The 7 Habits of People Who Age Slower: Dr. Steve Horvath (Transcript)

I think cardiorespiratory fitness and VO2 max, frailty — there are 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—

What Drives Aging at the Cellular Level?

DR. STEVE HORVATH: Yes. I mean, there is one key word that has to be mentioned in that context. It’s all about prevention. So what motivated my work was to understand aging in people who do everything right. For example, in you. Why do you age given that you and I really take care of ourselves and we try to optimize lifestyle, prevention, all of that? But something still changes deep inside of us, in our cells. And what is it? What drives aging?

And these methylation clocks that I’ve developed, they really track damage accumulation in one way or another, because that is something that just happens, and that drives then organ dysfunction many years and decades later. It’s almost unavoidable to age. And what I wanted to accomplish with these methylation clocks is to have a precise tool to allow researchers to actually identify novel interventions. How do we truly reverse the age — the ages of individual cells, of organs, and the whole organism?

DR. RHONDA PATRICK: You mentioned something that caught my attention. You said these methylation clocks or patterns are able to track the damage that occurs. And that’s, to me, always been a question. Is it tracking the damage that occurs, and/or if you’re changing these patterns, does that change the damage? So because you’re globally affecting the way genes are activated or not activated — gene expression, as we call it — then you would imagine: is it like a two-way street possibly, where you’re able to increase genes that we have that help take care of damage, repair, all these stress response genes better as well?

But I guess we’ll get into that. So I think one of the points of confusion I’ve heard repeatedly from my audience and just in general 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 different clocks that seem to be perhaps tracking different things, or have different strengths and weaknesses in what they’re tracking and what they’re sensitive to in the context of the aging process.

So maybe we can — can you walk us through some of these clocks and what their core strength is, like what they are tracking, and perhaps even what a common misconception is in terms of what they’re tracking?

Understanding the Different Epigenetic Clocks

DR. STEVE HORVATH: Yes. So maybe we start with the big picture. Aging is, of course, associated with the accumulation of damage on all levels — the proteomic level, metabolomic, intercellular communication — but also damage accumulated surrounding the DNA molecule, these chemical changes to the DNA. There is an accumulation of damage and that impairs then the cell function.

For example, certain cell identity genes need to be active in a liver cell, and different genes need to be active in a brain cell and so on. And so the damage impairs the function of cells, and then tissues, and then organs. And interestingly, methylation changes can be observed at really millions of locations on the DNA molecule. And many of these changes have actually no consequence.

And by the way, when I talk about changes on the DNA, I talk about gain of methylation at the wrong places, but also loss of methylation at the wrong places. So what is happening with aging is that the methylation landscape really flattens out. And conversely, in a young cell, you want to have really peaks of methylation at regions that need to be shut down, and conversely low methylation at regions that need to be accessible on the DNA.

So anyways, these methylation clocks typically look at hundreds of locations on the DNA that are carefully chosen. However, one can really look at tens of millions of locations, and people have developed different clocks based on tracking changes at different locations. And one of the great misconceptions is to expect that all clocks agree with each other, that all clocks give you this one readout. That wouldn’t be reasonable, right? Because you have millions of locations.

So methylation clocks really capture different properties of aging. Some clocks are very good at tracking inflammation. Other clocks are very good at metabolic syndrome. Then the so-called — these are now second-generation clocks — they really relate to inflammation and various stressors, smoking. But then the earlier generation of clocks, so-called first-generation clocks, had a totally different goal. They just want to measure calendar age.

And so the misconception is that people get disappointed that two different clocks lead to slightly different readouts. But the metaphor I want to use is: think of the world of proteomics. If I told you protein 1 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.

DR. RHONDA PATRICK: Okay, yeah, that’s really good to kind of clear up. And 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.

DR. STEVE HORVATH: I think it would be overly simplistic.

DR. RHONDA PATRICK: Right.

DR. STEVE HORVATH: And most clocks were tailor-made for blood for the sake of convenience. But arguably, you would want to develop special clocks for the brain, for the liver, for the kidney — and the field is moving in that direction. So people are developing actually these single-cell clocks and organ-specific clocks.

PhenoAge, GrimAge, and Second-Generation Clocks

DR. RHONDA PATRICK: Oh, that’s cool. Yeah. So let’s talk about some of the main ones that are used. And so we have the one that was the original Horvath Epigenetic Aging Clock — first generation for chronological age. And then we kind of get into these other clocks which were first generation, and then they have second-generation versions as well. But so the DNA PhenoAge — does that clock lean more towards inflammatory and metabolic function than pure chronological age?

DR. STEVE HORVATH: Yeah, for sure. So the so-called PhenoAge clock was a giant step forward when it came to mortality risk prediction. This clock was very much constructed to track really biochemical markers and also changes in blood cell composition. These markers measure organ dysfunction one way or another. And the idea was to actually develop a methylation surrogate of these clinical parameters. And we should discuss the pros and cons of that idea.

But yes, so this clock was then an impressive mortality risk predictor for humans. However, it was then superseded by the GrimAge clock, which was named after the Grim Reaper. It was published also many years ago, in 2019, but it continues to be very impressive for mortality risk. And from a mathematical perspective, these clocks were constructed in very different ways, but overall, they very often agree. When you have an intervention that appears to slow GrimAge progression, it also slows PhenoAge progression. So often there is actually agreement to some extent, which is impressive given that these clocks were constructed in very different ways.

DR. RHONDA PATRICK: Can you talk a little bit about the different ways they were constructed? So with the GrimAge, I think it was my understanding that smoking is somehow embedded in that calculation — or whatever you want to call it.

DR. STEVE HORVATH: Yeah.

DR. RHONDA PATRICK: Stress-related proteins, inflammation. But the PhenoAge also has some inflammation as well in there.

The GrimAge Clock: Methylation as a Mortality Predictor

DR. STEVE HORVATH: Maybe I’ll start with a much simpler example. C-reactive protein is a marker of chronic inflammation. It’s a very important biochemical readout. And the doctor will measure it when you have certain conditions. But interestingly, you can actually estimate C-reactive protein levels based on methylation. And I should say the estimate is not very tight. For the experts, they will say correlation may be 0.3 or lower, so it’s not a tight correlation. But I want to mention it as an example for this idea of using methylation to estimate a famous marker.

But now, imagine you actually get these two readouts from the lab. Let’s say you go to a longevity clinic, they can easily measure both. But which one is more informative for you? Now, a medical doctor will always focus on the plasma-based readout. They are trained to look at thresholds and then they diagnose maybe an acute infection. But the surprising finding is that the methylation estimate is actually a better predictor of your mortality risk, far better predictor of your mortality risk than the plasma measure. And that’s one famous example that has been validated.

I give you now another example, smoking. So you can ask someone, “How many cigarettes do you smoke per week? For how many years have you smoked?” And this is known as the smoking pack-year estimate of smoking exposure. Interestingly, you can use methylation to estimate smoking exposure as well. And you can ask the same question, “Well, which measure is more predictive of how long you end up living? Is it the self-reported measure or the blood measure?” And again, we know the answer from many studies by now. Again, the methylation estimator is actually superior to self-reported.

So I mention it because that then gives rise to an idea. Well, why don’t I build a clock that uses these methylation estimators of C-reactive protein, of many other famous proteins, and also the methylation estimate of smoking history? Why don’t I use these methylation biomarkers in a linear combination? I combine it in an optimal way to build a mortality risk predictor. And this idea is underlying the GrimAge Clock, the Grim Reaper Clock. And it just worked beautifully in many validation studies. We now know this idea worked. But that’s really the idea of the GrimAge Clock.

DR. RHONDA PATRICK: And this was developed in your lab, the GrimAge Clock?

DR. STEVE HORVATH: Yes, by Ake Luu in my lab. PhenoAge was developed by Morgan Levine when she was a postdoc in my lab.

DR. RHONDA PATRICK: Morgan was on our podcast a few years back as well.

DR. STEVE HORVATH: Yes.

Why Methylation Predicts Mortality

DR. RHONDA PATRICK: So why should methylation patterns be able to predict your mortality? And how accurate is that? What are we talking about?

DR. STEVE HORVATH: The first question, why does methylation relate to mortality? It is a good question because when I published the very first clocks, I remember I was extremely nervous about what I had published. I thought maybe these clocks have no use, maybe they just measure your calendar age. And I was so relieved that basically 6 weeks after I had published it, somebody came to me at UCLA and said, “We just applied your clock and it predicts mortality.”

But by now we know that these methylation clocks very much predict mortality risk to the point that certain startups pursue the idea of using methylation clocks for pricing life insurance policies or financial products. And of course, methylation clocks are used in serious randomized controlled trials, so the evidence is very strong and without any debate.

But why is that? It could be that these clocks really track long-term exposures of a stressor. For example, smoking again — maybe if you just smoke a bit, it doesn’t really show up in other biomarkers. But if you have really this prolonged stressor, it really alters the epigenome. Why? Because the epigenome creates a memory, really. Think of the epigenome as a memory of stressors and it primes the cell to respond. And you can imagine if the cell senses this onslaught of various stressors, it tries to remodel its regulatory system so that it prepares for future stress. That’s maybe one way to conceptualize it.

Epigenetic Memory and Transgenerational Effects

DR. RHONDA PATRICK: And I think this concept of the stressor affecting the epigenome — we even know it can affect the epigenome in gonads, right, in sperm and eggs. And that’s why we have those studies out of Sweden where they went through these periods of starvation, like famine, and then there was feasting depending on what food was available at the time. And I know that some researchers had looked at how the epigenome had changed, and that also seemed to affect life expectancy of the offspring as well. And then smoking.

DR. STEVE HORVATH: 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 mean.

DR. RHONDA PATRICK: Yes, it’s in the Netherlands.

DR. STEVE HORVATH: Yeah, that’s right. Very exciting work, that maybe a couple of years of starvation could already change the gonad methylome and that could then lead to changes in the offspring. So I think it’s very exciting, but I need to tell you I haven’t worked in that space.

DR. RHONDA PATRICK: Well, it’s been years since I’ve looked at those studies, but I think they were like prepubescent boys too, where it’s like if they have gone through these periods of hunger where they were calorically restricted, it obviously changed their gonads, epigenome, and their sperm in a way that was more permanent. And so they had offspring that were more resilient against type 2 diabetes and other age-related diseases as well. 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 also goes deeper, right? And affects the gonads, if I’m correct.

DR. STEVE HORVATH: I need to tell you regarding these findings, I’m usually interested and excited about them, but I want to emphasize to your audience, they are controversial, fundamentally. Very smart people disagree with these findings. Personally, I’m completely neutral. But I just want you to know that.

DR. RHONDA PATRICK: They disagree that the epigenome changes?

DR. STEVE HORVATH: No, just to be very precise — that an exposure from your parents, for example, has an effect on you. Again, brilliant people publish on it, and these studies go through rigorous peer review. But I just want you to be aware that there are strong counterarguments. It remains to be seen, I want to say, because I want to think that if your parents or grandparents went through severe stresses, I want to think that you still are born with a clean slate, so that you are in certain ways not predisposed or doomed in one way or another.

DR. RHONDA PATRICK: Well, sure, that would be a nice thing to think.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: But on the bright side of things, even if there is — and I’ve seen evidence that convinced me that there’s an epigenetic change that does happen. And in sperm DNA, for example, like if you have an obese male and then they lose weight, you can look at their sperm DNA and it changes from being obese to lean.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: And epigenetic changes, gene expression changes are happening. But even if it’s on the bad side, 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, even if you don’t have the cleanest slate.

DR. STEVE HORVATH: Yes. What I want to tell you briefly about sperm — yes, there are methylation changes and also changes with aging. So the sperm methylome of a 50-year-old is different from that of a 20-year-old. However, the changes that occur are at completely different locations from the changes that we use in any of our other clocks.

Another way to say it is if I take GrimAge or PhenoAge or any of my clocks and apply it to sperm, it completely fails. So, for example, what is known as the Horvath pan-tissue clock — you apply it to sperm, you get one number, 37 or so. But everybody has the same number in essence, uninformative. It’s just very different locations. The same statement also holds, by the way, for the placenta. So people have developed clocks applied to placenta to estimate the age of the newborn, meaning gestational age, or also various stressors from the mother. But again, these changes are very different from what we observe in blood or adult tissue.

DR. RHONDA PATRICK: Have there been clocks for sperm?

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: That have been developed that are more precise?

DR. STEVE HORVATH: Yes.

The DunedinPACE Clock: Measuring the Speed of Aging

DR. RHONDA PATRICK: I have a question about GrimAge, but it sort of leads us into the next clock that I want to have you discuss, which is the DunedinPACE. Is that right?

DR. STEVE HORVATH: I think it’s called DunedinPACE.

