variables, I mentioned are very strong predictors of mortality risk. And the question is Does GimHge add something or GrimH 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, 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, know, because these tests are not cost several hundred dollars, or is it worth it to measure? And by the way, that's the same question for any consumer. Is it really worth worth it to you to measure it, you know Um 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 if I were to go out and get a DNA grimge test Y. And it said that I was going to die when I was age Oh yeah. Yes. Am I actually going die at age eighty? How reliable is that number? How accurate is that number? orr am I going to die at perhaps age eighty five Yes, I want to tell you that Grim age It could lead to a prediction of when you die. That's the age eighty five. it could And We know though, that this estimate is accompanied by a large error bar plus minus six years, I'm just making it up. So let's say you are a fifty year old, you measure your grim age and And we apply the math, the mathematical algorithm, which by the way, is very complicated you know for estimating your age at death the error 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. So these It would be unethical to report literally the age at death to a person. Therefore, We have decided to only ever give people an age estimate, right? We will say, your grim age is fifty 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 ten years younger than your calendar age. It does not mean you will now live ten years longer than the average person. You see, you cannot compare this differential into a lifespan differential. Then what does it mean Yes. so what does grimage 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 pay it person of the same age and the same sex, you know So let's start with a fifty year old Um And let's say their grim age is fifty eight, eight years older than expected. And then their risk of dropping debt in the next year is more than twice that of the average fifty 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. But it's a very complicated formula, certainly highly nonlinear and, as I mentioned, associated with a strong arrow bar Are there companies that have consumer available tests doing that, where they're measuring The grrim age and then doing that translation to when you will die, Is that something you've seen? No, I have not seen that. 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 For the reasons I mentioned, there's a strong error bar, you know, so 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. We use grrimage, of course, to understand the effect of various stressors U and I'm a longevity researcher. I'm very excited about finding interventions that reverse it in humans and of course, in animal models. That's how I use it, you know For these for these clocks when When we're looking at the like aging process as a whole, you know, we were 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, 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 um have u gained a lot of insights into aging in general, by the way, and also which aging hallmarks really affect epigenetic clocks, you know? So ten years ago, we barely knew anything about mechanism epigenetic clocks were rightly criticized as black box readouts But after really ten, twelve years of research by the very best labs in the world. know we really have characterized these changes Maybe for 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 U to some extent as well And 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. in blood, we have many different blood cells 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, know. So we understand that epigenetic clocks also relate to inflammation in that biology So Epigenetic clocks should be conceptualized really as integrators 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, senolytics, very exciting intervention. I'm very much following that literature However, epigenetic locks really don't capture that well, you know So Let me give you the prime example. You have cells growing in a dish. You radiate them hide any radiation, you induce sen escence. The cells can no longer proliferate And by the way, radiation leads to double strand breaks. It really very much stresses the cells Wouldn't it be nice if methylation clocks pick that up? but they don't, you know So so radiation damage at least for. They don't pick up double shrined brakes even 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 of many people have heard of T lumas. In theory, you want reasonably long telometers at the ends of your DNA And for many years, people have thought aging is about telome attrition. Now we know better, it's not, Anyways, it's a famous hallmark of aging. Telumir shortening However, many of the clocks have only a weak correlation with telumar biology It's a frustrating aspect. U and twentywenty years ago, people had an exciting idea Ovexpress a part of telomerase the turd O expxpressed Turt And there were companies that pursued that as a rejuvenating intervention And in at least in our hands Um we did not see a beneficial effect at least in Vitro, you know So although I like epigenetic clocks for many studies, but they don't capture the totality of aging, you know. So you really want to lement epigenetic clots with other readouts That's interesting that they're not Because you mentioned that they do track with the DNA repair pro Yes, but not To some extent, I know I'm giving conflicting messages, but that's the biology. There's certain experiments that show that some aspects of DNA repair relate to epigenetic aging But others don't. It's just not a tight story, you know. So I think the field really needs to narow that down Yeah. I mean, well, there's a lot of thingsings that lead to aging. you know, it's a very complicated It's throughif factorial process. when when you actually are able to for perhaps reverse, you know biological aging or I guess, there's two ways of thinking about it. You're slowing age acceleration. Right 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 are that are that you describe 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 and Yes and no. I mean So epigenetic clocks such as Grimage and douned and pace and phenoge, they do track inflammation to some extent, no question. So yes, if you reverse that, these clocks will pick it up 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, So again, they're integrators And um, So there will be interventions that actually don't even touch the inflammatome in one way or another, but they could have a very strong effect on reversing your epigenetic age And the prime example would be U therapies that, for example completely rejuvenate your hematopetic stem cells I just assume You have an intervention where you really replace your your bone marrow, you know, the or hematobiadic stem cells that produce all of these blood cells. and you just 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. know the epigenetic age in a bone marrow transplant recipient often reflects the age of the donor So 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, is it also Perhaps rejuvenating other organs That's a great hope, you know, so My responses assume not because it wouldn't it be nice What have animal study shown have they looked at that? Yes, there have been animal studies, I want to say in the lab from Vadin Cladichv at Harvard and the studies My reading of the study says that they have been disappointing didn't rejuvenate other organs If anything, there was disappointing result that A X number of months, actually, the stem cells had aged. So the body has the memory of the old mouse and that then aged the blood really. So that these m get a hematopoetic stem cell graft or Yes. they did.es. Vadim carried out really an elegant set of experiments, various transplantation experiments And the scientific question is the following, Okaykay, if I replace let's say the blood by that of a very young mouse or take other organs by the way. shouldhould we replace the kidney? you know, so anyway or the heart or any other organ? and Would the rejuvenation of one organ translate to a bodywide 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 was 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 