The 7 Habits of People Who Age Slower | Dr. Steve Horvath

My question as a longevity researcher is why do you age? What drives aging? Dr. Steve Horvath, professor of human genetics. He's [music] got a lot of background that has led to a landmark finding in biio medicine, the Horvath [music] clock. >> I've heard people out there talk about reversing their biological age by 5 years in 7 months. Is that something that you think could be a real biologic effect? >> It's all about prevention. If you start with a person who was obese, had inflammation, diabetes, and they really changed [music] everything, it would perhaps be possible. >> Let's talk about the multivitamin. So, this was the Cosmos trial, [music] and at the end of the trial, the the people that were given the multivitamin had slowed their brain aging by 2.1 years. But another area that's very exciting [music] has to do with our mental health and our our social relationships. This was the biggest surprise to me and why would that translate to changes on the DNA molecule in blood and the great surprise to me was before we get started today. I just wanted to frame this episode. My guest Dr. Steve Horvath is really a legend and one of the most important scientists in the modern biology of aging. He's someone whose work has fundamentally changed how scientists can actually measure aging itself. For that reason, Steve and I go a little deep into explaining some of these epigenetic clocks because we have to lay the foundation. But I promise you, after the first 20 minutes or so, which may be a little technical for a few of you, we're going to get into all those practical questions that everyone wants answered, like, can vitamin supplements slow aging? What type of exercise is best to slow aging? Is there a good diet that can slow aging? And is it actually possible to reverse aging itself? So, all that's coming up, so please stick around. And lastly, I want to mention that only about 10% of you watching this podcast are actually subscribed to the YouTube channel. So, if you could please just press pause for a second and subscribe to my podcast, enable notifications, it's really one of the easiest ways that you can support what we're doing here. You can support the show, and you can help us amplify our message. We really greatly appreciate it. Thank you so much, and enjoy this episode with Dr. Steve Horvath. Welcome back to the podcast. I am sitting here with Dr. Steve Horvath. Steve, good to see you again. This is the second time you've been on this podcast. You have been incredibly influential in the longevity field. You are the developer of the original Horvath epigenetic aging clock, which is really revolutionized the way the aging field has been able to measure biological aging. So, thanks for coming back on the show. >> Yeah, thank you. I'm very excited to be here. Um, the science has evolved quite a bit from the last time we spoke. So, it's a wonderful opportunity for me to talk to you and your audience. >> I'm so excited. I mean, the last time we spoke was in 2019, so I would hope that there's been a lot of new exciting data to discuss. But 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. It's a good question. Everyone talks about biologic age but it has so many different definitions. So for many people biologic age refers to fertility issues as an example. Um, broadly it relates to this phenomenon that people of the same age have um different mortality risks, morbidity risks or people who um you know from your high school they look older or younger than you. All of that is in that concept of biologic age. Um however um longevity researchers or um geroscientists who study aging um really um conceptualize biological age using measurement technologies. How do you get a number uh for measuring biologic age and the field has really exploded over the last uh 13 14 years. Um people have developed biologic age measures based on variables, step counts, gate speed, which is very exciting. Many imaging data um you can measure your brain age um based on imaging for example. Um my field is um in in the realm of molecular markers of uh aging. Um so I work on um epigenetic marks um and we can talk about it later but I just want to uh um give an overview of the field. Um there are so many so-called genomic technologies um for measuring anything from gene expression proteome metabolom glycom really any ohm and for any readout people have developed clocks aging measures you know um I started with DNA methylation um back in 2011 we published our very first epigenetic clocks. Uh and um why methylation? Because the signal for aging and even mortality is very strong in methylation. Um but when you want to measure biologic age you really need to look at many uh levels of readouts molecular then um biochemical readouts blood biochemistry various measures of organ function fibrosis as an example and then of course above all functioning measures um um V2 max gate speed and um daily level living activities and >> fraily frailty. All of that. >> It's so important, you know, for people to understand that like you you know, as we have this chronological age, everyone knows their age, right? This is how long you've been alive since the time you were the day you were born. And and the interesting thing you you talked about biological aging, you know, you have this this these processes that are happening that affect your 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. Let's say I'm 50 years old, but I want, you know, the organs in my body and the cells in my body to seem like they're 30 years old, right? >> Yes. >> To be younger. And so that's why it's exciting to have these tools that do measure function like you mentioned I think you know cardiorespiratory fitness and V2 max you know frailty I there's a lot of different ways that people are measuring function but then on the molecular level that's very exciting because it's quantifying this process of aging so I >> yes I mean there is one key word that has to be 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? Um given that you and me, we we really take care of ourselves on we um try to optimize lifestyle, prevention, all of that. But something still changes deep inside of us in our cells. And what is it? What drives aging? And um um these methylation clocks that um I've developed, they they really track damage accumulation on one way or another, you know, because that is something that just happens, you know, and um that drives then um organ dysfunction many years and decades later, you know, but it's almost unavoidable to age. Um and um what I wanted to accomplish with these methylation clocks is to have a precise tool to allow researchers to actually identify novel interventions. How do we truly reverse the age the ages of individual cells of organs and the whole organism? You know, >> you mentioned something that caught my attention. And you said these methylation clocks or patterns are able to track the damage that occurs and and that's to me always been a question. Is it tracking the damage that occurs and or if you're changing these patterns, does that change the damage? So because you're globally affecting, you know, the way genes are activated or not activated, gene expression as we call it, then you would imagine is it like a two-way street possibly where you're able to increase, you know, genes that we have that help take care of damage, repair, you know, all these, you know, stress response genes better as well. But I guess we'll get into that. That's so I think I think one of the the points of confusion I've heard repeatedly, you know, from from my audience and just from, you know, in general like out there is that people think these biological aging clocks are just sort of like one thing. You hear biological age, it's like this one thing. You reverse biological age, it's just this one thing that's happening. But we actually have very, you know, different clocks that seem to be perhaps tracking or have different, you know, strengths and weaknesses and what they are tracking and what they are sensitive to in the context of the aging process. So maybe we can kind of just can you walk us through some of these clocks and you know what their core strength is like what they are tracking and perhaps even what a common misconception is in terms of what it's tracking. >> Yes. So um maybe we start with the big picture. Aging is of course associated with the accumulation of damage on all levels. Um the proteomic level, metabolomic um um intercellular communication but also damage accumulation surrounding the DNA molecule. these chemical changes to the DNA um 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 and so on. And so the damage impairs the function of cells and then tissues and then organs. And um interestingly um methylation um changes can be observed at really millions of locations on the DNA molecule. And um 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 methyl the methylation landscape really flattens out and uh conversely in a young cell you you want to have really uh 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 um these methylation clocks um 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 um 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 uh agree with each other that all clocks give you this one readout. Um that wouldn't be reasonable, right? Because you have millions of locations. So um methylation clocks really capture again different properties of aging. Some clocks are very good at tracking inflammation. Um other clocks are very good at metab metabolic syndrome. Then the so-called these are now second generation clocks you know they really uh relate to inflammation and various stressors smoking. Um but then the earlier generation of clocks so-called uh first generation clocks had a totally different goal. they just want to measure calendar age, you know, and um yeah, so the misconception is that people get disappointed that two different clocks lead to slightly different readouts. But um the metaphor I want to use is think of the world of proteomics. If I told you protein one measures the same as protein 2, 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 to kind of clear up. And um you know, I I guess if you understand that concept, you wouldn't want all these clocks to be giving you the same readout because then that would be kind of a problem, I think. Um >> it would be overly simplistic, right? And most clocks were tailor made for blood uh for the sake of convenience. But 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. >> Um so let's talk about some of the main ones that are used. And so we have the one that was, you know, the original Horvath epigenetic aging clock, first generation for chronological age, and then you we we kind of get into these other clocks which were first generation and then they have second generation versions as well. But so the DNA pheno age um 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. Um, this clock was very much constructed to track um really biochemical markers and also um um 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. Um but yes, so this clock um was then impressive mortality risk predictor for humans, you know. Um however, it it was then superseded by the grim age clock which was named after the grim reaper. It um was published also many years ago, 2019, but it continues to be very impressive for mortality risk. And um from a mathematical perspective, these clocks were constructed in very different ways, but overall they very often agree. you know when when you have an intervention that appears to slow uh grim age progression it also uh slows pheno age progression you know 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 I mean 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 uh calculation or you know whatever we want to call it um >> stress related proteins inflammation but the feno age also has some inflammation as well in there >> yes yeah maybe I'll start with a much simpler um uh example C reactive protein um as a marker of chronic inflammation it's a very important biochemical readout out and um 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 I will say correlation maybe.3 or lower you know so it's not a tight correlation but I want to mention it as an example for this idea of using methylation to estimate um 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. They are trained to look at thresholds and then they diagnose um maybe an acute infection. Um but 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 um 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. [laughter] Well, why don't I build a clock that uses these methylation estimators of C reactive protein of many other famous proteins or and also the methylation estimator 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 underlying the grim age clock, the grim reaper clock. And um it just worked beautifully in many validation studies. We now know this idea worked. But that's really the idea of the uh grim age clock >> and this was from this was developed with in your lab the grim age clock. >> Yes by au in my lab you know pheno age was developed by Morgan Lavine when she was a post in my lab >> when 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 and and I mean how accurate is that? I mean like what's what are we talking about you know? >> Yeah. Um yeah the first question um why does methylation relate to mortality? It is a good question because when I published the very first clocks I remember I was extremely nervous about what I had published. I thought maybe these clocks have no use. maybe they just measure your calendar age, you know, and um and now I'm I I was so relieved that um basically 6 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. Yeah, I was. But um anyways um but then um by now we know that these methylation clocks very much predict mortality risk to the point that um um certain startups pursue the idea of using methylation clocks for pricing um life insurance policies or financial products, you know. Um and of course u methylation clocks are used in serious randomized control trials you know so um the evidence is very strong and without any debate um but why is that you know [laughter] and um I it could be that these clocks really track long-term exposures of a stressor. So for example, smoking again, you know, so um maybe maybe if you just smoke a bit, it uh it doesn't really show up in other biomarkers, but if you have an ex really this prolonged stressor, it really alters the epiggenome. Um why? Because the epiggenome creates a memory. really think of the epiggenome as uh a memory of stressors and it primes the cell to respond. And you can imagine if um the cell senses this onslaught of various stresses, it tries to remodel its regulatory system so that it prepares for future stress. That's maybe one way to um conceptualize it. >> Yeah. And I mean we even I think the this concept of you know the stressor affecting the epiggenome you know we