DR. RHONDA PATRICK: DunedinPACE. That’s right. So the question I have is, with the DNA GrimAge, we’re talking about this methylation pattern being able to predict mortality — pretty accurately, mortality risk. And it’s able to measure this accumulation of damage that’s changed the epigenome in a way that’s obviously quantifiable. What if you’re 45 years old, you get your DNA GrimAge test done, it gives you your mortality because you’ve had all this lifetime exposure up until the age of 45 of, let’s say, air pollution, maybe you smoked a little bit, whatever, alcohol, poor diet, chronic stress, all those sorts of things. But you change your lifestyle and it gets better. Does that GrimAge change?

DR. STEVE HORVATH: If you had asked me that question 2 years ago, I would have hummed and hawed. I was always very cautious about that — in certain ways, how reversible are these changes. But the science has really advanced and now I’m confident in saying that you can reverse GrimAge to some extent. The keyword is “to some extent” because these changes appear to be very minor. We can talk about it later, but there have been very rigorous randomized controlled trials with supplements and medication. There’s a hopeful message. You can reverse it.

DR. RHONDA PATRICK: So that’s what we’re going to get into, folks. That’s going to be the exciting stuff. So this other clock that’s able to measure the pace of aging — can you talk a little bit about the Dunedin?

DR. STEVE HORVATH: Yeah. So there’s another widely used clock which is known as the DunedinPACE Clock. It was developed by Dr. Moffitt and Dan Belsky, and it was constructed in a very different logic from other clocks. And the metaphor is it’s supposed to be an odometer. It’s supposed to measure the speed of aging, or what they call the pace of aging, whereas previous clocks really measured in certain ways the accumulation of damage.

So the idea is very compelling. Maybe I’ll just review how it was constructed. So the team really looked at rate of change in established physiologic markers and biochemical markers, including also importantly — and we should discuss that — change in body mass index. But also measures of waist-to-hip ratio, measures of glucose impairment, markers of inflammation, many readouts.

And the study leveraged a unique epidemiologic cohort study in New Zealand, in the city of Dunedin. It’s a study where they tracked middle-aged people and younger people for many years and assessed these readouts repeatedly. For the experts, it’s a longitudinal study. And by having these longitudinal data, multiple measurements per person, they could really estimate the pace, each person’s individual trajectory.

So far, so good. So you have these 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 the pace of aging based on these physiological measures? And I think that’s a very good idea. Why? Because people care about what’s my current pace of aging. It’s a good question — I’m not quite sure what people care about. Some people want to know where they stand right now.

DR. RHONDA PATRICK: Or how an intervention is affecting how they’re aging, perhaps.

DR. STEVE HORVATH: Exactly. Yes. Thank you. That’s a good point. So if you have an intervention, you want to see, does it really change the pace? Does it affect the odometer? And so, therefore, people use DunedinPACE along with all the other clocks that I mentioned when they study interventions. It’s by now part of the standard repertoire of clocks. When people publish a paper on longevity interventions, they hopefully report about 5 clocks, just in order to give the reader a chance to judge the evidence, because the very best intervention will touch on many clocks — that would be a robust rejuvenation of the methylome.

The Best Clocks for Measuring Longevity Interventions

DR. RHONDA PATRICK: 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 PhenoAge, GrimAge, perhaps GrimAge 2. Yes. And I see the Dunedin PACE, that those are at least 3 of the ones that are— they seem to be. And then there’s a few others that sometimes are in the mix. But those 3 stand out to me when I’m reading the literature, maybe because I know them the best. But those are the ones that stand out.

With this disagreement, and we kind of— you kind of touched on this already, if you’re looking at an intervention, and we’re going to get into those in a minute, and you see your DNA GrimAge doesn’t change, so your mortality risk is the same, or determining when you’re going to die is the same, and yet 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, if you’re changing your pace of aging, why are you not changing the GrimAge?” And then the question in my mind is, well, how long was the trial? 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 GrimAge, or what’s the standard deviation here that we’re even talking about with GrimAge, right?

DR. STEVE HORVATH: 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. Why? Because these clocks are correlated with each other. And just to throw out a number, correlation 0.5 after you regress out age, sex, and various variables. But there’s still a fairly good agreement. This is the typical glass half full, half empty. Is a correlation of 0.5 high or low? To me it’s reasonably high if you have a very strong rejuvenating intervention. Now, when it comes to— I need to tell you, I’m obsessed about the question which clock is best. And so I—

DR. RHONDA PATRICK: Best for what?

DR. STEVE HORVATH: For judging longevity interventions. Because when it comes to mortality risk prediction, we know the answer right now after several large studies. There was a study in Scotland, Generation Scotland, 18,000 people were evaluated and GrimAge was best. And then there was a study from Harvard, I want to say 30,000 people were evaluated, GrimAge was best. So we know which clock is best for mortality.

GrimAge as a Surrogate Endpoint

DR. RHONDA PATRICK: Can I pause you right there? I just want to make this point because usually when we have these studies, at least observational studies looking at diet, because you’ll never have a randomized controlled trial that’s going to last 30 years or 40 years. So if you’re looking at observational data and how different lifestyle and diet 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 number. And what you’re saying is that you can actually now, instead of having to just have observational data looking at that all-cause mortality, you can now have an intervention. We’re going to give people fish or whatever. We’re going to do this intervention for a period of time. And you can have the GrimAge, which is kind of like this surrogate all-cause mortality, but it’s actually a very good estimate of it. Am I thinking of it a little bit correctly?

DR. STEVE HORVATH: Yeah, you think of it correctly, and that’s certainly the ambition. But I want to be very precise using the language of the FDA because I think we should do that. So the dream of the longevity field is to develop what is known as a surrogate endpoint for a clinical trial. In other words, you have a study where you apply, let’s say, multivitamin for 2 years, and then you see a change in any clock. It could be a proteomic clock, it could be GrimAge, any other clock. And let’s say you see a reversal. Now, you would like to jump to the conclusion that this actually translates into a lower mortality risk.

So we would like to think that is the case, but from a regulatory perspective, that hasn’t been proven. And in general, the FDA evaluates biomarkers. Why? They want to give guidance to companies, to biotechs, where they say, “If you show us that your treatment reverses that biomarker, therefore we believe that it actually helps patients.” And I just need to tell you and the audience, the biomarker field has not yet developed any biomarker that is credible to the FDA when it comes to this ambition of being an official surrogate endpoint of a clinical trial.

Having said this, we just can’t wait for this regulatory approval yet. Why? There are urgent questions, right? People have exciting interventions, so we need to make assumptions. And for the longest time, I’ve been very cautious when it comes to this claim — do methylation clocks meet this high standard? And I’m coming around, just because I see increasing evidence that these changes track what I call validated interventions, 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 gives me confidence that the clock does what it’s supposed to do. So that’s where I’m at.

The Most Robust Interventions for Reversing Biological Age

DR. RHONDA PATRICK: What’s the most robust intervention — it doesn’t have to be — 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 reversing biologic age by some of these clocks, GrimAge, PhenoAge?

DR. STEVE HORVATH: Yeah, I will start with interventions that are in certain ways boring to you and me. Why boring? You and I, we are hopefully healthy people and we want to optimize our health. But I want to start with people who have a condition, to answer your question. HIV-positive people exhibit epigenetic age acceleration. It’s actually a pronounced pro-aging effect, maybe 5 to 7 years in blood. And sure enough, if they stick to their antiretroviral therapy, that will reverse their epigenetic age. And I mention it because—

DR. RHONDA PATRICK: But how much?

DR. STEVE HORVATH: Several years. To give you a number, 4 or 5 years.

DR. RHONDA PATRICK: 4 or 5 years? Does it happen pretty immediately after taking the drug?

DR. STEVE HORVATH: Yes. Probably several weeks or months. But there have been many studies all over the world that have shown it. So it’s very well established. And yeah, so that’s one application. I mention it, I trust it 100%, but many people are not HIV positive. So therefore I say do not take antiretroviral therapy, it’s just not— so the other intervention that has very strong evidence is anti-TNF-alpha therapy, really anti-inflammatory drugs for people who have autoimmune disease. Again, that just makes sense, but yes, and metformin. Metformin is an interesting intervention to many of us. The problem is— and I’m coming around to believing that metformin affects epigenetic age. There have been a couple of studies that suggest it, but I need to emphasize the effect is way weaker than the above.

So these are really medical interventions, and in general, as you can expect, a medical intervention has a much stronger effect than a supplement. When it comes to supplements, we do have some answers. Omega-3 has a beneficial effect. Apparently multivitamins have an effect. The problem is that these supplements have much weaker effects. Suddenly we talk about a couple of months of rejuvenation.

Hype vs. Reality: Can You Reverse Biological Age by 5 Years?

DR. RHONDA PATRICK: And we’re going to talk about those more in depth and what that means. But I want to kind of get into the controversies and hype because you’re talking about these really robust effects if someone has HIV, which is obviously devastating for your body. And then they take the antivirals and that really does have a pretty robust effect on obviously their life expectancy.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: Many different features of health as well as epigenetic aging. So that makes sense. But I’ve heard people out there talk about reversing their biological age by 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? How do you feel about that statement?

DR. STEVE HORVATH: Yes. So it’s a very good question. I think the first thing I would ask is, what was their BMI before they started, and many other clinical readouts. So if you start with a person who was obese, had inflammation, diabetes, many of these stressors in their lives, and they really changed everything — they take their GLP-1 receptor agonist, they suddenly go to the gym and they do everything right — then it would perhaps be possible. But there are many pitfalls and I can discuss them later, but I don’t think it’s not possible when you start with this baseline.

DR. RHONDA PATRICK: So you’re very unhealthy.

DR. STEVE HORVATH: You’re very unhealthy. And above all, you actually start with an epigenetic age measure, let’s say GrimAge, that shows you are 8 years older than you should be. You’re in this highest percentile of risk. So then maybe you can go back to the average.

However, now let’s talk about the opposite case — a biohacker, obsessed about healthy lifestyle, who says, “I changed my diet and now I reversed my age by 5 years.” I would have the hardest time believing it. And by the way, this is something we see over and over again with various rejuvenating interventions. They seem to work in people whose epigenetic age is already accelerated. But not in the people who are very healthy. So anyways, I would be very skeptical, but I’m open-minded. I’m strictly data-driven. So I would have a long conversation with that person.

Age Acceleration and the Role of Lifestyle

DR. RHONDA PATRICK: Yeah. Well, you make a really good point. And that is, people that are already accelerating their aging at a faster rate — so they have this age acceleration, right? Their GrimAge is already higher than it’s supposed to be, is that correct?

DR. STEVE HORVATH: Yes, higher.

DR. RHONDA PATRICK: Higher than it’s supposed to be. Their biological age or PhenoAge is higher, their pace of aging is higher. So they’re already age-accelerating for whatever reason — they’re sedentary, they’re obese, they smoke, or perhaps they have vitamin deficiencies. That’s another one I’ve seen, like vitamin D deficiency has been shown to be associated with age acceleration. And if you correct those problems by losing weight, by getting physically active, by quitting smoking, by eating healthy, by getting your micronutrients and filling the gaps so you’re not deficient, then you see a more robust effect.

And that is also a recurring theme that I’ve seen from reading the scientific literature, where it’s like, okay, if you already have enough vitamin D — and we’ll talk about this — if you’re already sufficient, taking a vitamin D supplement is not going to slow your aging. The thing you’re doing, you’re already doing it. You’re avoiding deficiency, and that’s the key, right? You’re trying to stop that acceleration — things that cause the acceleration of aging seem to be easier, more responsive.

DR. STEVE HORVATH: Exactly. Yeah.

Can GrimAge Predict the Day You Die?

DR. RHONDA PATRICK: The other question I wanted to ask you goes back to something that you mentioned earlier when you were talking about these insurance companies being able to predict your mortality risk pretty accurately using the DNA 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.

DR. STEVE HORVATH: That’s not true.

DR. RHONDA PATRICK: Okay. Now, why is that not true?

The Reliability of GrimAge Predictions

DR. STEVE HORVATH: Yeah. So I want to start out by commenting on insurance companies. They are in the business of predicting how long you live. If they make an error, it will cost them a fortune and they are superb at that. And just to emphasize, they look at so much. So they will above all look at very traditional readouts such as what’s your blood pressure, what’s your medical history, prior history of cancer, 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, does GrimAge add something, or GrimAge or another methylation? That’s really the question for these companies. And scientifically speaking, I can say, yes, it adds something, but not that much. Clearly, the life insurance companies have done very well without having a methylation readout. But the exciting thing is methylation adds something, but then these companies have to weigh the costs, because these tests are not cheap. They cost several hundred dollars. So is it worth it to measure? And by the way, that’s the same question for any consumer. Is it really worth it? Is it worth it to you to measure it? Sorry, the other part of the— you had a second part of the question.