amm I mean, that that's I don't know if they were measuring using clocks, but they were doing cognitive function and a battery of tests and the cognitive function improved and things like that. for sure, you know So maybe to remind the audience this idea of heterochronic pibiosis, for example, where you really connect the circulation of an old mouse with a young mouse And this is really a phenomenal paradigm of rejuvenation, arguably one of the best ones we have, 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. U And also importantly, epigenetic clocks get rejuvenated, many organs. So we know that again from several studies, including from Vadinim Bladishhevsler, 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 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 in the longevity field because that is a very common story. You have a powerful intervention. It actually rejuvenates the organ The probleroblem is it's transient. But yes. it's kind of like the probiotics flow through you have to keep taking him to have a benefit in the gut as soon as you keep taking them because they don't stick there, right They're not taking residents there.. Well, let's talk about Calg restrictions since youve just mentioned that as a rejuvenating 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 GLP one receptor agonist are kind of doing that in a way. There was a very recent trial. The Calary trial And I'd love for you to talk about this was a two year randomized controed trial where individuals were basically eating twenty five percent fewer calories than they otherwise would or they were eating their normal you know, daily food intake as usual. and I wanted to ask you W this were the participants overweight in this trial or were they normal weight Do know? I don't remember. I know it's the US population so assume that they are on the chubby side for sure Okay.. Yeah. So in this in this trial, It was a two years two year random misciminal 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,. 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 U.S. population, very rigorous study, many, many readouts u But I want to acknowledge something and the experts know it. the adherence was not good, you know, 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 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 mentioned it because later we should talk about GLP one receptor agonists where the weight loss can be pronounced. and there' 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 my effect This new clock, a new clock at the time, Duned and Pace really picked up my fact. u And 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 urting leg not very much. Yeah, it was not impressive to me, at least. So So the clock that did pick up the It was D need and pace. And in hindsight Let's discuss why it picked up the. It looks like a two to three percent slowing at 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 Duned and Pace again was trained, that's the lingo of machine learning, but it was developed Tack changes in BMI. So yes, it picked it up By contrast, Grimage was never trained to look at weight loss. It was trained on mortality So So yes, Duned and Pace worked and My reading of Duned and Pace is that it is good at that biology. people losing weight, it will pick it up. Um, And u, Now, the question is why didn't the other clocks pick it up? And there could be several explanations, 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 sorry, there was a very exciting study U that involved actually obese people, BMI, thirty and higher who had been put on a GLP one receptor agonist treatment semi gllutide. And these people really lost a lot of weight over thirty three weeks. And By the way, this studatic 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 very beautiful study, very rigorous again, and large sample size, incredible 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 like polysis, you know, this inflammatory signal is reduced. I think all methylation clocks will pick it up Right. And I think it goes back to this concept that We were discussing earlier where if your baseline is unhealthy, if you are you' accelerating your aging. right. are 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 at a population that's either deficient or unhealthy, and then you're giving something to improve that deficiency or gate 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, that it's associated with, you know, decrease in life expectancy, you know, increase in cardiovascular disease, typeesood diabetes, cancer, right these all these diseases of aging. So it's not surprising that you would give someone 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. And you're obviously picking that up with the agent clocks for the Calorie trial you know, again, I don't know what the adherence was, but also as you mentioned, these these clocks are trained with different there's there's different specialties of them, so to speak, right? And BMI being trained on BMI, wow, that's going to make you sensitive to weight loss for sure. And so the, you know, the Duodinan pace clock, which is measuring the pace of aging you would imagine would be more sensitive than 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 grim H found an effect, phenoH found an effect based on multivitamin use, but Dunet 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 even I want to stay clear of this debate because we will never agree you. Therefore, I just love it that the field by now simply reports at least five clocks, know so the reader can just look at it and beat the judge Let's talk about the multivitamins. 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 trials 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 is about three point six years for this trial and They were looking at, I mean, there's a lot of end pointoints of this trial, but one of them was cognitive function and brain aging And at the end of the trial, the people that were given the multivitamin slowed their brain aging by two point one years. and there was a 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 two point one 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. 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 test And so that was very that's very encouraging, you know, and it's something that I do talk about a lot because I 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. And 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 phenoge and Grim 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 two point seven months to five months, right? Like they were basically they're slowing the aging by roughly that amount. Yes whichich to me is if you think about Now, this this trial that was done the Agent Clocks, I think it was like a subset of it of the larger trial two years or did they do the three point six years for that? Do you It was yeah, I think it was two years. twow years Yeah. And so to me, The question is now this wasn't you said the Duodinan pace didn't change No it changed in the right direction. It just wasn't statistically significant. Oh I see.'s now in the right direction, you I mean maybe a larger sample size would have led to a significant finding. It was definitely in the right direction. 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 phenoge clocks And you're to keep doing that, you know, you know, for years. So now we're talking Not just two years, we're talking twenty. We're talking thirty, forty years. Yes How do you think that do you think that you get this accumulative effect? Yes I think so. I think so I am Maybe to step back, if you tell an eighty year old that A multivitamin will reduce his or her age by three months, they will roll their eyes. They will say, Okay give me something that reverses my age by thirty years, you know. U So fair enough, 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 thirty years, right? You're fifty years old and you use it until you age eighty My expectation is that suddenly these three month benefit, they accumulate and suddenly you have a benefit of maybe two and a half years, you know 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? I think it's pretty great for that. amount 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 two point one years just after you know, in that trial it was three point six year trial, but you know, that's pretty robust. five years delaying brain episodic brain aging. And and now we're talking about like globally like biological aging. 