even know it can affect the epiggenome in gonads right in sperm and eggs and that's why certain we have those the studies out of Sweden where they went through these periods of starvation like famine and then there was feasting depending on you know the what food was available at the time and and I know that some researchers had looked at how the epiggenome had changed and that also seemed to affect life expectancy of the offspring as well. So, um, and then >> yes, I think this is a study from the Netherlands, the so-called Dutch hunger perhaps. I'm not sure whether that's what you meant. Yeah, that's right. >> Yeah, very exciting work. You know that u maybe a couple of years of starvation could already change the gonad methylme and that could then um 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, I I as far as as far it's been years since I've looked at those studies, but I think there were like prepubescent boys too where it's like if they have gone through these periods of like hunger where they were calorically restricted, it obviously changed their, you know, their gonads epigenome and and their sperm in a way that was, you know, more permanent. And so, um, they had offspring that were like more resilient against type two diabetes and, you know, other age- related diseases as well. So I think I think they also lived longer like their grandkids or something like it affected their life expectancy as well. But smoking is another one that would also go it gets I mean that's something that goes you know deeper right and affects the gonads if I'm correct. I mean >> um yeah I need to tell you regarding these findings I'm usually interested and excited about them but I want to emphasize to your audience they are controversial fundamentally. >> Okay. uh very smart people disagree with these findings. Personally, I'm I'm completely neutral. I um but I just want you to know that >> they disagree that the epino changes. >> Yeah. So that um no um just to be very precise that an exposure from your parents for example has an effect on you. >> Um again this brilliant people publish on it. And these studies go through rigorous peer review. But I just want you to be aware that there are uh strong counterarguments, you know. So it remains to be seen. I want to say because um they um I want to think that if your parents or grandparents um went through severe stressors, I want to think that you still are born with a clean slate, you know, so that you're in certain ways not predisposed or doomed in one way or another, you know. So, um >> well, sure that would be a nice thing to think. Yes. >> 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 convince me that there's an epigenetic change that does happen. Yes. >> And in you know sperm DNA for example like if you have an obese male and then they lose weight like you can look at their sperm DNA and it changes from being obese to lean and epigenetic changes gene expression changes are happening. So um but even 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. Um >> yes. Yeah. What I want to tell you briefly about sperm that is um yes, there are methylation changes and also changes with aging. So the sperm methyl of a 50 year old is different from that of a 20 year old. However, the changes that occur um um are at completely different location from the changes that we use in any of our other clocks. You know 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 it. Um so for example what is known as the Horvath pant tissue clock you apply to sperm you get one number 37 or so [laughter] 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 um for the placenta so people have um developed clocks um applied to placenta to estimate the age of the newborn meaning gestation age or also various uh stressors uh from the mother. But again, these changes are very different from what we observe in blood or um adult tissues. >> Have there been clocks um for sperm that have been developed that are more precise? >> Yes. Okay. >> Yeah. >> Um I have a question about grim age, but it it sort of leads us into the next clock that I want to have you discuss, which is the the duadin pace. Did I say it right? Do I I think it's called Dunidan paste. >> Dun needed and paste. That's right. Dun need and paste. >> So the question I have is you know with the DNA grimage we're talking about this methylation pattern being able to predict mortality and very you know pretty pretty accurately mortality risk and it's it's it's able to measure you know this accumulation of damage that's changed the epiggenome in a way that's obviously you know quantifiable. What if you're 45 years old? You get your DNA grim age test done. It gives you your mortality because you've had all this, you know, lifetime exposures up until the age of 45 of, you know, let's say air pollution, maybe you smoked a little bit, whatever, alcohol, poor diet, stress, chronic stress, all those sorts of things. But, you know, you change your lifestyle and it gets better. Does that does that grim age change? >> If you had asked me that question two years ago, I would have humped and hard, you know, and I was always very cautious about that in certain ways. How reversible are these changes, you know, but the the science has really advanced and now I'm confident in saying that you can reverse grimage to some extent. The key word is to some extent because these changes appear to be very minor. We can talk about it later, but there have been very rigorous uh randomized control trials with supplements and medications. So, there's a hopeful message you can reverse it. >> So, that's what we're going to get into folks. That's going to be the exciting stuff. >> Mhm. >> So, this this this other clock that's able to measure >> Yeah. >> the pace of aging. Can you talk a little bit about the >> Yeah. Um >> do can you say >> Yeah. Yeah. So there is another widely used clock which is known as a Junedan pace clock. It was developed by Dr. Moffett and Dan Bellski and um it was constructed in a very different logic from other clocks and um the metaphor is it's supposed to be an odometer. It it's supposed to measure the speed of aging or what what they call the pace of aging. whereas um previous clocks really measured in certain ways the accumulation of damage. So the idea is very compelling. Um [sighs] maybe I just review um how it was constructed. So um the team really looked at rate of change in established physiologic markers and biochemical markers including also importantly and we should discuss that change in body mass index. So um um but also measures of um waist to hip ratio. So um also measures of uh glucose um impairment, markers of inflammation, many readouts and the study leveraged a unique uh epidemiologic cohort study in New Zealand in the city of Duniden and um so it's a study where they tracked middle-aged people and younger people for many years and and assessed these readouts repeatedly. it um for the experts it's a longitudinal studies and by having these longitudinal data multiple measurements per person they could really um estimate the pace each person's individual trajectory so far so good so you have these um pace measures but then they went to the next step which is similar to Grimage they said why don't we use methylation to estimate ate the pace of aging based on these physiological measures and I think that's a very good idea. Um why? Because people care about what's my current pace of aging. You know it it actually it's a good question. I'm I'm not quite sure what people care about. Some people want to know let me know where I stand right now >> or how an intervention is affecting how they're aging perhaps. >> Exly. Yes. Thank you. Yeah, that's a good point. you know, so if you have an intervention um you want to see does it really change the pace? Does it affect the odometer, you know, um and um so um therefore people use Dunid and pace along with all the other clocks that I mentioned in when they study interventions. It's by now part of the standard repertoire of clocks. when people uh publish a paper on longevity interventions, they hopefully report about five clocks, I want to say, just um 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 uh 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 grimage perhaps Grimage 2. >> Yes. >> Um and I see the Duadinian pace that those are those are at least three of the ones that are they seem to be and then there there's a few others that sometimes are in the mix. But um those those three stand out to me when I'm reading the literature maybe because I know them the best, [laughter] but but um 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 an intervention, and we're gonna get into those in a minute, and you see, you know, your DNA grim age doesn't change. So, your mortality your when your mortality risk is the same or, you know, determining when you're going to die is the same. And yet, your rate of your rate of aging perhaps slows a little bit. Maybe it's not much, maybe it's 2%. Some people will look at that and go, "Oh, these are all like if you're changing your pace of aging, why are you not cha 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 the pace at which you age by 2% and the trial was 6 months, is that going to be reflected in the grim age or, you know, what's the standard deviation here that we're even talking about with grim age, right? >> Yes. I think you make a very important point. If you have an intervention that has a very strong effect, I would expect that most of these clocks will show it. Um why? Because these clocks are correlated with each other. And um just to throw out a number correlation five after you regress out age, sex, and various variables, but they still a fairly good agreement. This is the typical glass half full half empty is a correlation of 0.5 high on low you know to me it's reasonably high if you have a very strong rejuvenating intervention now when it comes to I I need to tell you I'm obsessed about the question which clock is best [laughter] and so I >> best for what >> for judging longevity interventions and >> okay >> um yeah because when comes to mortality risk prediction, we know the answer right now. After several large studies, there was a study in Scotland, Generation Scotland, 18,000 uh people were evaluated and Grimage was best. And then there was a study from Harvard, I want to say 30,000 people were evaluated, Grimage was best. So, so we know which clock is best for mortality respirator. >> Can I pause you right there? And and that I just want to make this point because usually when we have these studies at least observational studies looking at >> diet because you'll never have a randomized control trial that's going to last you know 30 years. Yes or 40 years. So if you have if you have if you're looking at observational data and how different lifestyle like affect or diet and lifestyle affect 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-c 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 for a period of time and you can have the grim age which is kind of like this surrogate all-c cause mortality but but it's very actually a very good estim 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 uh 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 um for a clinical trial. In other words, you have a study where you apply let's say a multivitamin for two years and then you see a change in any clock. It could be a proteomic clock, it could be a grim age, 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 um this um so we we would like to think that is the case but from a regulatory perspective that hasn't been proven you know and in general the FDA evaluates biomarkers you know um why they want to um give guidance to companies to biotech where they say if you show us that your treatment reverses that biioarker Therefore, we believe that it actually uh helps patients, you know, and um I just need to tell you and the audience, the biomarker field has not yet developed any biioarker 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, um we just can't wait [laughter] for uh for for this regulatory approval yet. Why? They are urgent questions, right? People um have exciting interventions. So, we need to make assumptions, you know, and um for the longest time I've been very cautious when it comes to this claim. Do methylation clock um um meet this high standard? you know, and I'm I'm coming around, you know, um just because I I see increasing evidence, you know, that um these uh uh changes um um track what I call validated interventions, you know, where we know the intervention has a benefit for human mortality risk. And then I see that it also touches methylation clock in the expected direction. It it gives me confidence, you know, that the clock does what it's supposed to do, you know. So, that's that's where I'm at, you know. >> What have you what's the most robust intervention or it doesn't have to you don't have 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, grim age, pheno age? What's like Yeah, I will start with um 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, you know, >> um to answer your question, um HIV positive people exhibit, um epigenetic age acceleration. It's actually a pronounced pro-aging effect. maybe five to seven years in blood and sure enough if they stick to their anti-retroviral therapy that will reverse their epigenetic age and that uh and and I mention it because that >> how much >> uh several years you know several years to give you a number four or five years >> four or five years does it happen pretty immediately after taking the drug? Yes. >> Um probably several weeks a month, you know, but um >> there have been many studies all over the world that have shown it, you know, so it's it's very well established and um yeah, so that's one application. I mention it it's um I trust it 100% but I um many people are not HIV positive, you know. So therefore I say do not take anti-retroviral therapy, you know, it's just not. So the other intervention that has very strong evidence is anti-TNF alpha therapy really anti-inflammatory um drugs for people who have an autoimmune disease again that just makes sense you know but um yes and um metformin is an interesting intervention to many of us um the problem is and and um I'm coming around to believing that metformin affects epigenetic age. There have been a couple of studies that suggested but I need to emphasize the effect is way weaker than than the above. So these are um really um medical interventions and in general as you can expect a medical intervention has a much stronger effect than a supplement you know. Yeah. When it comes to supplements we do have some answer. Um, omega-3 has an beneficial effect. Um, apparently vitamin u multiv vitamins have an effect. The problem is that these supplements have much weaker effects. Suddenly we talk about a couple of months of rejuvenation, you know. >> So, yeah. >> And we're going to talk about those more in depth and 