DR. RHONDA PATRICK: Yeah, the question is, I guess I can word it a different way. If I were to go out and get a DNA GrimAge test and it said that I was going to die when I was age 80, am I actually going to die at age 80? How reliable is that number? How accurate is that number? Or am I going to die at perhaps age 85?

DR. STEVE HORVATH: Yes. I want to tell you that GrimAge could lead to a prediction of when you die. Let’s say age 85, it could. And we know though that this estimate is accompanied by a large error bar, plus minus 6 years. I’m just making it up. So let’s say you are a 50-year-old, you measure your GrimAge, and we apply the math, the mathematical algorithm, which by the way is very complicated, for estimating your age at death. But the error rate is substantial. And this makes sense because human beings are so complex. Think how many things can happen even in the next year. You can go through a divorce, you get hit by a car, you get depressed, you start smoking, you stop smoking.

So it would be unethical to report literally the age at death to a person. Therefore, we have decided to only ever give people an age estimate. We will say your GrimAge is 50. And what I want to really explain to anyone who listens is that please do not translate that age estimate in your mind into an estimate of when you will die. In other words, if your GrimAge is 10 years younger than your calendar age, it does not mean you will now live 10 years longer than the average person. You cannot compare this differential into a lifespan differential.

DR. RHONDA PATRICK: Then what does it mean?

What GrimAge Actually Measures

DR. STEVE HORVATH: Yes. So what does GrimAge really measure? In a mathematical sense? What does it measure? It really measures the instantaneous hazard that you drop dead. I always say to people, it’s your risk that you will die in the next year. That’s how you need to think of it, compared to a person of the same age and the same sex. So let’s start with a 50-year-old and, let’s say their GrimAge is 58, 8 years older than expected, then their risk of dropping dead in the next year is more than twice that of the average 50-year-old of the same sex.

Does that make sense? So it’s really, mathematically speaking, it’s a hazard ratio, and the hazard ratio measures instantaneous mortality risk. Now, you can translate that then into an estimate of your lifespan. It’s easy to do, but it’s a very complicated formula, certainly highly nonlinear. And as I mentioned, associated with a strong error bar.

DR. RHONDA PATRICK: Are there companies that have consumer-available tests doing that where they’re measuring the GrimAge and then doing that translation to when you will die? Is that something you’ve seen?

DR. STEVE HORVATH: No, I have not seen that. And I’m glad because I would have a problem with that on two grounds. I find it on some level perhaps unethical, but I believe in freedom. So if people want to do something, I’m okay with it. My concern is it’s scientifically unsound. It really is, for the reasons I mentioned. There’s a strong error bar.

DR. RHONDA PATRICK: Right. If you’re talking 5 or 6 years either way, that’s a pretty big error bar for when you’re going to die. But it seems like people are using it more to estimate their biological age, right?

DR. STEVE HORVATH: In a way.

DR. RHONDA PATRICK: Right. And that’s typically what people are—

DR. STEVE HORVATH: Yes. Usually we use GrimAge, of course, to understand the effect of various stressors. And I’m a longevity researcher. I’m very excited about finding interventions that reverse it in humans and of course, in animal models. So that’s how I use it.

Epigenetic Clocks and the Hallmarks of Aging

DR. RHONDA PATRICK: For these clocks, when we’re looking at the aging process as a whole, we were talking about damage. There’s the insult that is the initial insult, and then you have perhaps the damage response, maybe the amplification of that damage with inflammation. Then you start to have tissue breakdown, stem cell exhaustion, things that are more downstream of the damage and amplification of that damage. Do these aging clocks, where do they sit on that?

DR. STEVE HORVATH: Yes, we have gained a lot of insights into aging in general, by the way, and also which aging hallmarks really affect epigenetic clocks. So, 10 years ago, we barely knew anything about mechanism. Epigenetic clocks were rightly criticized as black box readouts. But after really 10, 12 years of research by the very best labs in the world, we really have characterized these changes.

Maybe for the biologists, they are these hallmarks of aging. And we know that clocks relate to mitochondrial dysfunction, the energetics. They relate also to stem cell changes, very much so, stem cell biology. They relate to metabolic changes, nutrient sensing, to some extent as well. And also aspects of DNA repair. They clearly relate also to changes in what is known as cell composition. So in blood, we have many different blood cells, and some cells are aged, so-called stressed memory T cells, cytotoxic T cells that are exhausted. This is actually a technical term, exhausted T cells from aging. And conversely, there are these naive T cells. So we understand that epigenetic clocks also relate to inflammation and that biology.

So epigenetic clocks should be conceptualized really as integrators of many different stressors, but not all. They don’t capture everything. And the most striking blind spot I want to highlight, which is frustrating to me, but I want to emphasize it. People in the aging field have heard of senescent cells, senolytics, very exciting intervention. I’m very much following that literature. However, epigenetic clocks really don’t capture that well.

So let me give you the prime example. You have cells growing in a dish, you radiate them, any radiation, you induce senescence. The cells can no longer proliferate. And by the way, radiation leads to double-strand breaks. It really very much stresses the cell. And wouldn’t it be nice if methylation clocks pick that up? But they don’t. So radiation damage, at least for cells—

DR. RHONDA PATRICK: They don’t pick up double-stranded breaks even?

DR. STEVE HORVATH: Yes, at least when you induce it by radiation. So we know radiation is very bad for you, but methylation changes do not result directly. And I give you the converse of that when it comes to senescence. Many people have heard of telomeres. In theory, you want reasonably long telomeres at the ends of your DNA. And for many years, people have thought aging is about telomere attrition. Now we know better, it’s not. But anyways, it’s a famous hallmark of aging, telomere shortening.

However, many of the clocks have only a weak correlation with telomere biology. It’s a frustrating aspect. And 20 years ago, people had an exciting idea: overexpress a part of telomerase, the TERT, overexpress TERT, and there were companies that pursued that as a rejuvenating intervention. At least in our hands, we did not see a beneficial effect, at least in vitro. So, although I like epigenetic clocks for many studies, they don’t capture the totality of aging. So you really want to complement epigenetic clocks with other readouts.

DR. RHONDA PATRICK: That’s interesting that they’re not— because you mentioned that they do track with the DNA repair process, but not—

DR. STEVE HORVATH: To some extent. I know I’m giving conflicting messages, but that’s the biology. So there are certain experiments that show that some aspects of DNA repair relate to epigenetic aging, but others don’t. It’s just not a tight story. I think the field really needs to nail that down.

DR. RHONDA PATRICK: Yeah. I mean, well, there’s a lot of things that lead to aging. It’s a very complicated, multifactorial process.

DR. STEVE HORVATH: Yes.

Reversing Biological Aging: What the Clocks Track

DR. RHONDA PATRICK: When you actually are able to perhaps reverse biological aging, or I guess there’s two ways of thinking about it. You’re slowing age acceleration if you’re taking away something that’s negatively accelerating aging or negatively affecting your health. But then also, 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 you described that are sort of tracking with these clocks are being affected? You know, mitochondrial function, inflammation, those processes are improving and the clocks are sort of picking that up?

DR. STEVE HORVATH: Yes and no. So epigenetic clocks such as GrimAge and DunedinPACE and PhenoAge, they do track inflammation to some extent, no question. So yes, if you reverse that, these clocks will pick it up. But it would be a grave error to assume that the clocks only measure that biology. It’s really not true. The clocks very much relate also to stem cell functioning, and other aspects. So, again, they’re integrators. And so there will be interventions that actually don’t even touch the inflammasome in one way or another. But they could have a very strong effect on reversing your epigenetic age.

And the prime example would be therapies that, for example, completely rejuvenate your hematopoietic stem cells. Just assume you have an intervention where you really replace your bone marrow, the hematopoietic stem cells that produce all of these blood cells, and you just get hematopoietic stem cells with an epigenetic age of 0. That would very much rejuvenate your blood drastically. We know that from mouse studies, but also human studies. The epigenetic age in a bone marrow transplant recipient often reflects the age of the donor. So there are various interventions that could have a very strong effect, but they just don’t touch on that biology you mentioned.

DR. RHONDA PATRICK: If it’s rejuvenating the blood, is it also perhaps rejuvenating other organs?

DR. STEVE HORVATH: That’s a great hope. So my response is assume not, because— wouldn’t it be nice?

DR. RHONDA PATRICK: What have animal studies shown? Have they looked at that?

Organ Transplantation and Body-Wide Rejuvenation

DR. STEVE HORVATH: Yes, there have been animal studies. I want to say in the lab from Vadim Gladyshev at Harvard, and my reading of the studies is that they have been disappointing. They didn’t rejuvenate other organs. If anything, there was a disappointing result that after X number of months, actually, the stem cells had aged. So the body has the memory of the old mouse, and that then aged the blood, really. Does it make sense?

DR. RHONDA PATRICK: So did these mice get a hematopoietic stem cell graft or what?

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: They did?

DR. STEVE HORVATH: Okay. Vadim carried out really an elegant set of experiments, various transplantation experiments. And the scientific question is the following. If I replace, let’s say, the blood by that of a very young mouse or take other organs, by the way, should we replace the kidney? So anyway, or the heart or any other organ. Would the rejuvenation of one organ translate to a body-wide rejuvenation? And my current reading of the literature is that we haven’t found any such organ as a target.

DR. RHONDA PATRICK: 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, I don’t know if they were measuring using clocks, but they were doing cognitive function and a battery of tests and the cognitive function improved and things like that. But—

Heterochronic Parabiosis and the Challenge of Transient Rejuvenation

DR. STEVE HORVATH: No, for sure. So maybe to remind the audience, this idea of heterochronic parabiosis, for example, where you really connect the circulation of an old mouse with a young mouse. And this is really a phenomenal paradigm of rejuvenation, arguably one of the best ones we have, along with caloric restriction.

Yes, we know that when an old mouse is exposed to the circulation of a young mouse, it has multiple benefits, cognitive benefits, also muscle benefits. And also, importantly, epigenetic clocks get rejuvenated, many organs. So we know that, again, from several studies, including from Vadim Gladyshev’s lab, but others have found that too. So yes, young circulation rejuvenates the liver, the kidney, all of that, on the methylation level.

But there’s a problem. You disconnect these mice. 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.

DR. RHONDA PATRICK: But yes, 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.

DR. STEVE HORVATH: Yes.

Caloric Restriction and the CALERIE Trial

DR. RHONDA PATRICK: 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, but although GLP-1 receptor agonists are kind of doing that in a way.

There was a very recent trial, the CALERIE trial, and I’d love for you to talk about this. It was a 2-year randomized controlled trial where individuals were basically eating 25% fewer calories than they otherwise would, or they were eating their normal daily food intake as usual. And I wanted to ask you, were the participants overweight in this trial or were they normal weight? Do you know?

DR. STEVE HORVATH: I don’t remember. I know it’s a U.S. population, so assume that they are on the chubby side for sure.

DR. RHONDA PATRICK: Okay. Yeah. So in this trial, it was a 2-year randomized clinical trial, and it seemed there were many clocks that were measured and it seemed like they had different readouts. Do you want to talk a little bit about the findings?

DR. STEVE HORVATH: Yes. Yeah, I have a lot to say about weight loss. We should discuss it. So, the CALERIE study is a very famous study, US population, very rigorous study, many, many readouts. But I want to acknowledge something, and the experts know it, the adherence was not good. So there was an ambition that these people would lose more weight than they did. But as everyone knows, it’s so hard to adhere to a diet.

The age reduction was on some level very weak, I would say. I apologize, I don’t know the number, but I remember it was weak. I mention it because later we should talk about GLP-1 receptor agonists where the weight loss can be pronounced and there are discrepant findings actually.

But anyways, back to the CALERIE study. Again, there were multiple blood draws from these people, and so one could evaluate which methylation clocks pick up a beneficial effect. And I was disappointed that GrimAge and PhenoAge did not pick up an effect. But this new clock, DunedinPACE, really picked up an effect, which was 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.

DR. RHONDA PATRICK: How much weight did they lose, do you remember? It was critical, like not very much.

DR. STEVE HORVATH: Yeah, it was not impressive to me at least.

DR. RHONDA PATRICK: So the clock that did pick up the—

DR. STEVE HORVATH: It was DunedinPACE.

DR. RHONDA PATRICK: DunedinPACE.

DR. STEVE HORVATH: And in hindsight, let’s discuss why it picked up the effect.

DR. RHONDA PATRICK: Well, it was like a 2% to 3% slowing of the rate of aging. Over the 2 years.

DunedinPACE, GLP-1 Agonists, and Weight Loss

DR. STEVE HORVATH: Yes, that’s true. Yeah. So it picked it up and it makes mathematical sense to me because DunedinPACE again was 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 yes, DunedinPACE worked. And my reading of DunedinPACE is that it is good at that biology — people losing weight, it will pick it up.