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 vitamin supplement for two years iss doing that. Well, let's continue on and then combine the things and we'll get into some of the other trials that you show synergy. butes I think it's interesting. The other question is that and this is where You know, the cosmos trials, people, but they're looking at everything, right cancer, mortality, cardiovascular mortality all cause mortality. And those didn't really seem to change at least within the time frame. that was looked at. 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 I tell you my reading of it. and To me, this whole study was one triumph for epigenetic clocks and I explain 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 deficienies are important. especially, you know. So you would say, okay, I administer that to the U. S. population. hope to see an effect. 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 clelearly There must be very compelling reasons Okay, but there's a problem now. and These hard endpoints, mortality, cardiovascular disease, they didn't detect an effect. It deeply frustrating Oh was there a trend? It wasn't statistically significant Yeah, I let you summarize it. But to me, you know it 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 Now So 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 their signal. I call this testing the test. You have an intervention where, um 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 grimmage. 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 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 and Yeah. And I think it's reassuring in combination with the brain aging. I agree signal that it picked up. And just knowing that, you know, so many So many globally, people are not getting enough of these important vitamins and minerals and trace elements in essential fatty acids from their diet. then it's kind 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 into one pill. I mean, you know 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 and So so maybe maybe you pee a little bit more of 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 What have you got to lose, you know Yeah let's let's 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. But since we're on the vitamin train The big one is Omega three I mean that I've seen at least in the 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 starting out with the deficiency If you're starting out at an unhealthy point and you improve there, improve that. you fill thatut deficiency gap or you know improve your health, lose weight, whatever, then you're going to have a stronger signal, right?. ninety percent of Americans don't get enough omega three fatty acids. Nobody's eating seafood in the U. S. It's just you know, so you're starting with the population that's already you know want to say deficient, but they're not getting a sufficient amount of omega three 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 three, maybe you go to Japan and do the study. I don't know. It would be interesting to see. Yes.ap pererhaps there 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 three fatty acid whether it's from food suppupplementation, 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 last year we published a study, which was very rigorous. This was a study conducted by a Swiss professor, Heike Bishop Ferrari who looked at seven hundred and eighty people. and followed again The most rigorous design, randomized controlled T placebo control trial in a population that I was very interested in, peopleople seventy one years or older, really older people, reasonably healthy. average age, I want to say seventy five, I think. was seventy three. So older people and She u evaluated famous interventions. numberumber one, Omega three One graand vitamin D, and we should talk about The intervention about vitamin D was tricky. was High vitamin D versus low vitamin D It wasn't Vitamin D versus no vitamin D. That's a key distinction. What What was the low? I know the high vitamin D was two thousand I used. Yes. And the low was eight hundred I used. Yes. it was only double. Yeah exactly. And that's a limitation 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 controled trials showing the opposite if you start with the deficiency and add it. and we can talk about that. Okay. So' true But there was also another disappointing If you look at the exercise, Yeah, we need to talk about exercise. yeah so this was called a home exercise intervention. Now, to remind you, these are people in their seventies and think in terms of ethics approval. you cannot stress these people too much. So this home exercise intervention was very modest, okay And It was resistance training, right? Three times a week. Yes. But it was I'm telling you, it was mild, mild mildance straining, you know because no effect. Right. I was very disappointed. Did you read that the starting population eighty like around eighty eight percent 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 like that there's no way you would have had that many people physically active. But anyway, so that's these are people in Switzerland, hopefully, they hike in their m hking everywhere exactly. 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, you know, Great framing of Yeah. Yeah, so I think we already discussed the result. The most credible result was Omega three on epigenetic clocks, a couple of epigenetic clocks picked up GrimH version two. phheno H Dunid and Pace also worked very well in that context So nice result for Omega three. The other interventions disappointed themselves by themselves. by themselves. But yes, there was this one treatment arm where people actually did used all three beneficial interventions high dosage vitamin D, omega three plus exercise. And according to phenoH, that treatment arm best and also That's the finding that we would have liked to see, you know, for all clocks, but it's just the phenoH pictict. Well, I think there was even a dose dependent where there was the group that just got the Omega three and vitamin D and that also improved more than the Omega three alone. Y. And then all three improved the most. So you see this nice dose dependent effect with adding in these healthy lifestyle interventions, even an already presumably healthy population., whichich is exciting.. And I have the numbers here. I think it was three point eight months the pheno age delayed the biological aging was delayed by three point eight months. Yeah over three years over three years of that. And that doesn't sound like a lot again, but they also correlated with some other outcomes, right? So I think there was in the in all three interventions Yes, it was three point eight 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 twenty percent reduction in prefrailty, 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.. So it's not just a molecular readout y. think For me, the take home again is something that you mentioned when you have this already, healthy, they have to be a healthy population of eighty eight percent with them they're 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 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 we're talking, well, in this case, they're a little bit older, but people listening to this podcast Maybe in their thirties, maybe in their twenties in their forties. It's like, okay, well, I'm going to start training getting making sure I'm not vitamin D deficient, getting my omega three. and then you have like how is that going to compound over 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 whichich really messed me up. So yeah, good health behaviors, you know and supplements included, I think will have benefit, major benefits 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 eight hundred IUs to two thousand IUs. I wouldn't imagine to see a big difference there because you're already feeling Exactly Most of the participants had no insufficiency in vitamin D. They really started at normal levels. And And we know there have been in in my opinion, so many studies that I've come across and read over the years 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 likek the most recent one was the base to the Berlin studyes, where they took whichich was the thing that was nice about that was they had a deficient population and then in 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, 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 effect, which is againgain, 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 deficiencyies.. 