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 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 >> out there talk about reversing their biologic age biological age by 7 years in sorry they reverse their their biological age by 5 years in 7 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 um it's a very good question. I think I the first thing I would ask um what was their BMI before they started and um 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 they take their GLP-1 receptor agonist, they they they suddenly go to the gym and they do everything right, then it would perhaps be possible and um but there are many pitfalls and I can discuss them later, but I don't think it's um not not possible when you start with this baseline. >> So you're very unhealthy. >> You're very unhealthy and and and above all you actually start with an epigenetic age measure. Let's say grim age that shows you are 8 years older than you should be. Do you see you're in this in this highest percentile of risk? So then maybe you can go back to the average, you know. However, now let's talk about um the opposite case. A biohacker um obsessed about healthy lifestyle and now they say I changed my um diet and now I reversed my age by 5 years. I I would have the hardest time believing it, you know. And by the way, um this is something we see over and over again with various uh rejuvenating interventions. They seem to work in people whose epigenetic age is already accelerated, you know, but not in the people who are very healthy, you know. So, but yeah, so um anyways, I would be very skeptical, but I'm open-minded. I'm strictly datadriven, you know. So, I would have a long conversation with that person, you know. >> Yeah. Well, you make a really good point and that is, you know, people that are already accelerating, they're aging at a faster rate. So, they have this a age acceleration, right? Their grim age is already, you know, they're going to is higher than it's supposed to. Is that correct? Is it? >> Yes. Higher >> higher than it's supposed to be. You know, their their biological age, their feno age is higher, their pace of aging is higher. So, they're 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 um has been shown to be, you know, associated with age acceleration. And if you correct those problems by losing weight, by getting physically active, by quitting smoking, you know, by eating healthy, by >> getting your micronutrients and filling the gap so you're not deficient, then you see a more robust effect. And that is also a recurring theme that I've seen from reading the scientific literature where it's like okay if you already have enough vitamin D and we'll talk about this like you know if you're if you're if you're already sufficient taking a vitamin D supplement's not going to slow your aging the thing the thing you're doing you're already doing it you're avoiding deficiency and that's the key right you you're you're trying to stop that acceler things that cause the acceleration of aging >> um seem to be easy more responsive at least >> exactly yeah >> the other question I wanted to ask It goes back to something that you mentioned earlier when you were talking about, you know, these insurance companies being able to predict your mortality risk pretty accurately. Um, using the DNA grimage. I've also heard people say that you can take this DNA grimage test and predict the day you're going to die like within a month. >> No, no, that's not true. >> Okay. Now, why is that not true? >> Yeah. So, I want to start out by commenting on insurance companies. um they are in the business of predicting how long you live. If they make an error, it will cost them a fortune. And um they are superb at that. And u just to emphasize, they look at so much. So they will above all look at very traditional uh readouts such as what's your blood pressure, what's your medical history, prior history of cancer, you know, uh substance abuse. So 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 um does grim age add something or grim age or another methylation that's really the question for these companies and scientifically speaking I can say yes it adds something but not that much you know clearly the life insurance companies have done very well without having the methylation readout. But um but the exciting thing is methylation adds something. But then these companies have to weigh the costs, you know, because these tests are not cheap. They cost several hundred. So is it worth it to measure? And by the way, that's the same question for any consumer. Is it really worth it? Uh worth it to you to measure it, you know. Um um sorry, the other part of the uh you had a second part of the question. Yeah. The question is, I guess I I can word it a different way. If if I were to go out and get a DNA grimage test. >> Yes. >> And it said that I was going to die when I was age 80. >> Yes. >> Am I actually going to die at age 80? What how reliable is that number? How accurate is that number? Or am I going to die at perhaps age 85? >> Yes. I want to um um tell you that grim age could lead to a prediction of when you die. Let's say age 85. It could. And we know though that this estimate is accompanied by a large arrow bar plus - 6 years. I'm just making it up. So let's say you're a 50 year old. you measure your grim age and um we apply the math the mathematical algorithm which by the way is very complicated you know for estimating your um uh age at death. Um but the error error rate is substantial and um this makes sense because human beings are so complex you know think how many things can happen um 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 um it it would be unethical to report literally the age of death to a person therefore for we have decided to only ever give people an age estimate. Right? We will say you're a grim age is 50. And um what I want to really explain to anyone who listens is that please do not translate that age estimate in your mind into an estimate when you will die. In other words, if your grim age is 10 years younger than your calendar age, it does not mean you will now live 10 years longer than the average person. Do you see? You cannot uh uh um compare this differential into a lifespan differential. >> Then what does it mean? >> Yes. So um 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, you know, compared to a person of the same age and the same sex, you know. So, we let's start with a 50 year old um and um let's say their grim age is 58, 8 years older than expected. then their risk of dropping debt in the next year is more than twice that of the average 50year-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 um 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 you know >> are there companies that are have consumer available tests doing that where they're measuring the grim age and then doing that translation to when you will die. Is that something you've seen? >> No, I have not seen that. Yeah. And I'm glad because I would have a problem with that on two grounds. I find it um on some level perhaps unethical. Um but um I believe in freedom. So if people want to do something, I'm okay with it. My uh concern is it's scientifically unsound. It really is, you know, for the reasons I mentioned there's a strong arrow bar, you know. So >> right, if you're talking five or six years, >> either way, that's that's a pretty big error bar for when you're going to die. But it seems like people are using it more to to to estimate their biological age, right? In a way, right? And that's that's typically what people are >> Yes. Usually >> we use Grimage um of course to understand the effect of various stressors. Um and um I'm a longevity researcher. I'm very excited about finding interventions that reverse it in humans and of course in animal models. So, um, that's how I use it, you know, >> for these for these clocks. Um, when when we're looking at the like aging process as a whole, >> you know, we're talk we were talking about damage, you know, there's the insult that is the initial insult and then you have perhaps the the damage response, maybe the amplification of that damage with inflammation. Then you start to have tissue breakdown, right? stem cell exa exhaustion like things that are more downstream of the damage and ampl amplification of that damage. Do do these aging clocks where do they sit on that? Yes, we um have um gained a lot of insights into aging in general by the way um and also um which um aging hallmarks really affect epigenetic clocks you know so 10 years ago we barely knew anything about mechanism um epigenetic clocks were rightly criticized as blackbox readouts but after really 10 12 years of research by the very best labs in the world. You know, we we really um have characterized these changes. Um maybe for the biologists um there are these hallmarks of aging. Um and we know that clocks relate to mitochondrial dysfunction, the energetics. They relate um also to stem cell changes very much so, stem cell biology. um they um relate to um metabolic changes, nutrient sensing um um to some extent as well and um and also aspects of DNA repair you know so um that is part of the biology. They clearly relate also to changes in what is known as cell composition. So um in in blood we have many different blood cells and some cells uh are aged so-called um stressed memory uh tea cells um cytotoxic tea cells um um that um are exhausted this is actually a technical term exhausted tea cells from aging and conversely there are these naive tea cells you know so we understand that epigenetic clocks also relate to inflammation and um and that biology. So um epigenetic clocks should be conceptualized really as integrators of many uh different stressors but not all. Um 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. Um people in the aging field have heard of scinesscent cells senolytics very exciting uh intervention. I I'm very uh much following that literature. However, epigenetic clocks really don't capture that well you know. So um let me give you the prime example. You have cells growing in a dish. You radiate them high any radiation. You induce scessence. they the cells can no longer proliferate. Um, and by the way, radiation leads to double strand breaks. It really very much stresses the cells. And wouldn't it be nice if methylation clocks pick that up, but they don't, you know, so so radiation damage at least for >> they don't pick up double stranded 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 um so and and I give you the converse of that when it comes to scinessence many of uh many people have heard of tieumirs um in theory you want reasonably long tieumirs at the ends of your DNA and for many years people have thought aging is about tieumir attrition. Now we know better it's not but anyways it's a famous hallmark of aging tumir shortening however many of the clocks have only a weak correlation with tumir biology it's a frustrating aspect um and um 20 years ago people had an exciting idea um overexpress a part of tomease the turd um overexpress turd Um and there were companies that pursued that as a rejuvenating intervention and um in at least in our hands um we did not see a beneficial effect at least in vitro you know so um although I liked uh epigenetic clocks for many studies but they don't capture the totality of aging you know so you really um want to complement epigenetic clocks with other readouts That's interesting that they're not because you mentioned that they do track with the DNA repair process but not >> to some extent. I I know I'm giving conflicting messages um but that's the biology. >> So um >> there's certain experiment that show that um um some aspects of DNA repair relate to epigenetic aging but others don't. It's it's just not a tight story, you know. So, I think um the field really needs to nail that down. >> Yeah. I mean, well, there's a lot of things that lead to aging, you know. It's it's a very complicated, >> you know, multiffactorial >> uh process when when >> you actually are able to per perhaps reverse, you know, biological aging or I guess there's two ways of thinking about it. you're slowing age acceleration, right? If you're taking away something that's negatively accelerating aging or negatively affecting your health, >> but then also, let's say you're if you can actually somehow slow the aging process, at least on the readout, the clock is showing that you're younger after doing something. Where do you think do you think that's like inflammation like these processes that are that 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. Um yes and no. I mean um so epigenetic clocks such as grimage and do need and pace and feno age they do track inflammation to some extent. No question. So yes, if you reverse that um these clocks will pick it up. But it would be a grave error to assume that the clocks only measure that biology. It's really not true, you know. Um the clocks um very much relate also to stem cell functioning, you know, and um and other aspects, you know. So again they are integrators and um so there there will be interventions that actually don't even touch the in inflammosome in one way or another but they could have a very strong effect on reversing your epigenetic age and the prime example would be um therapies that for example completely rejuvenate your hematopoetic stem cells. Just assume you have an intervention where you really replace your your bone marrow, you know, the or hematopetic stem cells that produce all of these blood cells and you just um get um hematopoetic stem cells with an epigenetic age of zero. Um um that would very much rejuvenate your blood drastically. you know um we know that from mouse studies but also human studies you know the the epigenetic age in a bone marrow transplant recipient often um reflects the age of the donor you know so um so do you see there are various interventions that could have a very strong effect um 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 um my response is assume not because it would wouldn't it be nice if >> what animal studies shown have they looked at that? >> Yes, there have been animal studies I want to say in the lab from Vadim Gladishev at Harvard and um the studies um my reading of the studies is that they have been disappointing they didn't rejuvenate other organs. If anything, there was um a disappointing result that um after 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 the the blood. Really? Does it? >> So did these mice get a hematopoetic stem cell um graft or they did? Okay. >> Um um Vadim um carried out really an elegant set of experiments various uh transplantation experiments and the scientific question is the following okay if I uh replace let's say the blood by that of a very young mouse or take other organs by the way should we replace the kidney should you know so anyway the or or the heart or any other organ um would the rejuvenation of one organ translate to for bodywide rejuvenation and my current reading of the literature is that we