And now the question is, why didn’t the other clocks pick it up? And there could be several explanations, but my view is if there had been a larger sample size, if the people had adhered to the protocol, I’m as sure as you can be that the other clocks would have picked it up. It’s a sample size issue, or conversely, small effect size.

What I can tell you is there was a very exciting study that involved actually obese people, BMI 30 and higher, who had been put on a GLP-1 receptor agonist treatment, semaglutide. And these people really lost a lot of weight over 33 weeks. And, by the way, this study was published in medRxiv. It’s a preprint, so take it with caution. It was Michael Corley’s group in San Diego. But very beautiful study, very rigorous again, and large sample size, so credible.

And they looked at all methylation clocks and suddenly all methylation clocks picked it up, really all. And so that’s my thinking — if you have a strong weight loss intervention, you have really a strong reduction in fat, lipolysis, this inflammatory signal is reduced. I think all methylation clocks will pick it up.

DR. RHONDA PATRICK: Opinion, 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. Yes, right. You are in age acceleration mode, right? So you need to slow it down.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: And with any clinical trial, it’s always — you always get a better signal.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: When you’re starting with something that’s on a population that’s either deficient or unhealthy, and then you’re giving something to improve that deficiency or negate it or to improve their health and you get a more dramatic effect. So we know obesity accelerates aging. We know that it’s associated with decrease in life expectancy, increase in cardiovascular disease, type 2 diabetes, cancer, right? All these diseases of aging.

So it’s not surprising that you would give someone a drug that does cause rapid weight loss in a short amount of time. So you’re going to get a much more robust signal. And you’re obviously picking that up with the aging clocks.

With the CALERIE trial, again, I don’t know what the adherence was, but also, as you mentioned, these clocks are trained with different — there’s different specialties of them, so to speak, right? And BMI, being trained on BMI, wow, that’s going to make you sensitive to weight loss for sure. And so the DunedinPACE clock, which is measuring the pace of aging, you would imagine would be more sensitive than something that wouldn’t.

Which Clock Should Clinicians Use?

DR. STEVE HORVATH: But my question as a longevity researcher is which clock should a clinician use. If we could briefly talk about multivitamins, this study, interestingly, here GrimAge found an effect, PhenoAge found an effect based on multivitamin but DunedinPACE failed. It was not significant. So you can ask this question now for many interventions — what should be the go-to clock? And I even want to stay clear of this debate because we will never agree. Therefore, I just love it that the field by now simply reports at least 5 clocks, so the reader can just look at it and be the judge.

The COSMOS Trial: Multivitamins and Brain Aging

DR. RHONDA PATRICK: Let’s talk about the multivitamins. So this was the COSMOS trial. I’ve talked a lot about the COSMOS trial in the context of brain aging. So the larger — there’s the larger trials, and there were 3 randomized controlled trials where these older adults were given a standard Centrum Silver multivitamin a day, every day. And it was — what is it, about 3.6 years for this trial?

And they were looking at — I mean, there’s a lot of endpoints of this trial, but one of them was cognitive function and brain aging. And at the end of the trial, the people that were given the multivitamin had slowed their brain aging by 2.1 years. And there was 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 memory is a kind of memory where you’re remembering experiences, people, right? Like those sorts of things — 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’s very encouraging, 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 diet. And so they’re kind of filling that nutritional gap. And so, who doesn’t want their parents and grandparents to have better brain aging? So my parents are on a multivitamin, right?

When it comes to looking at these epigenetic aging clocks, the PhenoAge and GrimAge clocks were the ones that stood out to me. As you mentioned, there was a battery of clocks that were looked at, but it seemed as though they were slowing — or at least I’m not exactly sure all the calculations that go into this — but 2.7 months to 5 months, right? Like they were basically slowing the aging by roughly that amount. Which to me is, if you think about now this trial that was done with the aging clocks, I think it was like a subset of it, of the larger trial. Was it 2 years or did they do the 3.6 years for that? Do you?

DR. STEVE HORVATH: It was, yeah, I think it was 2 years.

DR. RHONDA PATRICK: 2 years, yeah. And so to me, the question is — now this wasn’t the — you said the DunedinPACE didn’t change.

DR. STEVE HORVATH: No, it changed in the right direction. It just wasn’t statistically significant.

DR. RHONDA PATRICK: Oh, I see.

DR. STEVE HORVATH: In the right direction, maybe a larger sample size would have led to a significant finding. It was definitely in the right direction.

The Cumulative Effect of Long-Term Supplementation

DR. RHONDA PATRICK: Well, the question I have for you is if you’re changing it by 3 to 5 months within that 2-year range according to the GrimAge and PhenoAge clocks, and you’re to keep doing that for years. So now we’re talking not just 2 years, we’re talking 20, we’re talking 30, 40 years.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: How do you think that — do you think that you get this cumulative effect?

DR. STEVE HORVATH: Yes, I think so. Maybe to step back, if you tell an 80-year-old that a multivitamin will reduce his or her age by 3 months, they will roll their eyes. They will say, “Give me something that reverses my age by 30 years.” So, fair enough. We just need to acknowledge the effect is very minor. However, I like the way you conceptualize it. If you really use it for 30 years, right? You’re 50 years old and you use it until you’re age 80, my expectation is that suddenly these 3-month benefits, they accumulate and suddenly you have a benefit of maybe 2.5 years. It’s still not great, but there is a benefit.

DR. RHONDA PATRICK: But think of the effort you have to put into just taking a multivitamin, right? I think it’s pretty great for that amount of effort, if you’re just having to take one vitamin supplement and it’s going to delay your brain aging by 2.1 years just after — in that trial it was a 3.6-year trial, but that’s pretty robust, 5 years delaying brain, episodic brain aging.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: And now we’re talking about like globally, like biological aging. If it’s slowing it by, let’s say, on the high end, 5 months after 2 years.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: I don’t know, that seems like a pretty great effect if you’re just taking a vitamin supplement for 2 years. It’s doing that. Well, let’s continue on and then combine other things, and we’ll get into some of the other trials that do show synergy. But yes, I think it’s interesting.

The other question is that, and this is where 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, at least within the timeframe that was looked at. And so we see these epigenetic clocks giving us a signal, we see the brain aging effects, and the question is why are those showing up before progress?

Multivitamins and Epigenetic Clocks: A Triumph of Biomarkers

DR. STEVE HORVATH: Yeah, I tell you my reading of it. To me, this whole study was one triumph for epigenetic clocks, and I explain to you why. Assume you knew nothing about multivitamins. You would think that there is a benefit, clearly vitamins are important. It’s a trivial tautology.

DR. RHONDA PATRICK: Avoiding deficiencies are important.

DR. STEVE HORVATH: Yeah, especially, so you would say, okay, administer that to the US population, I would hope to see an effect. And that, of course, is the reason why these large-scale studies were even initiated. Think about how difficult it is to raise the funding for such a large-scale study. Clearly, there must be very compelling reasons.

Okay, but there’s a problem now, and these hard endpoints, mortality, cardiovascular disease, they didn’t detect an effect. Deeply frustrating. Was there a trend?

DR. RHONDA PATRICK: It wasn’t statistically significant?

DR. STEVE HORVATH: Yeah, I let you summarize it, but to me, I just looked at it from the point of view as a consumer. 5 years ago, I wouldn’t take a multivitamin. I looked at the literature, no benefit. I won’t take it.

Now, a person can now make their own judgment. So what does it mean? To me, I take it as a wonderful triumph of epigenetic clocks that they did pick up the signal. And I call this “testing the test.” You have an intervention where you really think it’s got to move the needle. And then if a readout doesn’t show it, one interpretation is, well, maybe the readout is too crude. Maybe all-cause mortality is a real— I mean, I like it as a readout. I used it for GrimAge. Don’t get me wrong. I like that it’s hard and definitive. You can’t argue with it.

However, people die for 100 different reasons, reasons that may really not relate to the biology of aging. And so now that we have actually biomarkers that did pick up that signal, even though it’s very weak, is to me really reassuring.

DR. RHONDA PATRICK: Yeah. And I think it’s reassuring in combination with the brain aging signal that it picked up. And just knowing that so many people globally 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. You can only get a little bit of some things in there, right?

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: But I do think that it’s— again, I agree with you. I think it is a triumph. It’s something that I do think is safe. I mean, it’s really been shown to be safe. And so maybe you pee a little bit more of it out, so what? It seems to be doing something beneficial for the brain. And at least looking at these aging clocks, it seems like it’s affecting the way you’re aging as well.

DR. STEVE HORVATH: Yes. Yeah, so what have you got to lose?

Omega-3 Fatty Acids and Epigenetic Aging

DR. RHONDA PATRICK: Yeah. Let’s go back to maybe some of these other vitamins, other lifestyle interventions as well that I wanted to cover. But since we’re on the vitamin train, 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 that, you fill that nutrition deficiency gap, or you improve your health, lose weight, whatever, then you’re going to have a stronger signal, right?

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: 90% of Americans don’t get enough omega-3 fatty acids. Nobody is eating seafood in the US.

DR. STEVE HORVATH: That’s it.

DR. RHONDA PATRICK: So you’re starting with a population that’s already 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 if you start out with someone who’s already getting enough omega-3, maybe you go to Japan and do this study, I don’t know. It would be interesting to see.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: Perhaps it just keeps improving inflammation, and then you’ll keep seeing an effect. But it seems like many, many studies have shown that omega-3 fatty acid, whether it’s from food, supplementation, or a combination of both, seem to slow epigenetic aging by different clocks.

DR. STEVE HORVATH: Yes, there has been quite some literature. It started with observational studies that you cannot trust. But last year we published a study which was very rigorous. This was a study conducted by a Swiss professor, Heike Bischoff-Ferrari, who looked at 780 people and followed again the most rigorous design, randomized controlled trial, placebo-controlled trial, in a population that I was very interested in — people 71 years or older, really older people, reasonably healthy. Average age, I want to say 75, I think, or 73, so older people.

She evaluated famous interventions. Number 1, omega-3, 1 gram, vitamin D. And we should talk about the intervention about vitamin D — it was tricky. It was high vitamin D versus low vitamin D. It wasn’t vitamin D versus no vitamin D. That’s a key distinction.

DR. RHONDA PATRICK: What was the low? I know the high vitamin D was 2,000 IU.

DR. STEVE HORVATH: Yes. And the low was 800 IUs.

DR. RHONDA PATRICK: Oh, so it was only double kind of.

DR. STEVE HORVATH: 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 hastened to add.

DR. RHONDA PATRICK: Yeah, but we have other randomized controlled trials showing the opposite if you start with the deficiency and add it. And we can talk about that.

DR. STEVE HORVATH: Okay. So vitamin D. That’s true.

DR. RHONDA PATRICK: But there was also another disappointing result — if you look at the exercise.

Exercise Intervention in Older Adults: The DO-HEALTH Trial

DR. STEVE HORVATH: Yeah, we need to talk about exercise. So this was called the 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 this home exercise intervention was very modest.

DR. RHONDA PATRICK: And it was resistance training, right? 3 times a week.

DR. STEVE HORVATH: Yes. But it was mild, mild, mild resistance training. Because no effect. I was very disappointed.

DR. RHONDA PATRICK: Did you read that the starting population, around 88% of them already identified as being physically active?

DR. STEVE HORVATH: Exactly.

DR. RHONDA PATRICK: I mean, if you were to get a US population, not a chance. There’s no way you would have had that many people physically active. But anyway, so that’s another—

DR. STEVE HORVATH: No, these are people in Switzerland. Hopefully they hike in the mountains.

DR. RHONDA PATRICK: They’re walking everywhere. Exactly.

DR. STEVE HORVATH: No, but that was interesting to me because I’m very interested in that population, people who already do a lot of good things. What can they do to improve their outcomes?

DR. RHONDA PATRICK: Great framing of it.

DR. STEVE HORVATH: Yeah. And so I think we already discussed the results. The most credible result was omega-3 on epigenetic clocks. A couple of epigenetic clocks picked it up. GrimAge version 2, PhenoAge, DunedinPACE also worked very well in that context. So nice result for omega-3. The other interventions disappointed.

DR. RHONDA PATRICK: By themselves. By themselves.

DR. STEVE HORVATH: By themselves. But yes, there was this one treatment arm where people actually used all 3 beneficial interventions — high-dosage vitamin D, omega-3, plus exercise. And according to PhenoAge, that treatment arm did the best. And so that’s the finding that we would have liked to see for all clocks. But it’s just the PhenoAge picked it up.

DR. RHONDA PATRICK: Well, I think there was even a dose-dependent effect where there was the group that just got the omega-3 and vitamin D, and that also improved more than the omega-3 alone.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: 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.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: Which is exciting.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: And I have the numbers here. I think it was 3.8 months. The PhenoAge delayed — the biological aging was delayed by 3.8 months.

DR. STEVE HORVATH: Yeah. Over 3 years.

DR. RHONDA PATRICK: Over 3 years.

