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

29:33Dr. Rhonda Patrick:But I mean, 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, like you can look at their sperm DNA and it changes from being obese to lean. And epigenetic changes, gene expression changes are happening. So, but even if it's on the bad side, you know, the good news is that once you're born, you can do things in your life to change things in a positive way too, right? So, it's not like, you know, even if you don't have the cleanest slate.

30:11Dr. Rhonda Patrick:Yes. Yeah, what I want to tell you briefly about sperm, that is, yes, their 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 location from the changes that we use in any of our other clocks. Another way to say it is if I take Grimm age or Pheno age or any of my clocks and apply it to sperm, it completely fails. So, for example, what is known as the Horvath pan tissue clock, you apply it to sperm, you get one number, 37 or so. But everybody has the same number in essence, you know, uninformative.

31:00It'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 tissues.

31:29Dr. Rhonda Patrick:Have there been clocks for sperm that have been developed that are more precise? Yes. I have a question about grim age, but it sort of leads us into the next clock that I want to have you discuss, which is the duoden pace, is that right? I think it's called duoden pace. Duoden pace. That's right, duoden pace. So the question I have is, you know, with the DNA grimmage, we're talking about this methylation pattern being able to predict mortality and very, you know, pretty accurately mortality risk. And it's able to measure, you know, this accumulation of damage that's changed the epigenome in a way that's obviously, you know, quantifiable.

32:12Dr. Rhonda Patrick:What if you're 45 years old, you get your DNA grim age test done, it gives you your mortality because you've had all this, you know, lifetime exposures up until the age of 45 of, you know, let's say air pollution, maybe you smoked a little bit, whatever, alcohol, poor diet, stress, chronic stress, all those sorts of things. but you change your lifestyle and it gets better. Does that grim age change? If you had asked me that question two years ago, I would have humped and hard. 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 grim age to some extent.

33:05The key word is to some extent because these changes appear to be very minor. We can talk about it later. But they have been very rigorous randomized controlled trials with supplements and medication. So there's a hopeful message. You can reverse it.

33:21Dr. 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 do it in? Yeah, so there is another widely used clock, which is known as a Dunedin PACE clock. It was developed by Dr. Moffat 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.

34:10So 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, also 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. And so it's a study where they tracked middle-aged people and younger people for many years and assessed these readouts repeatedly.

35:10For the experts, it's a longitudinal studies. And by having these longitudinal data, multiple measurements per person, they could really estimate the pace, each person's individual trajectory. So far, so good. So you have these pace measures. But then they went to the next step, which is similar to Grimmage. 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. Actually, it's a good question. I'm not quite sure what people care about. Some people want to know, let me know where I stand right now.

36:02Dr. Rhonda Patrick:Or how an intervention is affecting how they're aging, perhaps. 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 Dunedin pace 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 five clocks, I want to say, just in order to give the reader a chance to judge the evidence. Because the very best intervention will touch on many clocks.

36:53That would be a robust rejuvenation of the methylone.

36:58Dr. 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 pheno age, grim age, perhaps grim age two. And I see the duodenian pace that those are at least three of the ones that are, they seem to be. And then there's a few others that sometimes are in the mix. But those three stand out to me when I'm reading the literature, maybe because I know them the best. But those are the ones that stand out. With this disagreement, and you kind of touched on this already. you know, if you're looking at an intervention, and we're going to get into those in a minute, and you see, you know, your DNA grim age doesn't change.

37:41Dr. Rhonda Patrick:So your mortality risk is the same, or, you know, 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, these are all like, if you're changing your pace of aging, why are you not changing the grim age? And then the question in my mind is, well, how long was the trial? You know, so if you're changing the pace at which you age by 2 % and the trial was six months, is that going to be reflected in the grim age? Or, you know, what's the standard deviation here that we're even talking about with grim age, right?