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.. drives me nuts when studies don't measure their baseline levels or if they only measure ten percent of the population and then use that to extrapolate like everyone else, like you can't do that.. 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 D three into, 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 do. Okay, so I want to we should talk about exercise. We can go into exercisees. Oh no but 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 and we've talked a little bit about it with the JLP one. Obviously, if you lose weightes It's probably a big confounder with all 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, I don't know too much about it, but I want to explain some properties of grim age that I'm aware of. So grim 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 don't reflect reality. I don't remember what I ate for breakfast. I ate any breakfast today, but Yeah, mean and people always know what they should answer, you know, but so that may bias their memory. They will say, oh, yeah, I ate servings of broccoli, but it just doesn't reflect reality. But fortunately They 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 postmenopausal women from the Women's Health Initiative was that this measure of vegetable intake has a strong correlation with grim age and other epigenetic clocks Strong meaning maybe minusz three. 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 minuszo point three Yeah, sorry, I could translate it, but estimate. Yeah now let me put it this way. smmoking has a correlation of zero point four So if you smoke a lot, it increases your age vegetable consumption minus zero point three. So it's actually wow. Yeah, I was very surprised. So in this And sorry, I add one more statistic. exercise. the correlation would be one. So do you see so vegetable intake has a much stronger effect I mean, orders of magnitude, stronger effect on grim a and these methylation clocks than, for example, exercise And you think it might come down to even the carotenoids perhaps? O are 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 one hundred percent accurate, but now teasing it apart. What is it, you know Yeah it probably so many things. I mean, You've got the fiber matrix, you're getting mic like vegetables especially greens. and if you're talking about carotenoids, you know, Lutines, Zanthin, are 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 zanthin People usually associate them with eye health. They accumulate in the eye. There've 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, crystallized intelligence improved brain aging in general. All right. And there's other carotenoids, beta carotene is probably what most people are familiar with, Lopene and tomatoes. So there's a variety of these carotenoids, which are very powerful at basasically u I would say buffering oxidative stress and singlet oxygen, for example, if you're talking about in the eye.. But it's interesting that vegetable intake can have such a profound Yeah back remember this was 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 a healthy omnivore trial and the I think the vegan trolley 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 three. that is pretty strong. You gave me that reference point of smoking being You said it was wait smoking was.ero point four. Okay, smoking zero point four, maybe zero point four five. So it's c increase. Okay. correlation Um exercise one 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, you probably see an effect when you analyze a couple of hundred people So much But regarding the question vegan versus carnivores, you, I honestly have not seen convincing data Omnivorenivore omnivore. Yeah, ye Cnivore would be the opposite. That's true. Yeah, let me rephrase it. So I have not seen any evidence People who let's say, eat a lot of red meat age much faster than people who are vegans. And we looked again in the womomen's Health Initiative I mean, there was a hint, I want to say when we analyzed three thousand 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, know So What I can tell you is I eat so much meat. hopefully it's not bad for me Vgetables. I eat meat and vegetables. I try to be easy on the carbs, you. I eat carbs, but I try to reduce them I mean, vegetables are carbohydrates, they're just Complex carbohydrates, not simple. So you're not eating this simple carbohydrates. Yeah, exactly. Yeah U that vegetable stuff is interesting. that there's so much in vegetables with the micronutrients and the phytochemicals, right? That's another thing in them fiber I mean there's a lot of things going on here that Yeah Somebody should really teh that apart. What kind of vegetables should be eaten, you know doorsages ye Lots of exciting PhD dissertations could be written on that topic. 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 twenty twenty five showing that six months of cycling It seemed to slow epigenetic aging Or Grimage, right? Grimge by seven point four months? Yes, mayaybe I'll frame it like that. So there have been very nice studies on the effect of exercise on grimage and phenoid and other clocks And so what do I mean by nice? Studies where they use one way or another a wearable to really measure your step count and activity. So it's a 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, you are epigenetic clgs pick up a small effect. and I mentioned earlier correlation minus point one. What it means, you need to study three thousand people then you will see a statistically significant effect of step count as an example. But I've been deeply dissatisfied with that finding because we all know exercise is what they call the poly pill, 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. yeah some people claim they see in effect, you know, but I just am not yet convinced. It is disappointing, 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 or what we discussed earlier than home exercise intervention, 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. So if you forced me to bicycle for and a half hour a week, I would struggle with that. why we are all busy people, you know. But anyways, the people who adhere to that trial They had strong effects on VO two max.cent twenty percent and many other readouts. so they didn't fake it, you know so they really saw physiologic benefits And then sure enough, suddenly the clocks worked, know So PC grimage as an example, we keep talking about PC. PC means principal component based grimage That's a version of grrimmage 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. whichich again dwarfves everything we just discussed, you know and that was a six month intervention These people were younger though. I want to say they were between thirty and sixty five. basasically a population that you can put under such a stringent regiment, you know? Well, they're young and middle aged, but yes. I would I mean, so I would argue, Steve that this is ten thousand steps, like that stuff is like, it's, okay, it's better than nothing. 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 that we talk about on the podcast. I mean, I've had Ben Levin on He is a rock star in the cardiovascular exxercise physiology world And he's done multiple randomized controlled trials, but he did one That was a two year study in fifty year olds. there were about fifty 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, you know 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 two max there' The heart structure. so he looks at like the structural aging of the heart. Soays we age our heart gets smaller with age, it gets stiffer And they improve the structure of their hearts it was like if you basically it looked like they reversed aging by about twenty years. Yeah. their hearts bigger and they were more flexible. it looked more like a thirty year old, even though they were fifty two at the end of the trial And so I would argue that you know, doing reallyally 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.. 