DR. STEVE HORVATH: Right.

DR. RHONDA PATRICK: And that doesn’t sound like a lot again, but they also correlated with some other outcomes. So I think in all 3 interventions, yes, it was 3.8 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?

DR. STEVE HORVATH: I agree with that. And I can tell you the same study looked at a new concept in the field called intrinsic capacity, which looks at various domains of functioning, frailty, cognition, psychology. Anyways, intrinsic capacity was also improved in that population.

DR. RHONDA PATRICK: Oh, okay.

DR. STEVE HORVATH: So it’s not just the molecular readout. Yes.

The Power of Compounding Healthy Habits Over Time

DR. RHONDA PATRICK: I think for me, the take-home again is something that you mentioned — when you have this already healthy population, 88% of them physically active, and you take that healthy population, you can still improve, right? You still can improve things.

Again, this comes down to the compounding factor, right? So this is 3 years, and then let’s say, okay, well, they’re going to start doing this for the rest of their lives, decades we’re talking. Well, in this case, they’re a little bit older, but people listening to this podcast may be in their 30s, maybe in their 20s, in their 40s. It’s like, okay, well, I’m going to start training, making sure I’m not vitamin D deficient, getting my omega-3. And then how is that going to compound over time? And I know it’s speculation, but it makes sense. That’s the way I think about it.

DR. STEVE HORVATH: I think of it the same way. I wish I could go back in time and tell myself to stop eating chocolates, which really messed me up. So yeah, good health behaviors, and supplements included, I think will have benefit, major benefit.

Vitamin D Deficiency and Age Acceleration

DR. RHONDA PATRICK: When it comes to vitamin D, that’s the one — this one study was a bit disappointing, but as you mentioned, comparing 800 IUs to 2,000 IUs, I wouldn’t imagine to see a big difference there because you’re already filling the gap.

DR. STEVE HORVATH: Exactly. And most of the participants had no insufficiency in vitamin D. They really started at normal levels.

DR. RHONDA PATRICK: And we know there have been, in my opinion, so many studies that I’ve come across and read over the years showing that vitamin D deficiency causes age acceleration, in some cases severe, like 3 years. And if you correct that deficiency, it’ll slow age acceleration, where then you say it reversed aging by, you know, 4 years or whatever.

I think my take-home — and I know the one that I like, the most recent one, was the BASE-2, the Berlin study.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: Where they took — and what was nice about that was they had a deficient population and then a sufficient population and gave them vitamin D.

DR. STEVE HORVATH: And this was a study in Berlin and they followed people for 7 years, which was also impressive, and it was a large population. And you can imagine Berlin is of course not blessed by sunshine, so they start out deficient. It all made sense.

DR. RHONDA PATRICK: Yeah, reverse aging — yes, if you’re deficient and fill that deficiency. But the people that were not deficient, actually there was no effect, which is again what you expect. It’s not about this being a magic supplement that’s slowing aging. It’s not doing that. It’s helping people that are deficient correct their deficiencies. And that’s why there’s so much even in the scientific literature with vitamin D, for example, if you’re looking at outcomes. It’s the same thing.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: 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 everyone else. You can’t do that. There are so many gene SNPs that are affecting vitamin D. There are other micronutrients. Magnesium really affects vitamin D. You need magnesium to convert vitamin D3 into the steroid hormone. So there are 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.

The Role of Diet and Exercise in Epigenetic Aging

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: Okay. So I want to—

DR. STEVE HORVATH: We should talk about exercise.

DR. RHONDA PATRICK: Yeah, we can go into exercise.

DR. STEVE HORVATH: Oh, no, but I follow your script. Sorry.

DR. RHONDA PATRICK: Oh, no, no. We were talking about calorie restriction, and I just wanted to mention dietary patterns in general, because you mentioned weight loss and we’ve talked a little bit about it with the GLP-1. Obviously, if you lose weight, yes, it’s probably a big confounder with some of these dietary pattern trials, right? Like if you’re getting someone who’s overweight and these participants are overweight and you’re putting them on a healthy diet or a Mediterranean diet or something like this and they lose weight on the diet, then how much of what you’re seeing is due to that weight loss, right?

DR. STEVE HORVATH: Exactly.

DR. RHONDA PATRICK: So do you want to talk about that? It was like the DIRECT trial. Is that what it was called?

Carotenoids, Vegetable Intake, and GrimAge

DR. STEVE HORVATH: Yeah. I need to tell you, I don’t know too much about it, but I want to explain some properties of GrimAge that I’m aware of. So GrimAge very much correlates with what is known as carotenoid levels in the blood. So what are those? 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, these food questionnaires often don’t reflect reality.

DR. RHONDA PATRICK: I don’t remember what I ate for breakfast. Well, I didn’t eat breakfast today, but—

DR. STEVE HORVATH: Yeah, and people always know what they should answer, but that may bias their memory. They will say, “Oh yeah, I ate X servings of broccoli,” but it just doesn’t reflect reality. But fortunately, there are blood tests. You can measure the so-called carotenoid levels in the blood and have an objective readout of fruit and vegetable consumption.

And the striking finding in postmenopausal women from the Women’s Health Initiative was that this measure of vegetable intake has a strong correlation with GrimAge and other epigenetic clocks. Strong meaning maybe -0.3. To me, that is a very strong effect, which really changed my behavior. By now, I really eat a lot of vegetables.

DR. RHONDA PATRICK: Can you translate that to months? Like, what would -0.3—

DR. STEVE HORVATH: Yeah, sorry, I could translate it, but—

DR. RHONDA PATRICK: An estimate.

DR. STEVE HORVATH: Yeah, let me put it this way: smoking has a correlation of 0.4. So if you smoke a lot, it increases your age. Vegetable consumption, -0.3. So it’s actually— Wow.

DR. RHONDA PATRICK: Yeah, I was very surprised.

DR. STEVE HORVATH: And I’m sorry, I’ll add one more statistic. Exercise, the correlation would be 0.1. So do you see? Vegetable intake has a much stronger effect — orders of magnitude stronger effect on GrimAge and these methylation blocks — than, for example, exercise.

DR. RHONDA PATRICK: 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?

DR. STEVE HORVATH: Yeah, 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 teasing it apart — what is it exactly? That remains to be seen.

DR. RHONDA PATRICK: Probably so many things. I mean, you’ve got the fiber matrix, you’re getting micronutrients — like vegetables, especially greens. And if you’re talking about carotenoids, lutein and zeaxanthin are carotenoids that are in greens. Interestingly, there have been a lot of studies coming out looking at blood levels of lutein and zeaxanthin. People usually associate them with eye health — they accumulate in the eye. There have been randomized controlled trials showing they can help prevent age-related macular degeneration. They also accumulate in the brain, and they’re associated with improved cognitive function, crystallized intelligence, and improved brain aging in general.

DR. STEVE HORVATH: All right.

DR. RHONDA PATRICK: And there are other carotenoids. Beta-carotene is probably what most people are familiar with. Lycopene in tomatoes. So there’s a variety of these carotenoids which are very powerful at basically buffering oxidative stress and singlet oxygen, for example, in the eye.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: But it’s interesting that vegetable intake can have such a profound effect.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: There was a vegan trial too, I think. There was a trial looking at people that are eating a lot of vegetables versus a healthy omnivore diet. And I think the vegan trial showed they also slowed 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 -0.3. That is pretty strong. You gave me that reference point of smoking — you said it was — wait, smoking was 0.4.

DR. STEVE HORVATH: Okay, smoking 0.4, maybe 0.45. So it’s an increase in correlation. Exercise, 0.1.

DR. RHONDA PATRICK: Okay.

DR. STEVE HORVATH: And we can talk later about exercise, but it’s a 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. But regarding the question of vegan versus carnivores — I honestly have not seen convincing data.

DR. RHONDA PATRICK: Omnivore.

DR. STEVE HORVATH: Omnivore. Yeah. Or omnivore.

DR. RHONDA PATRICK: Carnivore would be the extreme opposite.

DR. STEVE HORVATH: That’s true. Yeah, let me rephrase it. I have not seen any evidence that people who eat a lot of red meat age much faster than people who are vegans. We looked again in the Women’s Health Initiative. There was a hint, I want to say, when we analyzed 3,000 women — women who ate red meat — it was barely noticeable that red meat was ever so slightly increasing epigenetic age, but it was truly negligible. So what I can tell you is I eat a lot of meat and hopefully it’s not bad for me.

DR. RHONDA PATRICK: Vegetables.

DR. STEVE HORVATH: I eat meat and vegetables. I try to be easy on the carbs — I eat carbs, but I try to reduce them.

DR. RHONDA PATRICK: I mean, vegetables are carbohydrates. They’re just complex carbohydrates, not simple. So you’re not eating the simple carbohydrates.

DR. STEVE HORVATH: Carbohydrates.

DR. RHONDA PATRICK: Yeah, exactly. That vegetable stuff is interesting. There’s so much in vegetables — the micronutrients and the phytochemicals, right? That’s another thing in them. The fiber. There’s a lot of things going on here.

DR. STEVE HORVATH: Yeah. Somebody should really tease that apart. What kind of vegetables should be eaten, and in what dosages. Lots of exciting PhD dissertations could be written on that topic.

Exercise and Epigenetic Clocks

DR. RHONDA PATRICK: Exercise.

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: So let’s talk about that. There’s a trial that you sent me that was pretty convincing, and it was kind of a new one in 2025 showing that 6 months of cycling seemed to slow epigenetic aging — or GrimAge — by 7.4 months, right?

DR. STEVE HORVATH: Yes, maybe I’ll frame it like that. There have been very nice studies on the effect of exercise on GrimAge and PhenoAge and other clocks. And what do I mean by nice? Studies where they use one way or another a wearable to really measure your step count and activity. So it’s a very rigorous readout of your physical activity. The studies were also convincing because they were large-scale studies — many thousands of people in different countries: Japan, Germany, the US.

And the finding is the following: yes, if you move more, your epigenetic clocks pick up a small effect. I mentioned earlier a correlation of -0.1. What it means is you need to study 3,000 people to see a statistically significant effect of step count, as an example. But I’ve been deeply dissatisfied with that finding because we all know exercise is what they call the “polypill” — it touches so many systems and it’s very beneficial. So I would have loved to see a strong effect on blood methylation, but the literature shows a weak effect.

DR. RHONDA PATRICK: And what about muscle methylation?

DR. STEVE HORVATH: Yeah. People have built clocks for muscle — literally from human muscle biopsies. Some people claim they see an effect, but I’m just not yet convinced.

DR. RHONDA PATRICK: It is disappointing. So you’re asking—

DR. STEVE HORVATH: I would say it’s disappointing. So then there’s this study that was published — the first author I can remember is Van Damme, I think differently spelled from the actor, but anyways. This intervention was very different because it didn’t look at step count or the home exercise intervention we discussed earlier. That was the next level intervention. It was putting people on a bicycle and they bicycled 4.5 hours a week. Now, for the health nuts out there, that’s not much, but to me, this is daunting. If you forced me to bicycle 4.5 hours a week, I would struggle with that. We are all busy people. But anyways, the people who adhered to that trial had strong effects on VO2 max.

DR. RHONDA PATRICK: 20%.

DR. STEVE HORVATH: 20%. And many other readouts. So they didn’t fake it — they really saw physiologic benefits. And then sure enough, suddenly the clocks worked. PC-GrimAge, as an example — we keep talking about PC. PC means Principal Component Based GrimAge. That’s a version of GrimAge that’s even more robust than the original, in the sense of test-retest variability — a more reproducible measure. Anyways, it picked up a 7-month reduction in GrimAge, which dwarfs everything we just discussed. And that was a 6-month intervention. These people were younger though — I want to say they were between 30 and 65 — basically a population that you can put under such a stringent regimen.

DR. RHONDA PATRICK: Well, they’re young and middle-aged, but — yes. I would argue, Steve, that 10,000 steps — that stuff is okay, it’s better than nothing, but if you really want to move the needle on aging, you’ve got to go more than that.

And this is the kind of stuff we talk about on the podcast. I’ve had Ben Levine on. He is a rock star in the cardiovascular exercise physiology world, and he’s done multiple randomized controlled trials. He did one that was a 2-year study in 50-year-olds — people who had never been physically active but didn’t have any other diseases. He put them on a 2-year trial where they were working out about 5 hours a week on average, doing a lot of cycling, some high-intensity interval training, a little bit of resistance training, but a lot of it was aerobic.

They improved their VO2 max and their heart structure. He looks at the structural aging of the heart. As we age, our heart gets smaller and stiffer. And they improved the structure of their hearts — it was as if they reversed aging by about 20 years. Their hearts got bigger and more flexible and looked more like a 30-year-old’s, even though they were 52 at the end of the trial.