haven't found any such uh 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 am I I mean that that's I don't know if they were measuring doing using clocks, but they were doing cognitive function and a battery of tests and the cognitive function improved and things like that. But no, for sure you know. So maybe um to remind the audience this this idea of heterocchronic parabiosis for example where you really uh connect the circulation of an old mouse with a young mouse. And this is a really a phenomenal paradigm of rejuvenation. Arguably one of the best ones we have along with caloric restriction. And um um so yes um we know that um when an old mouse is exposed to the circulation of a young mouse it has multiple benefits cognitive benefits also muscle benefits. So um and also importantly epigenetic clocks get rejuvenated many organs. Um so we know that again from several studies including from Vadim Bladesf's lab but others have found that too. So yes, um young circulation rejuvenates the liver, the kidney, all of that, you know, um 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 problem is it's transient, you know. But yes, >> it's it's kind of like the probiotics flow through. You have to keep taking them to have a benefit in the gut as soon as you stop taking them because they don't stick there, right? They're not taking residence there. Yes. Yes. Well, let's talk about caloric restriction since you 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. Although GLP-1 receptor agonists are kind of doing that in a way. Um there was a very recent trial, the calorie trial, and I'd love for you to talk about this was a two-year randomized control trial where individuals were basically eating 25% fewer calories than they otherwise would or they were eating their normal, you know, daily food intake as as usual. And I wanted to ask you was this were the participants overweight in this trial or were they normal weight? Do you know? >> I don't remember. I know it's a US population so assume that they are on the chubby side for sure, you know. >> Okay. >> Yeah. >> Yeah. So in this in this trial, it was a two years rand two-year randomized control 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 the the findings? I mean I guess >> yes um yeah I have a lot to say about weight loss we should discuss it you know so but uh the calorie study is a very famous study um US population very rigorous study many many readouts um but I want to acknowledge something um and um the experts know it the adherence was not good you know so um 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 um the age reduction was on some level very weak. I would say I I I I apologize. I don't know the number, but I remember it was weak. I mention it because later we should talk about GLP-1 receptor agonist where the weight loss can be pronounced and the there discrepant findings actually, right? >> But anyways, back to the calorie study. Um um um again there were multiple blood draws from these people and so one could evaluate um which methylation clocks pick up a beneficial effect. And um I was disappointed that um grim age and feno age did not pick up my effect. But this new clock a new clock at the time Dunid and Pace really picked up my effect. Um and which was reassuring you know that um reassuring because everything I know about the biology of methylation clocks tells me that they should pick up a reduction in weight if it's strong enough. You know >> how much weight did they lose? Do you remember? It was >> pretty like not very much. >> Yeah, it was not impressive to me at least. >> So, so the clock that did pick up the >> It was Dun need and pace. And in in hindsight, um let's discuss why it picked up the >> like a 2 to 3% slowing of the rate of aging >> over the two years. >> That's true. Yeah. So it picked it up and it makes mathematical sense to me because Dunid and Pace again was uh um trained that's the lingo of machine learning but it was developed to track 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, Dunan pace worked and my reading of Dunan pace is um that it is good at that biology. People losing weight, it will pick it up. Um and um now the question is why didn't the other clocks pick it up? And there could be several explanations, you know, but my view is if there had been a larger sample size, if the people had adhered to the protocol, I'm I'm as sure as you can be that the other clocks would have picked it up. It's a sample size issue or conversely small effect size. What I can tell you is there was sorry there was a very exciting study um um that involved actually obese people BMI 30 and higher who had been put on a GLP-1 receptor agonist treatment semiglutide. And these people really lost a lot of weight over 33 weeks. And um by the way this um study um was published in MET archive. It's a pre-print so um take it with caution. It was Michael Kley's group in San Diego but very beautiful study very rigorous again and um a large sample size so credible and they looked at all methylation clocks and suddenly all methylation clocks picked it up really all you know and um so that's my thinking you know if you have a strong weight loss intervention you have really a strong reduction in fat lipolysis is you know this inflammatory signal is reduced um I think all methylation clocks will pick it up and >> right and I think it goes back to this concept that we were discussing earlier where if your baseline is unhealthy if you are obese you are accelerating your aging right you 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 at a population that's either deficient or unhealthy and then you're giving something to improve that deficiency or negate it or to you know improve their health and you get a more dramatic effect. So we know obesity accelerates aging we know you know that it's associated with you know decrease in life expectancy you know increase in cardiovascular disease, type two diabetes, cancer, right? All 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, right? >> Um, and you're obviously picking that up with with the agent clocks >> with the calorie trial. Um, 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. Um and so the you know the douadan pace clock which is measuring the pace of aging um you would imagine would be more sensitive than than something that would >> but you know my my question as a longevity researcher is which clock should a clinician use? You know um if we could briefly talk about multivitamins um um this study interestingly here grim age f found an effect pheno age found an effect based on multivitamin use but dunit and pace failed it was not significant you know so and you can ask this question now for many interventions what should be the go-to clock and you know I I even I want to stay clear of this debate because we will never agree agree, you know, therefore I I just love it that the field by now simply reports at least five clocks, you know, so the reader can just look at it and um be the judge. >> Let's let's talk about the multivitamin. 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 control trials where these older adults were given a standard Centrum silver multivitamin a day. Oh yes, >> every day. And it was what is it about 3.6 six years for this trial and they were looking at I mean there's a lot of end points of this trial but one of them was cognitive function and brain aging and at the end of the trial the the people that were given the multivitamin had slowed their brain aging by 2.1 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 2.1 years and their episodic brain aging So, episodic memories, a kind of memory where you're remembering experiences, people, right? Like those sorts of things. Um, that was slowed by almost 5 years compared to the placebo group, which is quite significant. And they did better on a battery of cognition tests. And so, that was very that's very encouraging, you know, and it's something that I do talk about a lot because 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, I'm my parents are on a multivitamin, right? >> Um, when it comes to looking at these epigenetic aging clocks, the phenoaging grimage clocks were the ones that stood out to me. As you mentioned, there was a battery of clocks that were that were looked at, but it seemed as though they were slowing or at least I'm not exactly sure all the calculations that go into this, but 2.7 months to 5 months, right? Like they were basically >> they're they're slowing the aging by roughly that amount. >> Yes. >> Um, which to me is, if you think about >> now this this trial that was done with the agent clocks, I think it was like a subset of it of the larger trial. Was it two years or did they do the 3.6 years for that? Do you >> It was Yeah, I think it was two years. >> Two years. Yeah. And and so um to me the question is now this wasn't that you said the Dodinan pace didn't change. >> No, it it it changed in the right direction. It just wasn't statistically significant. >> Oh, I see. No. Um >> in the right direction. You know, maybe a larger sample size would have um 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, 3 to 5 months within that 2-year range >> according to the the grimage and feno age clocks >> and you're to keep doing that, you know, you know, for years. So, now we're talking not just 2 years, we're talking 20, we're talking 30, 40 years. >> Yes. >> How do you think that? Do you think that you get this accumulative effect? >> Yes, I think so. I um I think so. I um maybe to step back. If you tell an 80year-old that um a multivitamin will reduce his or her age by 3 months, they will roll their eyes. They will say, "Okay, give me something that reverses my age by 30 years, you know. Um um 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 um really use it for 30 years, right, and you're 50 year old and you use it until you're age 80, my expectation is that suddenly these uh 3 months benefit they accumulate and suddenly you have a benefit of maybe two and a half years. You know, it's still not uh great, you know, but um there is a benefit, you know. So, um, >> but think of the effort you have to put into just taking a multivitamin, right? I 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 your brain aging, >> you know, by 2.1 years just after, >> you know, in that trial, it was 3.6 year trial, but, you know, that's pretty robust. Five years delaying brain episodic brain aging. >> Yes. And and now we're talking about like globally like biological aging. If it's if it's slowing it by let's say on the high end five months after two years. >> Yes. >> I don't know. That seems like a pretty >> great effect if you're just taking a vitamin supplement for two years it's doing that. Well, let's continue on and and then combine other things and we'll get into some of the other trials that do show synergy. But >> yes, >> um I think it's interesting. The other question is that and this is where um you know the Cosmos trials people they're looking at everything right cancer mortality cardiovascular mortality all cause mortality and those didn't really seem to change yes >> at least within the time frame >> yes >> that was looked at and so you know we see these epigenetic clocks giving us a signal we see the brain aging effects and the question is why why are those showing up before >> yeah I I tell you my reading of it and um To me, this whole study was one triumph for epigenetic clocks. And I explained to you why. Assume you knew nothing um about multivitamins. Um you would think that there is a benefit, you know. Um clearly vitamins are important. It's a trivial tology. >> Avoiding deficiencies are important >> especially, you know. So you would say, okay, I administer that to the US population. I would hope to see an effect and that of course is the reason why these largecale studies were even initiated. Think about how difficult it is to raise the funding for such a large scale study. Clearly there must be very compelling reasons. Okay, but there is a problem now and um these hard end points mortality cardiovascular disease they didn't detect an effect. deeply frustrating. Um, >> was there a trend? It wasn't statistically significant. >> Yeah, I let you summarize it, but to me, you know, it um I I I I just looked at it from the point of view as a consumer 5 years ago, you know, I wouldn't take a multivitamin. I looked at the literature, no benefit, I won't take it, you know. Now, um, so, um, a person can now make their own judgment, you know. So what does it mean to me? I take it as a wonderful triumph of epigenetic clocks that they did pick up um the the signal and I um 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 um all cause mortality is a real I mean we I like it as a readout. I used it for Grimage. Don't get me wrong, I 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 uh biology of aging, you know, and um so now that we have actually biomarkers that did pick up that signal even though it's very weak is to me um really reassuring, you know. >> Yeah. And I think it's reassuring in combination with the the the brain aging 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 and 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 in 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 out. So, what it's it seems to be doing something beneficial for the brain and at least for, you know, looking at these aging clocks, it seems like for the way you're aging as well. >> Yes. Yeah. So, what have you got to lose, you know? >> Yeah. Um, let's let's let's go back to um 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, um the big one is omega-3, right? 