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 G a stronger signal. let's not just walk, let's not just do ten thousand steps. Let's push them to improve their VO two max by twenty percent. like and see what that does to their aging clocks, right? Now we know. you know, I mean, this study didn't have a control arm which mentioned that, you know, so but I certainly was impressed by that and to argue against exercise, you know, so Yeah. I mean, there's so many studies showing it improves outcomes canancer mortality, cardiovascular mortality all cause mortality. It improves brain aging, Alzheimer's disease risk is lowered. Every. 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. We know it's good for aging for sure Yeah. And so it's nice to see that I mean, there might be a real threshold to pick it up with these 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. deffinitely. You know, its Hopefully there'll 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 ten minute hit hit, you every day. like how is intensity affecting it? How is volume, duration? There's so many things to look at. You know, we need to develop exercise in a pill for people who have lost mobility. happen. What do you tell someone who is in a wheelchair? What do you tell to an eighty five year old? you know We need to develop interventions that still rejuvenate them slow 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 agent clock, but So you can get in like a hot tub or a hot sauna Y heart rate starts to elevate you know, a lot of the same physiological mechanisms that are happening during modern intensity exercise. there's been head to head comparisons with like getting on a stationary bike And you know, doing about a hundred watts. so you' for twenty minutes and then comparing that to like a twenty 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 body temperatures going up so that we do have some interventions that may mimic it the pill There's so many things that change, you know, Steve, like I don't I mean, maybe we'll get that, but it seems like ye I'm joking. Yeah. I need something. It seems like a moonshot. Yeah I wanted 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 preoptic nerve, I think, you can actually lower the body temperature of a mouse And there was a team in Harvard, Zenisa Vatin, who did just that in the mice, and he lowered the body temperature of the mice, I want to say by three degrees Celsius or 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. But their metabolism has probably slowed, inflammation because you'd be going colder Vasal constriction also happens, I would assume. Yeah. that may be mean So inflammation maybe. It's interesting. and also I just want to mention. So benefits of SaNa and all of that are undisputed, you know, but I just want to mention that maybe lowering your core body temperature by a degree or so could be beneficial. Wh knows, you know? 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 marmots in Colorado, I think. And sure enough, during hibernation, the methylation clocks didn't advance you know Yeah. So interesteresting. 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, yourre firing of, you know, your cognitive function and, you know, neurotransmitter firing away. all this stuff is producing damage you know, So if you're just in if you're just in this slow everything down, I say cold, I associate the cold with slowing it down Um But att least in the hibernation state, for sure slowd down And so that would kind of make sense that you're kind of just slowing the whole process,. Yeah. sense. So u 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 are Lots of confounders there. Yes. So I worked with a team at UCLA, Judith Carroll, and she looked at sleep disturbances in the womomen'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 Yeah, I think I think we know that sleep deprivation, chronic sleep deprivation increases inflammation changes your appetite, P people gain weight too. I mean, so there's all the reasons why it would accelerate aging And that would make sense Um But yeah, I don't know that there's enough evidence looking at the specific stages of sleep and There's a lots of teas apart there and 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 in our social relationships. Yes. Right. I mean that's This was the biggest surprise to me in the last six months, perhaps. need to tell you, I'm not a social scientist. I don't study behavior. I really am not, you know I' So anyways, there was a researcher at Harvard Laura Katinsky, I butcher her last name, but She is a very rigorous scientist and she wanted to evaluate whether what she calls I think a social cumulative advantage. which is a measure of how connected you are in the community, 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 gotta 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. 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 six and various other readouts of inflammation But fortunately, she had enough research funding apparently and to measure methylation. becausecause I say that, because If I had been a researcher, I would have focused on urine and blood to measure ring hormones and inflammation And for methylation, I would have I would have advised that don't even measure it because I just don't think you pick pick that up And why do I say that? Why why would your connectivity, your friends your relationship with your spouse and your family whyy 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 the study and the great surprise to me was The methylation readout Warfed the other readouts. If anything, the other readouts didn't work Grim age again. D up who have this who are blessed really by having a wonderful family relations, community, just this social advantage, you know, sureure enough their grimage was reduced. It really taught me something. Do you you know how much it was reduced? Do you remember? No, you know, my problem is I only ever look at P values. I'm a statistician. I know everyone always wants to know how many months, but I just go by P value. You. 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 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 stududy looking at how social relationships and happiness really do correlate with longevity and why Yes, but you know, if you think about The flip side of that 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 Yeah 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 nuance there with respect to If you're someone that has a lot of social relationships U 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 stress or that's a stress I couldn't agree more. If you're in a toxic relationship get out, you know, or don't tolerate abuse. I mean, just for sure, you know. But those things probably make 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 Pe 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? So I'm always happy when a sleep study shows only a weak effect, you know so because I'm rooting for these people, you know. but Yeah. I'm not sure. let me say something about the elderly. Again, loneliness is the big killer in old age And unfortunately, geriatric patients are often isolated, you know, M 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 to entertain people. And 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 Yeah. Ideally, their kids would come visit them, but I guess you know that's not always the case. Just not realistic. You know many of these jobs that deal with geriatric patients are underpaid. There's a shortage, 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 give, 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 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 Um Some people are smokers and they 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? 