So I would argue that really taking time to exercise every day — and more than just walking — is very powerful for longevity and for slowing age acceleration. And it is really nice to see this new trial because I have also been very disappointed in some of the data. But no one has really been doing these kinds of studies where they say, “Hey, let’s not just walk. Let’s not just do 10,000 steps. Let’s push them to improve their VO2 max by 20% and see what that does to their aging clocks,” right?

DR. STEVE HORVATH: Now we know. The study didn’t have a control arm — we should mention that — but I certainly was impressed by it. It’s hard to argue against exercise.

DR. RHONDA PATRICK: Yeah, I mean, there are 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 — all these age-related diseases, frailty — 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 it’s nice to see that there might be a real threshold to pick it up with these epigenetic clocks, where you have to kind of put in the effort.

DR. STEVE HORVATH: Exactly.

DR. RHONDA PATRICK: And so are you going to put in more effort now?

DR. STEVE HORVATH: I mean, yeah, I will try. Yeah, definitely.

The Role of Body Temperature, Sleep, and Social Connection in Aging

DR. RHONDA PATRICK: Hopefully there will 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 looking at, because I want to see a 10-minute HIIT every day. How is intensity affecting it? How is volume, duration? There are so many things to look at.

DR. STEVE HORVATH: We need to develop exercise in a pill for people who have lost mobility.

DR. RHONDA PATRICK: It’s never going to happen.

DR. STEVE HORVATH: What do you tell someone who is in a wheelchair? What do you tell to an 85-year-old? We need to develop interventions that still rejuvenate them and slow aging.

DR. RHONDA PATRICK: 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 aging clock, but you can get in like a hot tub or a hot sauna, your heart rate starts to elevate. A lot of the same physiological mechanisms that are happening during moderate-intensity exercise.

There’s been head-to-head comparisons with getting on a stationary bike and doing about 100 watts for 20 minutes, and then comparing that to a 20-minute sauna, and you get a lot of the similar benefits. You get improvements in blood pressure, improvements in your resting heart rate. You’re sweating, your core body temperature is going up. So we do have some interventions that may mimic it. The pill — there’s so many things that change. Maybe we’ll get that, but it seems like—

DR. STEVE HORVATH: Yeah, I’m joking.

DR. RHONDA PATRICK: Yeah, I know.

DR. STEVE HORVATH: We need something.

DR. RHONDA PATRICK: It seems like a moonshot. Yeah.

Body Temperature and the Hibernation Effect

DR. STEVE HORVATH: I want to briefly comment on body temperature. There has been a very elegant study in mice. It turns out if you stimulate certain neurons in the brain — the preoptic nerve, I think — you can actually lower the body temperature of a mouse. There was a team at Harvard, Sinisa Vratin, who did just that in the mice. He lowered the body temperature of the mice, I want to say, by 3 degrees Celsius or some order of magnitude. And then he just looked at their methylation clocks, multiple organs, and guess what? Very strong effect. The mice whose body temperature was lowered really aged substantially more slowly than a control mouse. To me, that was very interesting.

DR. RHONDA PATRICK: Well, their metabolism is probably slowed, inflammation, because you’d be going colder, vasoconstriction also happens, I would assume.

DR. STEVE HORVATH: Yes. Inflammation, maybe — it’s interesting. I just want to mention it. The benefits of sauna and all of that are undisputed, but I just want to mention that maybe lowering your core body temperature by a degree or so could be beneficial. Who knows?

DR. RHONDA PATRICK: During hibernation, animals that hibernate—

DR. STEVE HORVATH: Yeah, same thing. There have been a couple of studies that suggest that there’s a slowing of aging. We did such a study at UCLA. We looked at marmots in Colorado, I think. And sure enough, during hibernation, the methylation clocks didn’t advance.

DR. RHONDA PATRICK: Yeah.

DR. STEVE HORVATH: So interesting.

DR. RHONDA PATRICK: It is. I think people need to realize that just normal neurotransmitter firing, your cognitive function firing away — all this stuff is producing damage. So if you’re just slowing everything down — I associate the cold with slowing it down — 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.

DR. STEVE HORVATH: Yeah, makes sense.

Sleep and Epigenetic Aging

DR. RHONDA PATRICK: 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. There may be some observational studies, but there are lots of confounders there.

DR. STEVE HORVATH: Yes. I worked with a team at UCLA, Judith Carroll, and she looked at sleep disturbances in the Women’s Health Initiative and other cohorts. Sure enough, people who report severe sleep disruptions exhibited increased epigenetic age. No surprise here. It was an observational study.

I know that people are looking at that, especially now we have these wonderful tools for tracking sleeping. I hope somebody will do the obvious study — 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.

DR. RHONDA PATRICK: I think we know that sleep deprivation, chronic sleep deprivation, increases inflammation, changes your appetite. People gain weight too. There are all the reasons why it would accelerate aging and that would make sense. But I don’t know that there’s enough evidence looking at the specific stages of sleep. There’s a lot to tease apart there, and a lot more research to be done in that area.

DR. STEVE HORVATH: Yes.

Social Relationships and Their Surprising Impact on Biological Aging

DR. RHONDA PATRICK: Another area that’s very exciting has to do with our mental health and our social relationships. Right? I mean, that’s—

DR. STEVE HORVATH: This was the biggest surprise to me in the last 6 months, perhaps. I need to tell you, I’m not a social scientist. I don’t study behavior. So anyways, there was a researcher at Harvard, Laura Kaczynski — I butcher her last name — but she is a very rigorous scientist and she wanted to evaluate what she calls “social cumulative advantage,” which is a measure of how connected you are in the community, your social behavior, your friends, your community. How does that affect biologic aging?

This is similar to the vitamin study we just discussed. It’s got to have an effect, right? We all know loneliness is the big killer in the elderly, at the level of smoking. You don’t want to be lonely and socially deprived. So anyways, she did a very rigorous study, large sample size, and she evaluated everything a researcher would evaluate. You want to evaluate cortisol levels, various hormones that measure stress. You want to measure inflammatory markers — IL-6 and various other readouts of inflammation.

But fortunately, she had enough research funding apparently to measure methylation. I say that because if I had been a researcher, I would have focused on urine and blood for measuring hormones and inflammation. And for methylation, I would have advised her, “Don’t even measure it because I just don’t think you pick that up.” Why would your connectivity, your friends, your relationship with your spouse and your family, translate to changes on the DNA molecule in blood? 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 GrimAge again picked it up. People who are blessed by having wonderful family relations, community, just this social advantage — sure enough, their GrimAge was reduced. It really taught me something.

DR. RHONDA PATRICK: Do you know how much it was reduced? Do you remember?

DR. STEVE HORVATH: No. My problem is I only ever look at p-values. I’m a statistician. I know everyone always wants to know how many months, but I just go by p-value.

DR. RHONDA PATRICK: I had Arthur Brooks on and he talks about the science of happiness. He’s amazing, by the way. If you don’t follow him on X, you should. He’s got really great content, great science out there. 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.

But if you think about the flip side of that — loneliness and not having those social relationships — there’s also the possibility that the relationships were unhealthy and so people separated from that. There’s stress probably that’s involved in that equation too. Loneliness itself has been shown to increase stress, as was picked up in this study and others. But there’s a lot of nuance there with respect to someone that has a lot of social relationships versus someone that doesn’t. A lot of times you look at the people that don’t, there’s usually some trauma too, right? And that definitely would cause stress.

DR. STEVE HORVATH: I couldn’t agree more. If you’re in a toxic relationship, get out.

DR. RHONDA PATRICK: Right.

DR. STEVE HORVATH: Don’t tolerate abuse. Just for sure.

DR. RHONDA PATRICK: But those things probably leave their mark on the epigenome — that stress.

DR. STEVE HORVATH: Yeah. 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.

DR. RHONDA PATRICK: Have you seen that study?

DR. STEVE HORVATH: I’m always happy when a sleep study shows only a weak effect, because I’m rooting for these people. But yeah, I’m not sure. Let me say something about the elderly. Again, loneliness is the big killer in old age, and unfortunately, geriatric patients become isolated — many of their friends have died — and what to do about it. There have been very nice studies in Japan, of course, where they deploy various robots to entertain people. And—

DR. RHONDA PATRICK: The robots are coming.

AI, Robotics, and Combating Loneliness in Old Age

DR. STEVE HORVATH: The robots are coming — the companions. 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 and upcoming robotics will give us companions at least to fill this urgent need to engage a geriatric patient. I just think it’s better if they interact with something as opposed to just sitting in a chair.

DR. RHONDA PATRICK: Yeah. Ideally, their kids would come visit them, but I guess that’s not always the case.

DR. STEVE HORVATH: It’s just not realistic. Many of these jobs that deal with geriatric patients are underpaid. There’s a shortage. So we need to think of creative ways of addressing really this need.

Using Epigenetic Clocks as a Consumer Tool

DR. RHONDA PATRICK: Well, let’s talk about— I want to talk about, we’re talking a lot about these diet, lifestyle, healthy, unhealthy patterns of living that affect the way we age. And now we have a tool that we can use to kind of give us a concrete number, to give us more data and more of an understanding of how we’re living and how that is affecting the way we age, right?

And this is obviously used at the level of research quite nicely, but it’s also something that’s available to the consumer. And I think a lot of people that are listening to this, we do have researchers listening, but we also have just people interested in their health and interested in living healthy. And everyone’s coming from a different starting point.

Some people are overweight and obese, and the thing they have to focus on is weight loss. That’s like, focus on that, and then everything else can come after, right? Some people are smokers and they need to focus on quitting smoking. Some people are not sleeping and they need to sleep. Some people are not exercising and they need to exercise, right? Vitamins, minerals, all these things come into the equation.

Some people want to do all of it. They want to do everything they can. They really want to feel as good as they can, age as good as they can, and give themselves the potential that they have to age the best way they can. And I’m definitely one of those people. I know a lot of listeners are in that category.

And so I think the excitement for them is they want to go out and perhaps try to experiment with some of these tools that are available to them. And get a baseline test of their DNA GrimAge 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 would you say to those people, in terms of, first of all, finding a reliable test? Do they have to go out and do a couple of tests to make sure you’re getting the same age at baseline, to make sure it’s a reliable test at first? And 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 VO2 max?

And then also, in addition to measuring their— either they measure their VO2 max or they measure an estimation of that, which is probably a lot more accessible to people. They can go out and do a 12-minute run test on a flat track and do the equation, get an estimation. It’s kind of what your Apple Watch does and a lot of wearable devices, but also add this DNA GrimAge and other perhaps tests of these epigenetic aging clocks in there.

DR. STEVE HORVATH: Yeah. Well, I would say several things. First of all, unfortunately, these tests are expensive. They cost several hundred dollars. And I always say, you don’t need to measure anything on yourself to know that you should stop smoking and exercise and eat vegetables.

But interestingly, longevity doctors always tell me that an epigenetic clock measure leads to better adherence. Because I go to conferences and then longevity doctors approach me and they thank me for developing epigenetic clocks. And I ask them, “Well, what are they good for in your practice?” And that’s what they say is the number one use case — that people who measure it, they are better motivated to stick to various regimens.

It’s important to, again, highlight the costs because companies are trying to develop cheaper readouts, which I very much applaud. I just want a $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, to really offer that.

But I mention it because companies will work on that, and what it then leads to is a different situation. When you go out there and you look at different providers, they may offer clocks that have been less characterized in the literature. I’m not saying these clocks are worse in any way. It’s just there’s not the same level of literature.

We discussed earlier today, there are these 5 clocks that everyone uses, why they all use a particular technology, the so-called Illumina array, and also DunedinPACE. Everyone uses that technology and therefore we can leverage legacy data that have been collected over the last 10 years, 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.

Finding a Reliable Epigenetic Clock Test

DR. RHONDA PATRICK: Where should someone— if someone wants to get one of these tests done, perhaps they have the money and they can afford it and they want the motivation because I absolutely agree that data does motivate you. What should they look for in terms of the— they want to make sure it’s one of those tests that use the Illumina array. They want to make sure it’s reliable. Does it have to say like DNA GrimAge? Does it have to say PhenoAge, the DunedinPACE? How does someone navigate that world and try to find the most reliable test to use?

DR. STEVE HORVATH: Yeah, I want to tell you that overall my reading of the community is that there are several good providers of tests, really, because the beauty of this Illumina array is that it follows a very standardized protocol, and many years of research went into how to preprocess the data, how to optimize the signal versus technical noise. That has been standardized. So I think as long as you go to a lab that has experience with generating this data, you’re in really good shape.

DR. RHONDA PATRICK: And why would people not want to go out and use the Horvath epigenetic aging clock for their biological age?

DR. STEVE HORVATH: When you use an Illumina array, they give you the Horvath clock. They will give you 100 readouts. If anything, you may get traumatized by what they give you. Remember, I started discussing various protein markers, CRP, or famous markers like plasminogen activator inhibitor 1, or various famous proteins — those also get estimated with methylation.