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're starting out with a deficiency, if you're starting out at an unhealthy point and you improve there, improve that, you fill that nutrition deficiency gap or you, you know, improve your health, lose weight, whatever, then you're going to have a stronger signal, right? >> Yes. >> Um 90% of Americans don't get enough omega-3 fatty acids. Nobody's eating seafood in the US. It's just, you know, so you're you're starting with a population that's already, you know, I don't want to say deficient, but they're not getting a sufficient amount of omega-3 fatty acids. >> And so I think it's probably why it's easy to keep getting this stronger signal because you're if you start out with someone who's already getting enough omega-3, maybe you go to Japan and do the study. I don't know. It would be interesting to see. >> Yes. Um perhaps perhaps there it just keeps improving inflammation and then you know you'll keep seeing an effect. But um it seems like many many studies have shown that omega-3 fatty acid whether it's from food supplementation a combination of both seem to slow epigenetic aging by different clocks. >> Yes, there has been quite some literature. It started with um observational studies that you cannot trust but um last year um we published a study um which was very rigorous. This was a study conducted by a Swiss professor Hiker Bishop Ferrari who looked at 780 people and um followed again the most rigorous um design randomized controlled trial, placebo control trial in a population that I was very interested in people 71 years or older really older people reasonably healthy um average age I want to say 75. five I think or 73. So older people and she um um evaluated um famous interventions. Number one, omega-3 1 gram um vitamin D. And we should talk about the intervention about vitamin D was tricky. It was high vitamin D versus low vitamin D. It wasn't vitamin D versus no vitamin D. That that's a key distinction. >> What was the what was the low? Oh, I know the high vitamin D was 2,000 IUs. >> Yes. And the low was 800 IUs. >> Yes. >> So, it's only double kind of. >> Yeah. Exactly. And that's a limitation because the results for vitamin D were disappointing. No effect on epigenetic clocks. But that's why I hasten to add [laughter] >> it. Yeah. But we have other randomized control trials showing the opposite. If you start with the deficiency and add it, and we can talk about that. Okay. So, vitamin D. >> That's true. But um >> but there was also another disappointing if you look at the exercise. Yeah, we need to talk about exercise. So, yeah. So, this was called a home exercise intervention. Now, to remind you, these are people in their 70s and think in terms of ethics approval. You cannot stress these people too much. So, the this home exercise intervention was very modest. Okay. And >> it was resistance training, right? Three three times a week. >> Yes. Yeah. But it was um I'm telling you it was a mild mild mild resistance [clears throat] training you know because because um no effect I was very disappointed. >> Did you read that the the the starting population 88 like around 88% of them already identified as being physically active. >> Exactly. >> I mean which is if you were to get a US 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 the mountain >> walking everywhere. Exactly. No, but that was interesting to me because I'm 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 it. >> Yeah. And um yeah, so um I think we already discussed the result. The most credible result was omega-3 on epigenetic clocks. A couple of epigenetic clocks picked it up. Grimage version two, phenino age, donan pace also worked very well in that context. Um so um nice result for omega-3. the other interventions disappointed and >> by themselves by themselves >> by themselves but yes there was this one treatment arm where people actually did uh used all three beneficial interventions high dosage vitamin D um omega3 plus exercise and according to phenoge that treatment arm did the best you know so um that's the finding that we would have liked to you know, for all clocks, but it's just the pheno age picked it. >> Well, I think there was even a dose dependent where there was the group that just got the omega-3 and vitamin D, and that also improved more than the omega-3 alone. >> Yes. >> And then all three improved the most. So, you see this nice dose dependent effect with adding in these healthy lifestyle interventions even in an already presumably healthy population. Yes. Which is exciting. Yes. >> And I have the the numbers here. I think it was 3.8 eight months the pheno age delayed the biological aging was delayed by 3.8 months >> yeah over three years of that yeah >> 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 3.8 eight months it delayed the biological aging but also that was associated with outcomes that were important 61% reduced chance of getting metastatic cancer it was like a 20% reduction in pre-frailty which is also nice to see these outcomes correlated with this as well right >> I agree with that and um I can tell you the same study looked at a new concept in the field called intrinsic capacity um which um looks at various do domains of functioning, frailty, cognition, psychology. Um anyways, um also intrinsic capacity was improved in that population. Okay. So it's not just the molecular readout. Yes. >> Um I think >> for me the take-home again is something that you mentioned when you have this already, you know, healthy, they have to be a healthy population of 88% with them physically active, right? So and and you take that healthy population, you can still improve, right? You still can improve things. Um, do you, again, this comes down to the compounding factor, right? So, this was 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 30s, maybe in their 20s, and their 40s. It's like, okay, well, I'm going to start training getting making sure I'm not vitamin D deficient, getting my omega-3, and then you have like how 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, which really messed me up. So [laughter] yeah, good health behaviors, you know, and supplements in included I think will have benefit, major benefits. >> When it comes to vitamin D, that's the one that I I mean, this one study was a bit disappointing, but as you mentioned, I mean, comparing 800 IUs to 2,000 IUs, I wouldn't imagine to see a big difference there because you're already feeling the gap. >> Exactly. And most of the participants had no um insufficiency in vitamin D. they really started at normal levels >> and that and we know >> yes >> there have been there have been in my in my opinion so many studies that I've I've come across and read over the years showing that vitamin D deficiency causes age acceleration in some cases severe like 3 years >> and if you correct that deficiency it'll slow age acceleration where then you say you know reversed aging by you know not four years or whatever I mean so Um, I think my takehome and I know the the one that I like the the the most recent one was the the base two the Berlin study. >> Yes. >> Where they took which was the thing that was nice about that was they had a deficient population and then a sufficient population and gave them vitamin D. >> Yes. And um 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 um Berlin is of course not blessed by sunshine so they start out deficient you know so um it all made sense you know >> yeah you re 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 >> again what you effect. It's not about this is a magic supplement that's slowing aging. It's not doing that. It's helping people that are deficient correct their deficiency. And that's why there's so much in the even in the scientific literature with vitamin D, for example, if you're looking at outcomes, it's the same thing. >> Yes. >> You know, and it drives me nuts when studies don't measure their baseline levels or if they only measure 10% of the population and then use that to extrapolate like everyone else. They're like, you can't do that. Yes, >> there's so many, you know, and there's gene snips that are affecting vitamin D. There's other micronutrients. Magnesium really affects vitamin D. You need magnesium to convert vitamin D3 into, you know, the steroid hormone. So, there's so many different things that are affecting your vitamin D. If you don't measure it before and after, it's hard to really make a statement that it did what it did or didn't do what it was supposed to. >> Yes. >> Okay. So, I want to um >> we should talk about exercise. >> We can go into exercise. No, no, but I follow your script. Sorry. >> Oh, no, no. We we we were I was 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 GLP1. Obviously, if you lose weight, >> Yes. >> 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? Um, 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 I I want to um um explain some properties of grim age um 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 you know um let's maybe back off and think of nutritional studies. Many people have so-called food questionnaires where they evaluate the diet of participants. And from all I know from analyzing data is that these food questionnaires often don't reflect reality. >> I don't remember what I ate for breakfast. Well, I didn't eat breakfast today. But >> yeah, I mean and and people always know what they should answer, you know, but so that may bias their memory. They will say, "Oh, yeah, I ate um x servings of broccoli." But it just doesn't reflect reality. But fortunately, there are blood tests. You can measure the so-called carotenoid levels in the blood and and have an objective readout of fruit vegetable consumption. And the striking finding in post-menopausal women from the women's health initiative was that this um measure of vegetable intake has a strong correlation with grim age and other epigenetic clocks strong meaning maybe minus.3 so it's a to me a very strong effect which really changed my behavior by now I really eat a lot of vegetables um >> can you translate that to like months like what would minus.3 three. >> Yeah, sorry. I'm [laughter] I could translate it, but uh an estimate like >> Yeah. No, let me put it this way. Smoking has a correlation of 0.4. So, if you smoke a lot, it increases your age. Um vegetable consumption minus.3. So, it's actually >> Wow. >> Yeah, I was very surprised how in this and I sorry, I add one more statistic. Exercise the correlation would be 0.1. So, do you see? So vegetable intake has a much stronger effect. I mean orders of magnitude stronger effect on grim age and these methylation clocks than for example exercise you know >> and you and and you think it might come down to even the carotenoids perhaps or just the vitamins and minerals and everything in the vegetables kind of compounding. >> Yeah. You know I never looked into that but I feel that would be such a worthwhile research study. What I can tell you is this vegetable association is 100% accurate but now teasing it apart what is it you know um to be >> seen probably so many things I mean >> you've got the fiber matrix you're getting micron like vegetables especially greens and if you're talking about carotenoids you know lutein zeazanthin these 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 zeazanthin People usually associate that them with eye health. They accumulate in the eye. There have been randomized control 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. Betaarotene is probably what most people are familiar with. Lycopine in tomatoes. So there's a v variety of these carotenoids which are very powerful at basically um I would say buffering oxidative stress and singlet oxygen for example if you're talking about in the eye. >> Yes. >> But um it's interesting that vegetable intake can have such a profound >> effect. There was a vegan trial too. I think also >> there was a trial looking at people that are eating a lot of vegetables versus like an healthy omnivore trial. on the I think the vegan trrowley 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.3 that is pretty strong you gave me that reference point of smoking being you said it was wait smoking was 04 >> okay smoking point4 maybe 045 so it's increased correlation >> um exercise 0.1 >> okay >> so and we we 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, you know. So um but um regarding the question vegan versus carnivores, you know, I honestly have uh not seen convincing data. Omnivore. Omnivore. >> Or omnivore. Yeah. So or Yeah. >> Carnivore would be the extreme opposite. >> That's true. Yeah. Let me rephrase it. So I I have not seen any evidence that people who let's say eat a lot of red meat age much faster than people who are vegans. And um we looked again in the women's health initiative. I mean, there was a hint, I want to say, when we analyzed 3,000 women and then women who ate red meat, it was barely noticeable that red meat was ever so slightly increasing epigenetic age, but it was truly negligible, you know. So, um, what I can tell you is I eat so much meat. Um, hopefully it's not bad for me. >> Vegetables. >> I eat meat and vegetables. I try to be easy on the carbs, you know. I I eat carbs, but I try to reduce them. Yeah. Well, I mean, veget vegetables are carbohydrates. They're just complex carbohydrates, not simple. So, you're you're not eating the simple carbohydrates. >> Yeah. Exactly. >> Yeah. Um that that vegetable stuff is is interesting, though, but there's so much in vegetables with the micronutrients and the phytochemicals, right? That that's another thing in them. The fiber, I mean, there's there's a lot of things going on here that's >> Yeah. Somebody should really tease that apart. What kind of vegetables should be eaten, you know, and um dosages. Yeah. lots of exciting PhD dissertations could be written on that topic. >> Um, exercise. >> Yes. >> That so let's talk about that. So you're you know what there's a trial that you sent me that was pretty convincing and it was kind it was a new one in 2025 showing that 6 months of cycling it seemed to slow epigenetic aging or grim age right grim age by 7.4 months. >> Yes. I maybe I I'll frame it like that. So there have been very nice studies on the effect of exercise on grimage and phenoage and other clocks and um so why what do I mean by nice um 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 largecale studies many thousands of people and in different countries Japan, Germany, US and the finding is the following. Yes, if you move more, yes, your epigenetic clocks um pick up a small effect and I mentioned earlier correlation minus.1. what it means. You need to study 3,000 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 um what they call the poly pill. You know, it touches so many systems and you it's very beneficial. So I would have loved to see a strong effect on blood methylation but it the literature shows weak effect. And >> what about muscle methylation? >> Yeah. So people have built um clocks for muscle. So literally human muscle biopsies. [sighs] I don't know what to tell you. It's Yeah. Um, some some people claim they see an effect, you know, but I I just am not yet convinced. >> It is disappointing. So, you're asking >> I would say it's disappointing. So then there's this study that was published um by first author I can remember Vanam I think differently spelled from the actor but anyways and this intervention was very different because it didn't look at step count or what we discussed earlier them home exercise intervention that was the next level intervention it was putting people on a bicycle and they now um bicycled 4 and 1/2 hours a week. Now for the health nuts out there that's not much but to me this is daunting you know so I if if you forced me to bicycle 4 and a half hour a week I would struggle with that um why we we are all busy people you know but anyways the people who adhereed to that trial they had strong effects on V2 max >> 20% >> 20% and many other readouts you know so they didn't fake it you know so they really saw physiologic benefits And then sure enough suddenly the clocks worked you know. So PC Grimage as an we keep talking about PC. PC means principal componentbased Grimage. That's a version of Grimage that's even more robust than the original. Robust in the sense of test retest variability. It's