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 where 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 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 something is it something that you think people can use? Let's say they find a reliable test. They establish 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 VO two max? And then also, in addition to measuring there Either they measure their VO two max or they measure an estimation of that, which is probably a lot more accessible to people. They can go out and do a twelve minute run test on a flat track and do the equation, get the estimation. It's kind of what your Apple Watch does and a lot of wearable devices but also add this DNA grim age and other perhaps, you know test of these epigenetic aging clocks in there. Yeah. I would say several things. First of all Unfortunately, these tests are expensive. They cost several hundred dollars And um 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 becausecause you know I go to conferences and then longevity doctors approach me and they thank me for developing epigenetic clocks and I ask them, well what are they good for in your practice And that's what they say as 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 readouts, which I very much applaud. I just want a fifty dollar test 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 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 that have been less characterized in the literature. I'm not saying these clocks are worse in any way. It's just' not the same level of literature. We discussed earlier today there are these five clocks that everyone uses why they all use a particular particular technology, the so called Illumina array. and also do need and pace. everyveryone uses that technology and therefore we can leverage legacy data that have been collected over the last ten 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 you Where should be 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 they absolutely agree that data does motivate you. What should they look for in terms of they want to make sure it's one of those tests that use the alumin array? They want to make sure it's the reliable. doeses it have to say like DNA grim age? Do it have to say pheno age the dud in and pays 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 they are several good providers of tests really, you know, because beauty of this illumina array is that it follows a very standardized protocol, you and many years of research went into how to pre process the data, how to optimize the signal versus technical noise, So that has been standardized. So I think As long as you go to a lab that has experience with generating these data, you're in really good shape And why would people not want to go out and use the Corbath epigenetic agent clock for their biological age. No, you know, when you use an illumina array, they They give you the Howth clock. 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, CRP or famous markers like plasminogen activateor inhibitor one 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 it's a blood measure, but they will say, your kidney is older or your young, you know, so that's where the field is at developing organ specific methylation markers And consumer available That's already available to the consumer. You know So you may end up with a report fifty pages, one hundred pages. you may be overwhelmed by it, you know Um, but u 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, you know. How would you do that You know, they're web pages. you upload the data to a webpage and it outputs the results Like what web page? Yeah. I started a nonprofit 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 know using these clocks on the individual level and then trusting the conser what's consumer available, 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 I'm going do some experiments, but we didn't have enough time. It was two weeks to do all this and come on the packus 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 Um, in Sing seeing seeing what I get from my data and see what room for improvement I have and whether or not I does get picked up because again, I'm already healthy and I do take a lot of supplements already. so I want to briefly mention the most obvious medical use case, perhaps. 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 knew, 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 Yeah, maybe let's talk a little bit about variability because there have also been major insights that surprised me as mayaybe with a background. So we talked about these principple component based versions of clocks such as PC GrimH that was used in the Cosmos multivitamin study. And anyway, these are very reproducible And I give you a number. Let's say you measured that marker two days apart. you measure PCC grage on Monday and then another measure on Wednesday and nothing 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 variantance, you. but And and u U other clocks U Duned 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. So if you take grimage and then compare it to what people call Horwths pan tissue clock, You may get very discrepate results because they measure different aspects of biology The Horvas pantissue clock is very good for stem cell biology, Hmatoportic stem cells Purses of leukemia type of biology, just not good for mortality risk you. Yeah. I think raises another question in my mind, especially for people and and consumers that are interested in maybe measuring some of these clocks and seeing where're where they're at Um and if they're going to do any interventions where they're at after the intervention, but You know, Which clock is best? are we talking about like if you' wanting to look at the Duodinine pace and the pace of your aging m versus your DNA grim age, right? I mean, What is maybe you kind of need both almost. or I would look at both, you know.ight 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 A one C? Do you focus on cystatin C or Give me all, you know, let me look at it. because they do give you different lenses at the changes in the meth alone. But you would you would predict and this isn't this is something that again, with some of these trials, we're seeing the Duodendon pace is picked up, but then the grrimage is not. or vice versa. and's the question then becomes how these clocks areort of, 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 bothoth would pick it up, 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. Grimge was better than Dun need and Pace, you know And so Glammation, right? Does Grimage pick up inflammation? 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. Because when you do a clinical trial, you need to you tell the regulator what is the primary readout? You can tell them, I look at ten clocks in So and the very fortunate situation is that There's 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 RPAH to study interventions, 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 you. How do you think AI might change you know clocks and development and the you progress in them as well, like are you hopeful that using AI technology will help you them better? Yes, absolutely. and maybe to give you some perspective. Ak Lu in the lab published Grimage twenty nineteen way before Chat GPT, before anything. And now it's twenty twenty six Grimage still seems to be the best mortality predictor. To me, that's deeply frustrating because I want to see step changes in these biomarkets. And I'm sure it can be achieved Now, the good news is people have already published new clocks based on AI. know they do use large language models one person Lucas published what he called Grimage version three, but they are now new clock systems H, then there's OmMic MH. 