And maybe if I want to mention a very important innovation in the last year, really — people use methylation to estimate the ages of different organs. So it’s a blood measure, but they will say, “Your kidney is older,” or, “Your lung.” So that’s where the field is at, developing organ-specific methylation markers.

DR. RHONDA PATRICK: And those are consumer available as well?

DR. STEVE HORVATH: That’s already available to the consumer. So you may end up with a report of 50 pages, 100 pages, you may be overwhelmed by it. But you don’t need to obsess too much about who does the analysis because as long as you have access to the data, you could then apply these latest tools that are being developed to analyze it.

DR. RHONDA PATRICK: How would you do that?

DR. STEVE HORVATH: There are web pages — you upload the data to a web page and it outputs the results.

DR. RHONDA PATRICK: Like what webpage?

DR. STEVE HORVATH: I started a nonprofit foundation. It’s called the Epigenetic Clock Foundation. I know they have a calculator where people upload data and they get an output. But I just want to emphasize there are many other outlets, so you can do some Google searches on who offers—

Personal Experimentation with Epigenetic Clocks

DR. RHONDA PATRICK: I think based on our last conversation and my skepticism on using these clocks on the individual level and then trusting what’s consumer available, I haven’t really experimented with them since. It’s been years. And so now we were talking a couple of weeks ago and I was going to— I’m going to do some experiments, but we didn’t have enough time. It was 2 weeks 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, including the consumer-available tests that are out there, in seeing what I get from my data and see what room for improvement I have and whether or not it does get picked up. Because again, I’m already healthy and I do take a lot of supplements already, so.

DR. STEVE HORVATH: Yes. I want to briefly mention the most obvious medical use case — perhaps it’s really finding people who age faster and then thinking about what to do about it. And we talked about various interventions. The problem with you and me is we probably are already optimized. I would be surprised if you learn anything new, but maybe you start a completely different regimen and then it would be interesting — how does it affect your methylation readouts?

DR. RHONDA PATRICK: Right. And then presumably, don’t want to measure it when you’re sick or—

Understanding Variability in Epigenetic Clocks

DR. STEVE HORVATH: Yeah, maybe let’s talk a little bit about variability because there have also been major insights that surprised me. I’ll start maybe with the background. So we talked about these principal component-based versions of clocks such as PC GrimAge that was used in the COSMOS multivitamin study. And anyway, these are very reproducible.

To give you a number, let’s say you measured that marker 2 days apart. You measure PC GrimAge on Monday and then another measure on Wednesday and nothing has happened. I would expect a technical variation of maybe 4 or 5 months perhaps. Or 2 months. It’s a few months — this is just technical variance. But other clocks — DunedinPACE is slightly less robust, but also very high technical reproducibility.

However, if you use different types of clocks, you will get different measures. So if you take GrimAge and then compare it to what people call the Horvath pan-tissue clock, you may get very discrepant results because they measure different aspects of biology. The Horvath pan-tissue clock is very good for stem cell biology, hematopoietic stem precursors of leukemia, that type of biology — just not good for mortality risk.

DR. RHONDA PATRICK: Yeah, I think that raises another question in my mind, especially for people and consumers that are interested in maybe measuring some of these clocks and seeing where they’re at and if they’re going to do any interventions, where they’re at after the intervention. But which clock is best? So are we talking about like if you were wanting to look at the DunedinPACE and the pace of your aging versus your DNA GrimAge, right? I mean, what is— maybe you kind of need both almost, or which one?

DR. STEVE HORVATH: Absolutely. I would look at both. It’s a bit like the example of a biochemical test when you go to a doctor — do you focus on hemoglobin A1C? Do you focus on cystatin C? Give me all, let me look at it, because they do give you different lenses at the changes in the methylome.

DR. RHONDA PATRICK: But you would predict — and this is something that again, with some of these trials we’re seeing, the DunedinPACE is picked up, but then the GrimAge is not, or vice versa. And it’s like the question then becomes how these clocks were trained and developed and what they’re more sensitive to. And that’s another thing. So if you are someone that loses a lot of weight, then both would pick it up. But presumably the one that’s trained more on BMI would be more sensitive.

DR. STEVE HORVATH: Yes. Remember the exercise study that we discussed, 4.5 hours of bicycling — GrimAge was better than DunedinPACE. And so we—

DR. RHONDA PATRICK: Inflammation, right? Does GrimAge pick up inflammation?

DR. STEVE HORVATH: Yes. Yes. But we are really learning about these clocks, because all of them were built with AI machine learning models. And we are trying to understand what perturbs them, 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 the regulator what is the primary readout. You can’t tell them, “I look at 10 clocks.”

And the very fortunate situation is that there’s a Biomarker of Aging Consortium that really rigorously evaluates all of these clocks. And also substantial research funding goes into that field. There was an announcement by ARPA-H to study interventions, but also to develop biomarkers for tracking longevity interventions. And so I’m very hopeful actually that the science will advance, that next time you and I talk, I can tell you this clock is the primary readout.

The Role of AI in Advancing Epigenetic Clocks

DR. RHONDA PATRICK: How do you think AI might change these clocks and development and the progress in them as well? Are you hopeful that using AI technology will help you make them better?

Epigenetic Clocks, Yamanaka Factors, and the Future of Aging Research

DR. STEVE HORVATH: Yes, absolutely. And maybe to give you some perspective, so Ake Luu and the lab published GrimAge 2019, way before ChatGPT, before anything. And now towards 2026, and GrimAge still seems to be the best mortality predictor. To me, that’s deeply frustrating because I want to see step changes in these biomarkers. And I’m sure it can be achieved.

Now, the good news is people have already published new clocks based on AI. They do use large language models. One person, Lucas, published what he called GrimAge version 3, but there are now new clock systems, age, then there’s OmicMH. So these clocks have all come out in the last few months. And the reason why I don’t talk much about them is because they haven’t gone through this extensive review by the community. But fingers crossed that any of these newer clocks are way better than GrimAge. Why? Because we need even better clocks for clinical trials.

Yamanaka Factors and Cellular Reprogramming

DR. RHONDA PATRICK: Yeah. I think since we’re talking about new technology, and it’s something that I’m super interested in, as you know, that is this concept that goes back to the Yamanaka factors and basically the birth of these induced pluripotent stem cells, right? I mean, Shinya Yamanaka won the Nobel Prize in, was it 2006, for discovering you could add 4 transcription factor proteins. These, for people listening, are a type of protein that can change the way several different genes are expressed, activated, deactivated.

And he could add them to any cell, an old cell, a skin cell from an 80-year-old, and revert that cell to a pluripotent stem cell state, which is so cool and fascinating. And you could just sit there and think about that for hours and all the things that it means and how it happens. So the question is, what happens to the epigenome when you reset it from an older, more differentiated type of cell like the skin to a stem cell? And it seems like the epigenome changes, right?

DR. STEVE HORVATH: For sure. So back in 2013, I published the Pan-Tissue Clock. Figure 5 in that paper showed Yamanaka factor reversed the age to a prenatal state. So you take a skin cell from a 50-year-old and the epigenetic age of induced pluripotent stem cells is a negative number, meaning prenatal. And of course, so many people have worked on the idea then to apply these Yamanaka factors briefly — briefly interrupted reprogramming. There are many names in that field: Juan Carlos Belmonte, Manuel Serrano, but so many more who have worked on — David Sinclair famously, who now has a clinical trial for optic nerve regeneration based on that idea. But the idea being, apply these factors or a subset of these factors to rejuvenate organs. And why —

DR. RHONDA PATRICK: Rejuvenate but keep their identity. Their identity. Right. They’re not going to become a stem cell.

DR. STEVE HORVATH: Exactly. Because you don’t ever want a skin cell to forget that it’s a skin cell, or a liver cell that it’s a liver cell. And why is that dangerous? Cancer. That’s a great danger.

And there have been substantial developments. So on the one hand, I mentioned the study from David Sinclair where he now administers adeno-associated virus, an AAV, to the eye of people who really need to regrow optic nerve. And the study apparently will start this year, 2026. So the longevity field is waiting with bated breath. Will that succeed? It would be a triumph for the whole field. There have been extensive characterizations in mice — which kind of organs benefit if you target them — and also in vitro. So we understand quite a lot, but what companies struggle with is where exactly do you deploy it for what kind of condition, always keeping in mind to ensure safety.

The Hallmarks of Aging and Cellular Damage

DR. RHONDA PATRICK: Yeah. And there are questions in my mind that are even more mechanistic, just because that interests me, which is, if you are taking an old cell that has these hallmarks of aging — there are like 12 of them now, right? You’re talking about mitochondrial dysfunction, inflammation is now even a hallmark. It used to be just this amplifier, and it still is an amplifier, but you have proteostasis that isn’t working right. So your proteins are not folding properly and they’re also not being degraded properly. You’ve got DNA damage, nuclear damage, genome instability — all these things that happen with age in older cells. And if you’re basically just going to change the way the gene expression pattern is in the epigenome, so to speak —

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: How does that get rid of all this damage? And what doesn’t it get rid of?

DR. STEVE HORVATH: Very good question. Apparently it doesn’t get rid of all types of damage. And the obvious damage is, of course, various somatic mutations in the DNA. You just don’t touch it. The impressive part is how many hallmarks do get reset. I seem to remember one aspect that wasn’t restored was telomere length.

DR. RHONDA PATRICK: Right.

DR. STEVE HORVATH: Yeah. So that wasn’t — and also even when it comes to the epigenome, there are vestiges that don’t seem to be touched by that. Certain cytosines that do not get completely reversed. So it’s so interesting.

DR. RHONDA PATRICK: Do mitochondria get healthier?

DR. STEVE HORVATH: Yes. So mitochondria, oxidative phosphorylation.

DR. RHONDA PATRICK: What about mitochondrial DNA?

DR. STEVE HORVATH: Yeah, sorry, I forgot.

DR. RHONDA PATRICK: So mitochondria get healthier. Yes. Stem cells — do they get rejuvenated, or do they just start working better? I mean, what?

DR. STEVE HORVATH: I want to draw attention because most of our conversation was about epigenetic clocks, and now we’re talking about other readouts.

DR. RHONDA PATRICK: Yes.

DR. STEVE HORVATH: It’s important to distinguish because methylation clocks do detect a benefit of interrupted reprogramming in certain organs, but not all. I just want to allude to that.

DR. RHONDA PATRICK: Which organs do they not, or what type?

DR. STEVE HORVATH: I remember — I’m trying to think of old publications — but I remember in skin, there was a strong effect, I want to say. Also muscle. It’s just not all organs. And now I’m talking about interrupted reprogramming because, as we said, if you go all the way, you will find an effect.

But I mention it because when it comes to that intervention, you really want to measure many readouts. Above all, organ function tests — 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, or kidney — just show functional restoration.

On a molecular level, there have been very detailed analyses of gene transcription that indicate that gene expression reverts back to a more youthful profile. But there’s a problem with that statement that many people may not appreciate, which is it’s actually very difficult to build clocks based on gene expression. So what does it mean that gene expression is rejuvenated? And the field has struggled with that for many, many years.

But I can mention, so people look at so-called mesenchymal markers. Some of you may have heard of epithelial-mesenchymal transition. Cells change their phenotype as we age, in part due to inflammatory signals. So an epithelial cell forgets that it’s an epithelial cell — it thinks it’s a mesenchymal cell. But anyway, so that’s a readout, along with inflammatory markers. We mentioned oxidative phosphorylation. So various readouts that convince a researcher, “Okay, the cell seems to be younger.” If we talk about the extreme case of making an induced pluripotent stem cell —

DR. RHONDA PATRICK: Do the somatic mutations persist in that as well?

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: That’s disappointing.

DR. STEVE HORVATH: Because you cannot touch it, right? The DNA is changed.

DR. RHONDA PATRICK: Yeah. I mean, we’ve got to solve that problem.

Do Somatic Mutations Drive Aging?

DR. STEVE HORVATH: You need to ask a different question perhaps, that has a hopeful answer, which is: do somatic mutations actually matter? Now, to be clear, cancer is often due to somatic mutations. So if you say, “Does cancer matter?” Of course it does. But what happens as we age is that all cells in your body accumulate somatic mutations. They really do. And the question is, does that actually translate to biologic aging?

DR. RHONDA PATRICK: Doesn’t it depend where the mutations are?

DR. STEVE HORVATH: And you already asked the right question, because most of these somatic mutations have zero consequence. And I love that, actually. By the way, the same statement holds for methylation. As I mentioned, millions of changes, but fortunately, many of them don’t matter. But same with somatic mutations. And when you ask aging researchers how important somatic mutations are for true blue aging, you will get different answers. Some people will say it’s hugely important, and then there are other people who will say it’s negligible. The field is really split on that question.