a um very uh reproducible measure. So anyways um it picked up a 7month reduction in grimage which again dwarfs everything we just discussed you know so and that was um um a six-month intervention. These people were younger though I want to say they were between 30 and 65 basically a population that you can um um um put under such a stringent regiment you know. Well, they're young and [clears throat] middle-aged, but >> yes, >> I would I mean, so I would argue with Steve that this is 10,000 steps. Like that stuff is like it's okay. It's better than nothing, >> but >> if you really want to move the aging, I mean like you got to go more than that. And and this is the kind of stuff I mean that that we talk about on the podcast. I mean, I've had Ben Lavine on. He is a rock star in the cardiovascular exercise physiology world. And he's done multiple randomized control trials, but he did one that was a two-year study in 50 year olds. They were about 50 year olds and they had never been physically active, but they didn't have any other diseases. Put them on a a two-year trial where they were working out, exercising about five on average 5 hours a week, doing a lot of cycling. They were doing, you know, some some highintensity interval training in there, a little bit of resistance training, but a lot of it was aerobic and they improved their V2 max and their their heart structure. So, he looks at like the structural aging of the heart. So, as we age, our heart gets smaller with age. It gets stiffer and [snorts] um they improve the structure of their hearts by it was like if you basically it looked like they reversed aging by about 20 years. their hearts, you know, got bigger and they were more flexible and it looked more like a 30-year-old even though they were 52 at the end of the trial. >> And so I would argue that, >> you know, doing really taking time to exercise every day something and and more than just walking Yes. >> you know, is very powerful for for longevity and for, you know, slowing age acceleration. >> Yes. Um, and so it's it is really nice to see this new trial because I have also been very disappointed in, you know, some of the data, but no one's really doing these kinds of studies where they're saying, "Hey, again, it's like getting a stronger signal. Let's let's not just walk. Let's not just do 10,000 steps. Let's push them to pro improve their V2 max by 20%." Like, and see what that does to their aging clocks. Right. >> Yes. Now, we know, you know, I mean, the um this study didn't have a control arm. We should mention that. you know so but it um I certainly was impressed by that and um it's hard to argue against exercise you know so >> yeah I mean there's so many studies showing it improves outcomes right cancer mortality cardiovascular mortality all cause mortality it improves brain aging Alzheimer's disease risk is lowered everything like all these age related diseases frailty you know you're you're stronger you're more capable you're healthier your heart's working better your lungs are working better it's improving organ function. So, we know it's good for aging for sure. And so, it's nice to see that. Um, >> I mean, there might be a real threshold to to 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, definitely. >> You know, it's >> I >> hopefully there'll be more studies now as these epigenetic clocks become more available for researchers as tools. it's something they can add to other things that they're they're looking at, you know, because >> I want to see a 10-minute hit hit hit, you know, every day. Like h how is how is intensity affecting it? How is volume duration? I mean, there's so many things to look at. >> Yeah. You know, we need to develop exercise in a pill um for people who have who have lost mobility. What what do you um tell someone who is in a wheelchair? What do you tell to an 85year-old, you know? So we we need to develop interventions that still rejuvenate them and 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 um so you can get in like a hot tub or a hot sauna, your heart rate starts to elevate. you know, a lot of the same physiological mechanisms that are happening during moderate intensity exercise. There's been head-to-head comparisons with like getting on a stationary bike and, you know, doing about 100 watts. So, you're for 20 minutes and then comparing that to like a 20-minut sauna and you get a lot of the similar benefits. You get improvements in blood pressure, improvements in your resting heart rate, [snorts] you get, you know, again, you're sweating, your core body temperature is 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 I it's it seems like >> Yeah, I'm I'm joking. >> Yeah, you need something. [laughter] >> It seems like a moonshot. >> Yeah. Um >> um >> I want to briefly comment on body temperature. There has been a very elegant study in mice. So um it turns out if you stimulate certain neurons in the brain the uh pre-optic nerve I think you can actually lower the body temperature of a mouse and um there was a team in Harvard um Sinisa Veratin who did just that in the mice and he lowered the body temperature of the mice I want to say by 3° C or some order of magnitude >> and then he just looked at their methylation clocks, multiple organs, and guess what? Very strong effect. So the mice whose body temperature was lowered, they really aged substantially more slowly than a control mouse. You know, to me that was very interesting. >> Well, their metabolism is probably slowed inflammation because if you're going colder, vasoc constriction also happens, I would assume. >> Yes, >> that maybe. I mean so inflammation maybe >> it's it's interesting you know so I just want to mention so um the benefits of sauna and all of that are undisputed you know but I just want to mention that >> um maybe lowering your core body temperature by a degree or so could be beneficial who knows you know >> during hibernation animals that hibernate >> yeah same thing there have been a couple of studies that um suggest um that there's um a slowing of aging. Um we did such a study at UCLA. We looked at marmmets in um Colorado, I think. Um and um sure enough, during hibernation, the methylation clocks um didn't advance, you know. So, >> yeah. So interesting. >> It is. It's interesting. I think I think that things kind of just you know just I think people need to realize that just normal metabolism normal neuro you know your firing of you know your cognitive function and you know neurotransmitter firing away all this stuff is producing damage yes you know so if you're just in if you're just in this slow everything down um I say co cold I associate the cold with slowing it down um but at least in the hibernation state for sure everything slowed down >> and so that would kind of make sense that you're kind of just slowing the whole process, you know. >> Yeah, makes sense. >> So, um, 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, uh, Judith Carol, um, and she looked at sleep disturbances in the Women's Health Initiative, um, and other cohorts. And sure enough, um, people who report u severe sleep disruptions, these people exhibited increased epigenetic age. No surprise here. I mean, it was a um, observational study, you know. Um I know um 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. >> Yeah. I think I think we know that >> sleep deprivation chronic sleep deprivation increases inflammation changes your appetite people gain weight too. I mean so there's all the reasons why it would accelerate aging and and that would make sense. Um but yeah I I don't know that there's enough evidence looking at the specific stages of sleep and there's there's a lot to tease apart there and you know a lot more research to be done in that area. >> Yes. But another area that's very exciting has to do with our mental health and our our social relationships. >> Yes. >> Right. I mean that's >> this was the biggest surprise to me in the last 6 months perhaps. So I um need to tell you I'm not a social scientist. I don't study behavior. I really am not. you know I'm so anyways there was a um researcher at Harvard um Laura Kachinsky or I I butcher her last name but um she is um a very rigorous scientist and she wanted to evaluate whether what she calls uh I think a social cumulative advantage um which is a measure of um how connected you are in the community your social behavior your your friends, your community. Anyways, how does that affect biologic aging? And this is similar to the vitamin study we just said. We it's got to have an effect, right? I mean, so we all know loneliness is the big killer in the elderly at the level of smoking, right? You you don't want to be lonely and socially deprived. So anyways, um she did a very rigorous study, large sample size and she evaluated everything a researcher would evaluate. So what am I talking about? Um you want to evaluate cortisol levels, various um hormones that measure stress. You want to measure inflammatory markers, you know, IL6 and um various other readouts of inflammation. But fortunately she had enough research funding apparently to measure methylation because um I say that because um if I had been a researcher I would have focused on urine and blood for measuring hormones and inflammation and for methylation I would have I would have advised that don't even measure it because I just don't think you pick pick that up. And why do I say that? Why? Why would um your connectivity, your friends, your relationship with your spouse and your family um why would that translate to changes on the DNA me molecule in in blood, you know, think think about the mechanism. It's so far removed. But anyways, fortunately she did do this study and the great surprise to me was the methylation readout dwarfed the other readouts. If anything, the other readouts didn't work. So grim age again picked it up. People who have this uh who are blessed really by having wonderful family relations, community, just this social advantage, you know. Sure enough, their grim age was reduced. So I um it really taught me something. Yeah. >> Um do you do 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. [laughter] >> I know everyone always wants to know how many months, but I just go by P value. >> You know, [laughter] there's a lot of there's a lot of things here. I had Arthur Brooks on and you he talks about the science of happiness. He's amazing, by the way. If you >> don't follow him on X, you should. He's got really great, you know, science out there. But, um, and Richard Davidson's coming on the podcast. He's at Harvard and he's been involved with the Harvard Health Study looking at how social relationships and happiness really do correlate with longevity and why. >> Yes. >> But, you know, if you think about the flip side of that, the loneliness and not having those social relationships, there's also the possibility that the relationships were unhealthy and so people separated from that. You know, there's so there's stress probably that's involved in that equation. Yeah. Too. um loneliness itself has been shown to increase stress, you know, as as was picked up on this this study and others. But um there's a lot of I think nuance there with respect to, you know, if you're someone that has a lot of social relationships um 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 a stress or that's a stressor. >> Oh, I couldn't agree more. If you're in a toxic relationship, get out. Of course, you know, don't tolerate abuse. I mean, just uh 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 that people who are terribly stressed and depressed and don't sleep well that they don't age too fast. You know, >> have you seen that study? [laughter] So I'm always happy when uh a sleep study shows only a weak effect, you know, and so [laughter] because I'm rooting for these people, you know, but um yeah um I'm I'm not sure. Um let me um say something about the elderly. Again, loneliness is the big killer in old age. Um and unfortunately geriatric patients are often isolated. you know, many of their friends have died and um what to do about it. Um and there have been very nice studies in Japan, of course, where they deploy various robots, you know, to entertain people. And um >> the robots are coming. the robots are coming, the companions, you know, and um 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, um and then upcoming robotics will give us companions at least to fill this urgent need to engage a geriat geriatric patient. I I just think it's better if they interact with something as opposed to just sitting in a chair, you know. >> Yeah. Ideally, their kids would come visit them, but I guess, you know, that's not always the case. It's >> just not realistic, you know. We many of these um jobs um um that deal with geriatric patients are underpaid. There's a shortage, you know. So, we need to think of creative ways of addressing really this need, you know. Um Yeah. 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 um 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 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 need to focus on quitting smoking. Some people are not sleeping and they need to sleep. Some people are not exercising and they need to exercise, right? 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 one 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 what their biological age is and do they have room for improvement and can they start to improve things and then see that improvement. What 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 and do a couple of tests to make sure you're getting the same age at baseline to make sure it's a reliable test at first? And and is something is it something that you think people can use? Let's say they find a reliable test. They establish that they got the same close to the same age a couple of times. Then can they perhaps start doing the cycling for 6 months and improving their V2 max? And then also in addition to measuring their either they measure their V2 max or they measure an estimation of that which is probably a lot more accessible to people. They can go out and do a 12minute run test on a flat track and do the equation get an estimation. It's kind of what your Apple Watch does and a lot of wearable devices >> but also add this DNA grimage and other perhaps you know test of these epigenetic aging clocks in there. >> Yeah. Um well um I would say several things. First of all, unfortunately, these tests are expensive. They cost several hundred dollar. 