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 I fingers crossed, know that any of these newer clocks are way better than Grimmage Why? Because we need even better clocks for clinical trials I think Since we're talking about new technology and you know, it's something that I'm super interested in as you know That is It's just this concept in that goes back to the Yamanaka factors and basically the birth of these induced poipotent stem cells, right? I mean Chinya Yamanaka won the Nobel Prize in was it two thousand six? for discovering you could add four transcription factor proteins. theseese 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 eight year old and revert that cell to a to a, you know, plurip potent 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 mean 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. So Back in twenty thirteen, I published the pant tissue clock. Figure five in that paper showed Yamanaka factors reversed the age prenatal state. you take a skin cell from a fifty year old and the epigenetic age of an induced pluripotent stem cells is a negative number, meaning prenatal. And of course, so many people have worked on the idea then to apply these Yamanaka factors briefly and and briefly interrupted reprogramming. There are many names in that field, Juan Carlos Belmonte, Manuel Serano, but so many more who have worked David Sinclair famously, who now has a clinical trial for optic nerve regeneration based on that idea. Yeah, but the idea being so apply these factors or a subset of these factors to rejuvenate organs. Why Jjuvenate, but keep their identity They're not going to become a stem cells Exactly, because you don't ever want that a skin cell forgets that it's a skin cell or a liver cell that it's a liver cell and why is are dangerous to cancer. that's Great danger. And u There have been substantial developments. So on the one hand, I mentioned the study from David Sinclair where he now administers adino associated virus and AAV to the eye of people who really need to regrow optic nerve or and the study apparently will start this year, twenty twenty six. so The longevity field is waiting with a bated breath. Will that succeed? It would be a triumph for the whole field There have been extensive characterizations in mice Which kind of organs benefit if you target them And also in Vitro So we understand quite a lot, but what companies struggle with is Wh exactly do you deploy it for what kind of condition alwaysways keeping in mind to ensure safety There's questions in my mind that are even more mechanistic, you know, just because that interests me which is, you know, if you are If you're taking an old cell that has These hallmarks of aging, there's like twelve of them now, right? You're talking about mitochondrial dysfunction, you know, your inflammation is now even a hallmark. It used to be just this amplifier still is an amplifier, but you know you have proteo proteostasis isn't working right. so it's um Your proteins are not folding properly and they're also not degraded properly. You've got DNA damage, nuclear damage, genome inst stability, all these things that are that happen with age older cells And if you're going to ch if you're basically just going to change the way the gene expression pattern is in the epigenome, so to speak. Y. How does I get rid of all this damage And what doesn't it get rid of 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 telumar length. so that wasn't And also even when it comes to the epigenome, cert there vestiges that don't seem to be touched by that, you know, So certain cytoines that do not get completely reversed, you know so It's so interesting Do mitochondria get healthier Yes So mitochondria Oxyidata for. What about mitochondrial DNA Yeah sorry, No I forgot. So mitochondria get healthier. Yes. Stem cells, stem cells get Yes rejuvenated or what do you what do they just start working better? I mean, I want to draw an attention because most of our conversation was about epigenetic clocks. and now we talk about other readers.. It's important to distinguish because Um Methylation clogs do detect a benefit of interrupted reprogramming in certain organs, but not all. I just want to Which organs do they not or what should they do do dect? 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. Um And now I'm talking about interrupted reprogramming Because as we said, if you go all the way, you will find an effect, know. But I mentioned it because When it comes to that intervention you really want to measure many readouts that we discussed, you know so abbove all organ function test, you know, so depending on the target organ, you need to really establish that it works well. as an example, if you study the liver really measure their liver functioning or kidney and that just show functional restoration on a molecular level, There have been very detailed functions of gene transcription re 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 based on gene expression. So what does it mean that gene expression is rejuvenated? the field has struggled with that for many, many years and u I can mentioned. so people look at so called Mesenchyimml marker. So some of you may have heard epithelial mesenchyml transition. So cells change their phenotype as we age in part due to inflammatory signals. so they An epithereial cell forgets that it's an epithereial seellf. It thinks it's as and chymal cell But anyway, so that's a readout, inflammatory markers. we mentioned oxidative phosphorylation. So various readouts convince a researcher, okay the cell seems to be younger If we talk about the extreme case of making an induced plponon stem cell Do the somatic mutations persist in that as well? Yes That's disappointing because you cannot touch it, right? It's DNA is Yeah. I mean, it's just You you We got to solve that proble. You know, but you need to ask a different question, perhaps. this has a hopeful answer, perhaps which is Do somatic mutations actually matter? That's 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 And the question is Does that actually translate to biologic aging Andesn't it depend where the mutations are? Of course. And you already asked the right question. Most of these zomatic mutations have zero consequence That 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. The same with somatic mutations. And when you ask aging researchers how important are somatic mutations for true blue aging, you you will get different answers. someome people will say it's hugely important and then there are other people will say it's negligible. The field is really split on that question Yeah. I mean, if you're getting somatic mutations and regular regulatory parts of the genes or even, you know, parts that are promoter, 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 if is the keywd 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 chance of you having it in a part that matters goes up, right? For sure. So 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? I mean, can't we He's Cisper to sort of, I mean, if there was a way you could every time you got a mutation use CISPR to change Yeah. and also coming back to DNA repair, right? So 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 that's where I'm at, you know. For me A lot of aging way you age slower No question. It has a benefit. You would still age, you know still age for sure. It's not Now you would. because aging happens at all levels. We mentioned the epigenome today a lot. but also the transcriptome and the proteiome., rightight 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. the debate is in certain ways which How much do we gain if we clean up damage at a certain level I mean all the damage. So there's twvellmarks, right? That's why I mean, obviously genome stability is just one. So if you take care of that, you've still got eleven more to take care of. you're still going to be aging. But so if you were to clean up all twelve I mean,' no doubt you have a benefit. Then what happens? 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 sarcopedia. You keep your muscle strength Could it be that this benefits so many organs and suddenly we increase health span by five years or We have another pill that really preserves your kidney function, 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. 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. I'm with you on that, you know? Yeah. But let's now again talk about the eighty five 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 I s longer I hope they will, but I'm just saying that these are the interventions. But what about their what about the their cardiovascular disease risk?. I mean, if it's true that People's organs age at different rates, and there is individual variation there. you know maybe maybe my heart is aging faster than yours, mayaybe you are more susceptible to your brain aging more. I don't know. If that is true It is true. It is. I mean that's We know that even from methylation clocks, Yeahah that there that that even even within a person and you know, obviously they're diet and their lifestyle, everything's like it should be the same, affecting the same orggan is the same, but it doesn't, right? Y. Either it doesn't or there's other things that are that are happening that we don't quite understand, but Um 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 people that are going to die from their falls or whatever, you know, I don't know Yeah. I think I think it's the u It's an interesting it's an interesting question in terms of like, organs are aging faster in you, And you know there's biomarkers that can help you understand that risk, but The agent 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 so measure them. 