DR. RHONDA PATRICK: Yeah. I mean, if you’re getting somatic mutations in regulatory parts of the genes, or even in promoter regions or whatever, you’d think that you start to have dysfunction at the level of the proteins, right? Things aren’t going to work properly. But again, “if” is the key word — if you get them in those regions. So you would think the more of these mutations you accumulate, the greater the chance of having one in a part that matters, right?

DR. STEVE HORVATH: For sure. I mean, we just — to be clear, we don’t want them. The question is how bad are they? Let me turn it around and ask a question to you and the audience. Imagine you had a way to completely stop somatic mutations. You have the perfect therapy. Would you stop aging?

DR. RHONDA PATRICK: I mean, can’t we use CRISPR to sort of — I mean, if there was a way you could every time you got a mutation just use CRISPR to change it?

DR. STEVE HORVATH: And also coming back to DNA repair, right? So if you have ways to improve DNA repair — I’m asking the question because my answer is the following. I think if you completely stopped somatic mutations, I think you would still age. I don’t have definitive proof, but that’s where I’m at. For me, a lot of aging —

DR. RHONDA PATRICK: But would you age slower?

DR. STEVE HORVATH: Yeah, no question. It has a benefit. You would still age. You would still age for sure.

DR. RHONDA PATRICK: But it’s not —

DR. STEVE HORVATH: No. Because aging happens at all levels. We mentioned the epigenome today a lot, but also the transcriptome and the proteome, right? Proteins aggregate, and that protein aggregation may have nothing to do with somatic mutations or even methylation. And so, damage accumulation happens at so many levels. And the debate is, in certain ways, how much do we gain if we clean up damage at a certain level?

DR. RHONDA PATRICK: All the damage.

DR. STEVE HORVATH: All the damage.

DR. RHONDA PATRICK: So there are 12 hallmarks, right? That’s why genome stability is just one. So if you take care of that, you’ve still got 11 more to take care of. You’re still going to be aging. But if you were to clean up all 12, there’s no doubt you have a benefit. Then what happens? I mean —

Silver Bullet Interventions and Organ-Specific Aging

DR. STEVE HORVATH: I liked our earlier discussion about organ transplantation, because I’m looking for a miracle intervention. I’m making something up. Imagine somebody has a pill that really prevents sarcopenia. You keep your muscle strength. Could it be that this benefits so many organs and suddenly we increase healthspan by 5 years? Or we have another pill that really preserves your kidney function. How much do you gain? So I like these silver bullet dreams. You have one intervention, you really improve one organ, and it has massive benefits.

DR. RHONDA PATRICK: Well, we know that. We know resistance training absolutely helps you not only maintain but increase your muscle mass, and that’s hugely important for life expectancy and quality of life. So I would imagine if you just improved muscle function with age, you would have an effect.

DR. STEVE HORVATH: I’m with you on that.

DR. RHONDA PATRICK: Yeah.

DR. STEVE HORVATH: But let’s now again talk about the 85-year-old. So let’s say we have such a pill, we give them this intervention and you really even restore muscle functioning. Will they suddenly live 5 years or longer? I hope they will, but I’m just saying these are the interventions. But what about their —

DR. RHONDA PATRICK: What about their cardiovascular disease risk? I mean, if it’s true that people’s organs age at different rates and there is individual variation there — so maybe my heart is aging faster than yours. Maybe you are more susceptible to your brain aging more. I don’t know. If that is true, I mean —

DR. STEVE HORVATH: It is true.

DR. RHONDA PATRICK: It is, right? I mean, that’s —

Personal Health Routines and Closing Thoughts

DR. STEVE HORVATH: We know that even from methylation clocks, yeah.

DR. RHONDA PATRICK: That even within a person, and obviously their diet and their lifestyle, everything should be the same, affecting the same organs the same, but it doesn’t, right?

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: Either it doesn’t, or there’s other things that are happening that we don’t quite understand. Where was I going with this? Yeah, that basically if our organs are aging at different rates, then obviously the muscle would only affect the people that are going to die from their falls or whatever. I think it’s an interesting question in terms of what organs are aging faster in you. And there are biomarkers that can help you understand that risk. But the aging clocks — that is something that people can now go and test, right?

DR. STEVE HORVATH: Yes, that’s where the field is at. Now I’m talking about the biomarker field in general. People have developed protein markers of various organs, which is the obvious thing — organs secrete various proteins, so measure them. The exciting aspect is that the same has happened at the level of methylation, so people have methylation readouts of different organs. I’m not saying they’re optimized. There’s room for improvement perhaps to be seen. But that’s how I envision really Medicine 2.0, preventative medicine. You measure many readouts of organ function. You diagnose that something is going the wrong way, and then you target it, you restore it — precision medicine, really.

DR. RHONDA PATRICK: I’ve done my gene array before and looked at all these different companies that are able to go and look at your SNPs or even your whole genome. And even those tests, when you get the raw data back and sort of look at them, you’ll have genes that say, “Oh, you’re predisposed to coronary heart disease,” or “you’re predisposed to neurodegenerative disease like Alzheimer’s disease.” There are even genes that are involved in predisposing you to certain diseases that are based on your organs. And so it makes sense that the methylation patterns would also play a role in that because they play a role in—

Genetics vs. Epigenetics: What Actually Moves the Needle

DR. STEVE HORVATH: Yeah, I want to briefly comment on that because I used to be a human geneticist, actually. At some point I studied genetics. And you’re entirely correct. Of course, there are these SNPs and also polygenic risk scores for various disorders, but I would like people to know these associations are absolutely minute more often than not. There are famous associations — APOE4 for Alzheimer’s, there are strong associations — but I just want you to know that if you have a genetic risk for a certain cardiovascular disease, these effects are absolutely minute and they are dwarfed by you just walking your 10,000 steps. Yes, yes.

DR. RHONDA PATRICK: Okay?

DR. STEVE HORVATH: I mean — I agree. However, interestingly, methylation is a far stronger signal than SNPs. So epigenetics is an order of magnitude more informative than genetics.

DR. RHONDA PATRICK: So looking at the epigenetic, organ-specific epigenetic clocks even.

DR. STEVE HORVATH: Yes. You just can’t compare it. I’m a health nut. I’ve spent many hundreds of dollars on various tests. Many tests have no use. But I haven’t spent money on a GWAS test. I mean, I did for Ancestry. I just want you to know that it doesn’t inform me personally. So I just think we have better readouts. We mentioned proteomics clocks, and above all, just your regular biochemical markers — just go with what the doctor orders. There’s a reason why your medical doctor doesn’t order a genetic test for you. It’s less informative.

DR. RHONDA PATRICK: Right. Yes.

DR. STEVE HORVATH: You’re not doomed if you have a bad prognosis based on genetics.

DR. RHONDA PATRICK: Exactly. Absolutely not. I mean, there are a lot of people that have APOE4 that do not have Alzheimer’s disease, and there are a lot of people with Alzheimer’s disease that do not have an APOE4 allele. It’s not a sure thing.

DR. STEVE HORVATH: There’s a hopeful message.

DR. RHONDA PATRICK: Yeah, diet and lifestyle matter, and that’s kind of the point of the conversation that we had. We were talking about these epigenetic clocks as a biomarker readout that is a little bit more comprehensive than just getting a C-reactive protein or HbA1c, or even looking at your lipid levels, because it can actually look at your biological age, right? And that’s so cool. So thank you so much for coming on. Is there anything else that we need to discuss that we didn’t get to?

DR. STEVE HORVATH: No, I think we covered everything. That was a real pleasure.

Dr. Horvath’s Personal Biological Age Results

DR. RHONDA PATRICK: Have you done any of these biological tests on yourself?

DR. STEVE HORVATH: Yes, for sure.

DR. RHONDA PATRICK: Do you like the results?

DR. STEVE HORVATH: Yeah, I do. I remember my PhenoAge 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 biological tests.

DR. RHONDA PATRICK: How old are you?

DR. STEVE HORVATH: I’m 58 right now.

DR. RHONDA PATRICK: Oh, you’re 58. You look great.

DR. STEVE HORVATH: No, I don’t. I look horrible. Thank you, but I look horrible.

DR. RHONDA PATRICK: Have you done the organ-specific one?

DR. STEVE HORVATH: Not yet. Yeah.

DR. RHONDA PATRICK: Okay.

DR. STEVE HORVATH: I am — again, I’m trying all sorts of health behaviors. I actually don’t need any readout for motivation. I’m a bit of a health nut, so I don’t—

Dr. Horvath’s Daily Health Routine and Supplements

DR. RHONDA PATRICK: So what’s your routine? What do you eat? What’s your health nut routine, your supplements?

DR. STEVE HORVATH: I go with validated interventions. We talk about omega-3, multivitamin, creatine — I take a lot. By the way, I love your podcast. I learn a lot from you. I started multivitamin after you started talking about it. That motivated me. From you, I learned the importance of having a cooling mattress for sleeping. So I implemented that advice from you.

DR. RHONDA PATRICK: Do you sleep better?

DR. STEVE HORVATH: I think so, yeah. But by the way, I love placebo effects. They always work.

DR. RHONDA PATRICK: I love placebo effects.

DR. STEVE HORVATH: Nothing wrong with that.

DR. RHONDA PATRICK: I don’t like nocebo effects, but I love placebo effects.

DR. STEVE HORVATH: That’s right. Yeah, so the reason why I mention it — I think it worked, but I don’t have hard data on that.

DR. RHONDA PATRICK: Do you take vitamin D?

DR. STEVE HORVATH: Yes.

DR. RHONDA PATRICK: Vitamin D. And you eat a lot of vegetables. Exercise? How does that come in?

DR. STEVE HORVATH: Yeah, I do every day, 30 minutes. Not too much.

DR. RHONDA PATRICK: That’s great.

DR. STEVE HORVATH: I follow routines.

DR. RHONDA PATRICK: Yeah. I mean, exercise needs to be a routine. It needs to be part of your personal hygiene.

DR. STEVE HORVATH: Yes. I also take medications against high glucose. I’m actually a pre-diabetic because of my decades of eating hundreds of grams of chocolate each day. So I take something called Acarbose. But also I take—

DR. RHONDA PATRICK: Does that have any effect on aging, Acarbose?

DR. STEVE HORVATH: I have no idea. So anyways, I take statins, I take ezetimibe — various interventions where there’s very credible evidence that they move the needle. I’m always impressed by people who swallow 120 pills, but that’s not me.

DR. RHONDA PATRICK: No, I take a lot, but not 120. Do you take ubiquinol? If you’re taking a statin, you might want to think about that because statins target the mevalonate pathway, which is HMG-CoA, important for cholesterol synthesis. That’s why it’s the most widely prescribed drug for lowering LDL cholesterol, but also that pathway is important for making CoQ10 in your mitochondria. And so that’s something to consider as well. Taking CoQ10 — I say ubiquinol, it’s the reduced form. Ubiquinone also does the trick, but you might want to look into that as well.

DR. STEVE HORVATH: Thanks. I knew I would learn something from visiting you. Will do.

Where to Follow Dr. Horvath

DR. RHONDA PATRICK: Well, Steve, thank you so much for all your contributions to the aging field and the ones that you continue to make. People can look up your publications — many, many, many publications. You’re on X. What’s your handle?

DR. STEVE HORVATH: I have a handle, Prof_Horvath — H-O-R-V-A-T-H. My Twitter account is all about epigenetic clocks and longevity interventions. But yeah, I want to thank you. I think you really do a great service to the public to educate them. All I can say is I follow you, I listen to you. I think it’s awesome.

DR. RHONDA PATRICK: Thank you. Thank you so much. I really appreciate that. Is there anywhere else you want to direct people to besides your Twitter and your publications?

DR. STEVE HORVATH: No. Stay young. Try not to stress too much, and yeah, enjoy life.

DR. RHONDA PATRICK: Enjoy life. I think that’s good. Try not to stress too much because at the end of the day, your deadline doesn’t really matter, right?

Short-Term Stress and Epigenetic Clocks

DR. STEVE HORVATH: I need to tell you, though, the hopeful message about stress is that short-term stress does not seem to affect epigenetic clocks — psychological stress. So I always love that.

DR. RHONDA PATRICK: But repeat it. Short-term — is that repeatedly or just like—

DR. STEVE HORVATH: So there is 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 these short-term stresses don’t seem to touch you, which is a hopeful message for everyone who is terribly stressed.

DR. RHONDA PATRICK: Like being worried about a podcast.

DR. STEVE HORVATH: That’s right. I have no—

DR. RHONDA PATRICK: Grant deadlines.

DR. STEVE HORVATH: Exactly. Seen evidence that this has a strong effect.

DR. RHONDA PATRICK: Well, don’t stress too hard. That’s the bottom line. Thank you so much for this conversation.

DR. STEVE HORVATH: Thank you. Yeah, it was a pleasure.

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