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 um longevity doctors um always tell me that an epigenetic clock measure um leads to better adherence because I you know I go to conferences and then uh longevity doctors approach me and they thank me for developing epigenetic clocks and I ask them well what are they good for for in your practice you know and that's what they say is number one uh use case that people who measure it they are better motivated to stick to various regimens you know um um it's important to again highlight the costs because um companies are trying to develop cheaper readouts um which I very much applaud um I I just want a $50 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 know but I mention it because um companies will work on that and um what it then leads to is a different clock. So um when you go out there and you look at different providers they may offer clocks that have been less characterized um in the literature. I'm not saying these clocks are worse in any way. It's just there's not that the the same level of literature. We discussed earlier today there are these five clocks that everyone uses um why they all use a particular particular technology the so-called illuminina array and um also do need and pace everyone uses that technology and therefore um we can leverage legacy data that have been collected over the last 10 years you know to see well what is the effect of eating vegetables or exercise whereas if you lower the cost you don't have these legacy data so less characterized you know >> where should someone if someone wants to get one of these tests done perhaps they have the money and they can afford it and they want the motivation because I absolutely agree that data does motivate you um what what should they look for in terms of the they want to make sure it's one of those tests that use the aluminina array they want to make sure it's the reliable does it have to say like DNA grim age does it have to say pheno age uh the duadin and paste like how does someone navigate [clears throat] that world and try to find the most reliable test to use. Yeah, I want to tell you that overall my um um um reading of the community is that there are several good providers of tests really you know because the beauty of this illuminina array is that it follows a very standardized protocol you know and um uh many years of research went into how to pre-process the data how to optimize the signal versus technical noise you know that has been standardized. So I I think um as long as you go to a lab that has experience with generating these data, you're in really good shape, you know. >> Yeah. >> And and why would people not want to go out and use the Horvath epigenetic agent clock for their biological age? [laughter] >> No. Um you know, when you use an illuminina array, they they give you the Horvath clock. They give you they give you they will give you a hundred readouts. If anything you may get traumatized by what they give you. Remember I started discussing various protein markers CRP or um famous markers like plasminogen activator inhibitor one or anyways various famous proteins also get estimated with methylation you know um and maybe if I um want to mention an very important innovation in the last year really people use methylation to estimate the ages of different organs you know so it's a heart measure but they will say your kidney is older or your lung you know so that's where the field is at developing um organ specific uh methylation markers and >> and those are consumer consumer available as well >> that's already available to the consumer you know so you may end up with a report 50 pages 100 pages you may be overwhelmed by it you know um but um you don't need to obsess too much about um who does the analysis because as long as you have access to the data you could then apply these latest tools that are um being developed to analyze it. You know >> how would you do that? >> You know there are web pages you upload the data to a web page and it outputs the results. >> Like what web page? >> Yeah. Um I started a um nonprofit foundation. It's called Epigenetic Clock Foundation. I know they have a calculator where people upload data and they get an output but um I just want to emphasize there are many other um outlets you know so you can do some Google searches on who offers that. Yeah. >> Well I've I've kind of not >> I think based on our last conversation and my skepticism on you know using these clocks at the on the individual level and then trusting the consu what's consumer available. I haven't really experimented with them since it's been years. And so now I we were talking a couple of weeks ago and I was going to I'm going to do some experiments, but we didn't have enough time two weeks to to do all this and come on the podcast and talk about it. But I'm now interested because of all the progress that's been done in the field and in including the consumer available tests that are out there um in you know seeing seeing seeing what I get from my my data um and see what room for improvement I have and whether or not I it does get picked up because again I'm already healthy and I do take a lot of supplements already. So >> yes, >> I want to briefly mention the most obvious medical use case perhaps. It's really finding people who age faster >> um and then thinking about what to do about it. And we talked about various interventions. The problem with you and me is we probably are already optimized, you know. Um let's um um I would be surprised if you learn anything new you know um but maybe you start a completely different regimen and then then it would be interesting how does it affect your methylation readouts you know >> right and then probably presumably don't want to measure it when you're sick or >> yeah maybe um let's talk a little bit about variability because they have also been major insights that surprised me um I'll start maybe with a background. So um we talked about these principal componentbased versions of clocks such as PC grim age that was used in the cosmos multivitamin study and anyway these are very uh reproducible and um I to give you a number let's say you measured that marker two days apart you you you um measure PC grimage on Monday and then another measure on Wednesday and nothing has happened. I would expect a technical variation of maybe four or five months perhaps and or two months. It's a few months, you know, and um so this is just technical variance, you know, but um and and um um but um um other clocks um um do need and pace is slightly less robust but also very high technical reproducibility, you know. Um 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 Horvath pant tissue clock you may get very discrepant results because um they measure different aspects of biology. The Horvath pantissue clock is very good for stem cell biology um hematopoetic stem cells precursors of leukemia that type of biology just not good for mortality risk you know. Yeah, I think that raises another question in my mind, especially for people and consumers that are interested in maybe measuring some some of these clocks and seeing where they'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. So, are we talking about like if you're wanting to look at the douadan pace and the the pace of your aging um versus your DNA grimage, right? I mean, what is Maybe you kind of need both almost or >> absolutely I I would look at both you know I really would it's a bit like the example of a biochemical test in when you go to a doctor you know do you focus on hemoglobin A1C do you focus on cyatin C or um give me all you know let me look at it because they do give you different lenses at the changes in the methylone >> but you would you would predict and this isn't some This is something that again with some of these trials we're seeing the do a dindenon pace is picked up but then the grimage is not or vice versa and it's the question then becomes how these clocks were I don't know trained and >> yes >> developed and what they're more sensitive to and that's another thing so if you are someone that loses a lot of weight then you would you know both would pick it pick it up but presumably the one that's trained more on BMI would be more sensitive. Yes, remember the exercise study um um that we discussed four and a half hours of bicycling grimage was better than Dunid and Pace you know and so we >> inflammation 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 um AI machine learning models and um 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 tell you tell the regulator what is the primary readout you can tell them I look at 10 clocks you know so and and the very fortunate situation is that um um there's a biomarker consortium biomarker of aging consortium that really rigorously evaluates all of these clocks um and also substantial um research funding goes into that field there was an announcement by ARPA our age to study interventions but also to develop then um biomarkers for tracking longevity interventions you know and so I'm very hopeful actually that um the science will advance that next time you and I talk you know I can tell you this clock is the primary readout you know >> how do you think AI might change >> you know these clocks and development and the you know progress in them as well like are are you hopeful that using AI technology will help you make them better? >> Yes, absolutely. And maybe to give you some perspective, so Akalu in the lab published Grimage 2019, way before Chad GPT, before anything. And now it's 2026 and Grimage still seems to be the best mortality predictor. To me that's deeply frustrating because I want to see um um step changes in these biomarkers and I'm sure it can be achieved. Now the good news is people have already published um new clocks based on AI. You know they do use large language models. Um I um one person um um Lucas um um published what he called Grimage version three but there are no new clock systems age then there's OMIC 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 you know but I fingers crossed you know that any of these newer clocks are way better than grim age. Why? Because we need even better clocks for clinical trials. >> Yeah. >> Mhm. 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 and it's just this this concept that in in that goes back to the Yamanaka factors and basically the the birth of these induced potent stem cells right I mean Yam Chinya Yamanaka won the Nobel Prize in was it 2006 >> for discovering you could add four transcription factor proteins. These, for people listening, are a type of protein that can, you know, change the way several different genes are expressed, >> activated, deactivated, >> and he could add them to any cell, old cell, a skin cell from an 80-year-old, and revert that cell to a to a, you know, pur potent stem cell state, which is so cool. >> Yes. >> And fascinating. Yes. 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 the and we I think we talked a little bit about this in our last conversation which is you know what happens to the epiggenome 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 epiggenome changes right? >> For sure. you know so um back in 2013 I published the pan tissue clock figure five in that paper showed yamanaka factors reversed the age to a prenatal state so so you take a skin cell from a 50 year old and um the epigenetic age of an induced puripotent stem cells is a negative number meaning prenatal you know and of course so many people have worked on the idea then to apply these um Yamanaka factors briefly um and briefly interrupted reprogramming. There are many names in that field. Juan Carlos Belmont um Manuel Serrano but so many more who have worked on David Sinclair famously who who now um has a clinical trial for optic nerve regeneration based on that idea. Yeah, but um the idea being so apply these factors or a subset of these factors to rejuvenate organs and why inter >> rejuvenate but keep their their identity, right? They're not going to become a stem cell. >> Exactly. Because you don't ever want that skin cell forgets that it's a skin cell or a liver cell that it's a liver cell. And why is that dangerous to cancer? That's a um great danger. And um there have have been substantial um developments. So on the one hand I mentioned the study from David Sinclair where he now administers um adeno associated virus and AAV to the eye of people who um really need to regrow optic nerve or um and um the the study apparently will start this year 2026. So the the longevity field is waited waiting with a baited breath. Will that succeed? It would be a triumph for the whole field. [sighs] There have been extensive characterizations in mice. So which kind of organs benefit if you target them um and also in vitro. So we understand quite a lot but um what companies struggle with is where exactly do you deploy it for what kind of condition always keeping in mind um to ensure safety. >> Yeah. And there's questions in my mind that are even more mechanistic you know just because that interests me. Yes. which is, you know, if you are if you're taking an old cell that has these hallmarks of aging, there's like 12 of them now, right? You're talking about mitochondrial dysfunction. You know, inflammation is now even a hallmark. It used to be just this amplifier that still is an amplifier, but you know, you have your proteostasis isn't working right. So, it's um your proteins are fold not folding properly and they're also being not degraded properly. You've got DNA damage, nuclear damage, genomic instability, all these things that are that happen with age in older cells. And if you're going to change if you're basically just going to change the way the gene expression pattern is in the epiggenome, so to speak. >> Yes. >> Like how does that 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. Um the obvious damage is of course um various somatic mutations in the DNA if um you just don't touch it. Um the impressive part is how many hallmarks do get reset you know um I seem to remember one aspect that wasn't restored was tumier length so that wasn't um >> and also um even when it comes to the epiggenome c there are vestigages that don't seem to be touched by that you know so certain cytoines that >> do not get completely reversed you know so Um, >> it's so interesting. Do Do mitochondria get healthier? >> Yes. Mhm. So, mitochondria >> oxidative. >> What about mitochondrial DNA? >> Yeah. Uh, sorry, no, I I forgot. Yeah. >> So, mitochondria get healthier. Yes. >> Um, stem cells stem cells get >> Yes. >> rejuvenated or what do you what do they just start working better? I mean what >> um I want to um draw an attention because most of our conversation was about epigenetic clocks and now we talk about other readers. >> Yes. >> Um it's important to distinguish because >> um methylation clocks do detect a benefit of interrupted reprogramming in certain organs but not all. I just want to alert >> which organs do they not or which do they do do detect? You know, I remember um I'm trying to think of old publications, but I remember in skin there was a strong effect. I want to say um also muscle, you know, >> it's just not all organs. Um um and now I'm talking about interrupted reprogramming because as we said if you go all the way you will find an effect you know but I um I mention it because um um when it comes to that um intervention you really want to measure many readouts that we discussed you know so um above 