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 optimized there's room for improvement, perhaps, to be seen But that's how I envision really medicine two point zero preventative medicine. measure many readouts of organ function, you diagnose that something is going the wrong way and then you target it, you restore it, you know, precision medicine really. I even You know, I've done my my een array before and looked at there's like all these different companies that are able to go and look at your SNIPs or even your whole genome. and even those tests when 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, so they're already sort of targeting organs or neurodegerive disease like Alzheimer's disease. 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 in Yeah. I want to briefly comment on that. because I used to be in a human geneticist actually, at some point I studied genetics and you're entirely Correct. O 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' famous association AI for Alzheimer's, there' 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 ten thousand steps. Yes, okay. I mean's I agree. It's way However, interestingly, methylation is a far stronger signal than sNips. So epigenetics order of magnitude, more informative. 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. I spent many hundreds of dollars on various tests. Many tests have no use. but I haven't spent money on a GBOS test And 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. and we mentioned proteomics clocks, you know and above all, just ir regularem 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. 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 ApV four that do not have Alzheimer's disease. and there's a lot of people with Alzheimer's disease that do not have an Apo four allele. So It's not it's not it's not aull message. Yeah, Diet and lifestyle matter and that's kind of point of the conversation that we had We're talking about these epigenetic clocks as a you know, biomarker readout that is a little bit you know, more comprehensive than just getting ac reactive protein or HBA one C or even, you know, looking at your You' lipping. 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. Oh, I think we covered everything. That was a real pleasure Have you done your your 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 phenoH result a couple of maybe half a year ago I was thirteen years younger if I remember that. I liked that So I'm actually doing well on various biologic test. How old are you I'm fifty eight right now. Oh, you're fifty eight. 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. againgain, I'm trying all sorts of health behaviours. I actually don't need any readouts, you know for motivation I'm a bit of a hell snut. don't What's your what's your what's your routine What do you eat what's your health net routine, your supplements I go with validated interventions. We talk about omega three, multivitamin, creatine, I take a lot By the way, I love your podcast. I learn a lot from you. ye I started multivitamin after you started talking about it. That motivated me Um, 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 But by the way, I love placebo effects. they always work I love placeo. Nothing wrong with that, you know? I don't like nobo effects, but I love placebo effects. That's right. Yeah, so the reason why I mentioned it I think it worked, you know, I don't have hard data on that. Do you take vitamin D? Yes. Vitamin D. And you eat a lot of vegetables, exercise, How does that come in Yeah, I do. everyvery day, thirty minutes, I know to exp and not great I follow routines yeah. I mean E exercise needs to be a routine. It needs to be part of your personal hygiene. Y I also take medications again against high glucose. I'm actually a p diabetic because of my decades of eating hundredundreds of grams of chocolate each day. so But yeah, so I take something called A carbos you know but also I doeses that have any effect on aging A cararbos I have no idea. I just Yeah, so anyways, I take statins, I take azetamype you know, so various interventions where there's very credible evidence, you know that they moved the needle. I'm always impressed by people who swallow one hundred and twenty pills, but it's not me. No I take I take a lot but not one hundred twenty. Do you take Ubicquinol If you're taking aatin, you might want to thinkink about that because it Statins target the Melvonite pathway, which is HMG coA. important for cholesterol synthesis. That's why it' widely prescribed drug for lowering LDL cholesterol, but also that pathway is important for making CoU ten in your mitochondria And so that's something to consider as well. So taking Koku ten 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 knew I would learn something from visiting you. Well do. Well, Steve, thank you so much for all your contributions to the aging field. and thank you. the ones you continue to make Um peopleeople can look up your publications and many, many, many publications where else you're on X what's your I have a handle prof underscore Hth HO R VATH My Twitter account is all about epigenetic clocks 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. Thank you so much, Dave. I really appreciate that Is there anywhere else you want to direct people to besides your Twitter and your publications No stay young. Try not to be stressed too much, you know and ye enjoy life. Enjoy life. I think that's good. Try not to stress too much because at the end of the day, your deadline I need to tell you though the hopeful message about stress is that short term stress does not seem to affect epigenetic loocks. psychological stress. So I always say repeated. shhort term is that repeatedly or just So there' some literature that really severe psychological stress. We're talking now childhood, sexual abuse pererhaps even PTSD affects your epigenetic age But I always like it that these short term stresses don't seem to touch you, so which is a hopeful message for everyone who is terr. been worried about a podcast. That's right. I have never deadlines. Exactly. So I've never seen evidence that this has a strong effect But don't stress too hard. That's the bottom line. Thank you so much. Thank you It was a pleasure I want to thank doror Steve Horbath 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 He helped define it If you haven't already, you should follow Dr. Horbath 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 Horbath He regularly posts interesting papers, updates, and insights on aging biology, epigenetic clocks, rejuvenation, and where the field is heading highighly suggest you follow him. And for everyone listening, we've also put together detailed show notes for this episode. You can find them at foundoundyfitness. com forward slash episodes E P I S O D E S At the bottom of 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 If you value these long form deeply researched conversations, one of the most meaningful ways to support our work is by becoming a found My Fitness premium member The Premium membership gives you access to the Alacquat, this is our members only podcast, where we go deeper into practical evidence based protocols and emerging science Recent episodes include how to prerevent and Recover from jet lag how to slow joint degeneration, and how to protect immune function with age You'll also get access to a monthly live and recorded Q and A with me 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 premium member at foundoundyfitness. com Forward slash, premium Again, that's foundyfitness d. com forward slash Premium P R E M I U M. Thank you so much for listening and thank you for supporting Found My Fitness Talk to you soon