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 the liver functioning, you know, or kidney, you know, that um just show functional restoration on a molecular level. Um there have been very detailed functions of gene transcription rever um that indicate that the gene expression reverses reverts back to a more youthful profile. But there's a problem with that statement that many people may not appreciate which is um it's actually very difficult to build clocks based on gene expression. Um so what does it mean that gene expression is rejuvenated and the field has struggled with that for many many years you know but um but I can mention so people look at so-called um mezenymal markers so um um some of you may have heard epithelial messenymal transition so um change their phenotype as we age in part due to inflammatory signals. So the an epithelial cell forgets that it's an epithelial cells. It thinks it's um meenyal cell. Um but anyway, so so that's a readout inflammatory markers. Um um um we mentioned oxidative phosphorilation. So various readouts that convince a researcher okay the cell seems to be younger. Mhm. >> If we talk about the extreme case of of making an induced pipotent stem cell, do the somatic mutations persist in that as well? >> Yes. >> That's disappointing >> because you cannot touch it, right? It's a DNA is changed. >> Yeah. I mean, it's just >> you you we got to solve that problem, you No, but you need to ask a different question perhaps that is has a hopeful answer perhaps >> which is do somatic mutations actually matter >> that's a and um now um to be clear um 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? And >> doesn't it depend where the mutations are? Of course, and you already asked the right question because most of these zomatic mutations have zero consequence. That's 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. But same with somatic mutations you know and um when you ask aging researchers how important are somatic mutations for true blue aging you know you will get different answers. So some people will say it's hugely important and then there are other people will say it's negligible. It um the field is really split on that question. >> Yeah. I mean if you're getting somatic mutations in 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 of the proteins right things aren't going to work properly but again if if is the key word if you get them in those regions so you would think the more I mean obviously if you get more and more of these mutations then the chance of you having it in a part that matters goes up right like >> for Sure. I mean, we just to be clear, we don't want it. The question is uh how bad are they? Let me um 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 use crisper to sort of I mean, if you if there was a way you could every time you got a mutation just use crisper to change it. >> Yeah. And also coming back to DNA repair, right? So you you let's say you have ways to improve DNA repair. >> Um I'm asking the question because um um my answer is the following. I think if you stopped all sorts of um if you completely stopped somatic mutations, I think you would still age. Um I don't have uh definitive proof, but I that's where I'm at. You know, for me, um, a lot of aging. >> But would you age slower? >> Yeah, no question. It has a benefit. You would still age, you know, >> still age for sure. It's not No, >> but you would because, um, aging happens at all levels. We mentioned the epiggenome today a lot, >> but also the transcriptto and the proteome. Yeah. Right. proteins aggregate and that protein aggregation may have nothing to do with zomatic mutations or even methylation you know and so I mean damage accumulation happens at so many levels and the debate is in certain ways um which um how much do we gain if we clean up damage at a certain level you know >> all the all the damage >> so there's 12 hallmarks right that's why I mean obviously genome stability is just one right >> so if you take care of that, you're still got 11 more to take care of. You're still going to be aging. But so if you were to clean up all 12, >> I mean, there's no doubt you have a benefit. >> Then what happens? I mean, >> but you know, I liked our earlier discussion about um let's say organ transplantation because I'm looking for a miracle intervention. I'm making something up. >> Okay. >> Imagine somebody has a pill that really prevents sarcopenia. you keep your muscle strength. Could it be that this benefits so many organs and suddenly we increase health span by 5 years, you know, or we have another pill um that really um preserves your kidney function, you know, how much do you gain? So, I I like uh these silver bullet dreams. You have one intervention, you really improve one organ and it have has massive benefit. We know that. We know resistance training absolutely helps you not only maintain but increase your muscle mass and that's hugely important for life expectancy and quality of life. So I mean I would imagine if you just improved muscle function with age that you would have an effect on >> I'm I'm with you on that you know. >> Yeah. >> But let's now again talk about the 85y old. So you let's say we have such a pill. give them this intervention and um you really even restore muscle functioning, will they suddenly live 5 years >> longer? >> I hope they will, but I'm I'm just saying that these are the interventions. >> But what about their what about their heart their cardiovascular disease risk? >> I mean, if if if it's true that people's organs age at different rates and there is individual variation there. So you know maybe maybe my heart is aging faster than yours. Maybe you are more susceptible to your brain aging more. I don't know like if that is true. I mean >> it is true. >> It is right. I mean that's >> we know that even from methylation clocks. Yeah. >> That their or that that even even within a person and you know obviously their diet and their lifestyle everything's like it should be the same affecting the same organs the same but it doesn't right. Yes. either it doesn't or there's other things that are that are happening um that we don't quite understand. But um where was I going with this? Yeah, that basically if our organs are a aging at different rates then you know obviously the the muscle would only affect the people that are going to die from their falls or whatever. You know I I I don't know. Yes. >> Um I think I think it's the uh it's an interesting it's an interesting question in terms of like what organs are aging faster in you and you know there's biomarkers that can help you understand that risk but the aging clocks that is something that people can now go and test right >> yes that's where the field is at so um and now I'm talking about the biomarker field in general so um people have developed um protein markers of various organ orans which is the obvious thing you know organs secrete various proteins or measure them you know >> the exciting aspect is that um the same has happened at the level of um methylation so people have methylation readouts of different organs I'm not saying they are optimized there's room for improvement perhaps to be seen but um that's how I envision really um medicine 2.0 And O preventative medicine, you 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 I even, >> you know, I've done my my gene 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 you when you get the raw data back and sort of look at them, you'll have genes that say, "Oh, you're predisposed to coronary heart disease or you know, so they're already sort of targeting organs or neurogenerative disease like Alzheimer's disease." So we know there are even genes that are involved in predisposing you to certain diseases. >> True. >> 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. You know, >> I want to briefly comment on that. Um because I used to be an um a human geneticist actually at some point I studied genetics. Um and you're entirely correct. Of course there are these snips 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 are famous association APOE4 for Alzheimer's. there's strong association but I just want you to know that if you have a a genetic risk for a certain cardiovascular disease these effects are absolutely minute and they are dwarfed by you just walking your 10,000 steps okay I mean it's like I um >> however interestingly methylation is a far stronger signal than um snips so epigenetics um order of magnitude more informative than genetics, you know. >> So, looking at the epigenetic organ specific epigenetic clocks even. >> Yes. It's it's just you can't compare it, you know. I'm a health nut. I I spent uh many hundreds of dollars on various tests. Many tests have no use. I just But I I haven't spent money on a G-W was test. Um um I mean I did for ancestry. I just want you to know that it doesn't inform me personally, you know. So I I just think we have better readouts and we mentioned proteomics clocks you know so and and above all just your regular biochemist biochemical markers you know um just go with what the doctor orders there's a reason why your medical doctor doesn't order a genetic test for you know it's less informative >> right yes >> you're you're not doomed if you have a bad prognosis based on genetics you know just >> exactly absolutely not I mean there's a lot of people that have APOE4 that do not have Alzheimer's disease and there's a lot of people with Alzheimer's disease that do not have an ApoE4 alil. So >> true. >> It's not it's not it's not a >> hopeful message. Yeah. >> Yeah. Diet and lifestyle matter and that's kind of the point of the conversation that we had. We're talking about these epigenetic clocks as a, you know, biioarker readout that is a little bit, you know, more comprehensive than just getting a C reactive protein or HBA1C or even, you know, looking at your your lipid levels because it can actually look at your biological age, right? And that's so cool. So, um, thank you so much for for coming on. Is there anything else that we need to discuss that we didn't >> get to um so much? >> No, I think we covered everything. That was a real pleasure. Yeah. >> Have you done your your have you done any of these biological tests on yourself? You >> Yes, for sure. Um >> do you like the results? >> Yeah, I do. You know, so um I remember a pheno age result a couple of maybe half a year ago was 13 years younger if I remember that. I like that. So, I'm actually doing well on various um uh biologic tests. >> How old are you? >> I'm 58 right now. >> Oh, you're 58. Wow, you look great. >> I don't I look horrible. [laughter] >> Thank you. But I look horrible. >> Have you done the organ specific one? >> Uh not yet, you know. So, yeah. >> Okay. >> I um again, I'm trying all sorts of health behaviors. I actually don't need any readouts, you know, for motivation. I'm a bit of a health nut. So I don't >> So what's your what's your what's your routine? What do you eat? What like what what's your health nut routine? Your supplements? >> Um I I go with validated interventions. We we talk about omega-3, multivitamin, creatin I take a lot. I By the way, I love your podcast. I learn a lot from you. >> It's um Yeah, I started multivitamin after you started talking about it. [laughter] that motivated me. Um, from you, I learned the importance of, uh, having a cooling mattress for sleeping. So, I implemented that advice from you. >> Are you sleeping better? Do you sleep better? >> I think so. Yeah. But, um, by the way, I love placebo effects. They always work. Nothing wrong with that, you know. >> I don't like no SIBO effects, but I love placebo effects. >> That's right. Yeah. So I um the reason why I mentioned it I I do I think it worked you know but uh I don't have hard data on that you know. >> Do you take vitamin D? >> Yes >> vitamin D. And you eat a lot of vegetables exercise where how does that come in? >> Yeah I do every day 30 minutes you know not too much you know >> I follow routines you know. >> Yeah. >> I mean exercise needs to be a routine. It needs to be part of your personal hygiene. >> Yes. I also take medications again against high glucose. I'm I'm actually a pre-diabetic because of my decades of eating hundreds of grams of chocolate each day. So I I um but yeah, so I take something called a carbos, you know, to um but um also I take >> Does that have any effect on aging? A carbos has >> I have no idea, you know. So yeah, >> I I just um >> Yeah. So anyways, um I take statins, I take isettoype, you know, so >> various interventions where there's very credible evidence, you know, that they move the needle. I'm always impressed by people who swallow 120 pills, but it's not me. You know, I take a >> I take a lot, but not 120. Do you take ubiquininal? If you're taking a statin, you might want to >> think about that because it statins target the melonate pathway which is HMG COA important for cholesterol synthesis. That's why it's most widely prescribed drug for lowering LDL cholesterol, but also um that pathway is important for making CoQ10 in your mitochondria. Um and so that's something to consider as well. So taking CoQ10, I say ubiquininal, it's the reduced form ubiquinone also does the does the trick, but uh you might want to look into that as well. >> Thanks. I know I would learn something from visiting you. Well do. >> Well, Steve, thank you so much for all your contributions to the aging field and the ones that you continue to make. >> Um people can look up your publications and many many many publications. Where else you you're on X? What's your what's your >> I have a handle prof um my Twitter account is all about epigenetic clocks and um and longevity interventions. Um um but yeah um I want to thank you. I think you um 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. I I really appreciate that. Um, is there anywhere else you want to direct people to besides your Twitter and your publications? >> Um, no. Um, stay young. Um, um, try not to be stressed too much, you know, and, um, yeah, enjoy life. >> Enjoy life. I think that's good. [clears throat] Try not to stress too much because at the end of the day, your deadline >> doesn't really matter, right? I need to tell you. So the hopeful message about stress is that short-term stress does not seem to affect epigenetic clocks, psychological stress. So I I always love that. >> Repeat it. Short term is that repeatedly or just >> like >> So there's some literature that really severe psychological stress, we're talking now childhood sexual abuse, perhaps even PTSD that affects your epigenetic age. But I always like it that um these short-term stresses don't seem to touch you. So which is a hopeful message for everyone who is terrible >> like being worried about a podcast. >> That's right. I I have never deadlines. >> Exactly. So I've never seen evidence that this has a strong effect, you know. >> Well, don't stress too hard. That's the That's the bottom line. Thank you so much for this conversation. It was a pleasure. Yeah.