38:23Yes, 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 is still a fairly good agreement. this is the typical glass half full half empty is a correlation of 0.5 high on low you know to me it's reasonably high if you have a very strong rejuvenating intervention now when it comes to i i need to tell you i'm obsessed about the question which clock is best and so I best for what for judging longevity interventions and yeah because when it comes to mortality risk prediction we know the answer right now after several large studies there was a study in Scotland generation Scotland 18 ,000 people were evaluated and grimmage was best and then there was a study from Harvard I want to say 30 ,000 people were evaluated grimmage was best.

39:43So we know which clocks is best for mortality risk prediction.

39:47Dr. Rhonda Patrick:Can I pause you right there? And I just want to make this point because usually when we have these studies, at least observational studies looking at diet, because you'll never have a randomized controlled trial that's going to last, you know, 30 years or 40 years. So if you have, if you're looking at observational data and how different lifestyle like effect or diet and lifestyle affect mortality, you're typically looking at, okay, how much seafood did they eat? How many people died from cardiovascular disease? How many people died from cancer, right? So you get this all-cause mortality, right, number.

40:20Dr. Rhonda Patrick:And what you're saying is that you can actually now, instead of having to just have observational data looking at that all-cause mortality, you can now have an intervention. We're going to give people, you know, fish or whatever. We're going to do this intervention for a period of time, And you can have the grim age, which is kind of like the surrogate all-cause mortality, but it's very actually a very good estimate of it. Am I thinking of it a little bit correctly? Yeah, you think of it correctly, and that's certainly the ambition. But I want to be very precise using the language of the FDA because I think we should do that.

40:59So the dream of the longevity field is to develop what is known as a surrogate endpoint for a clinical trial. In other words, you have a study where you apply, let's say, multivitamin for two years, and then you see a change in any clock. It could be a proteomic clock. It could be a grimmage, any other clock. And let's say you see a reversal. Now you would like to, I want to call it, jump to the conclusion that this actually translates into a lower mortality risk. and this so we we would like to think that is the case but from a regulatory perspective that hasn't been proven you know and in general the FDA evaluates biomarkers you know why they want to give guidance to companies to biotech where they say if you show us that your treatment reverses that biomarker.

42:06Therefore, 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? They are urgent questions, right? People have exciting interventions. So we need to make assumptions, you know. And for the longest time, I've been very cautious when it comes to this claim, do methylation clock meet this high standard, you know. And I'm coming around, you know, Just because I see increasing evidence that these changes track what I call validated interventions, where we know the intervention has a benefit for human mortality risk.

43:15And then I see that it also touches a methylation clock in the expected direction. it gives me confidence you know that the clock does what it's supposed to do you know so that

43:30Dr. Rhonda Patrick:that's where i'm at you know what have you what's the most robust intervention or it doesn't have to you don't tell me what the intervention is or you could but what's the most robust data that you've seen in terms of you know reversing biologic age by some of these clocks grim age pheno age? What's like? Yeah, I will start with interventions that are in certain ways boring to you and me. Why boring to you? You and I, we are hopefully healthy people and we want to optimize our health. But I want to start with people who have a condition, you know, to answer your question. HIV positive people exhibit epigenetic age acceleration.

44:18It's actually a pronounced pro-aging effect, maybe five to seven years in blood. And sure enough, if they stick to their antiretroviral therapy, that will reverse their epigenetic age. And I mention it because that… For how much? Several years. Several years. To give you a number, four or five years. Four or five years.

44:44Dr. Rhonda Patrick:Does it happen pretty immediately after taking the drug? 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 an autoimmune disease, again, that just makes sense. But yes. and metformin is an interesting intervention to many of us.

45:38The 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 answer. Omega-3 has a beneficial effect. Apparently, vitamins have an effect. The problem is that these supplements have much weaker effects. Suddenly, we talk about a couple of months of rejuvenation.

46:26Dr. Rhonda Patrick:you know so yeah and we're going to talk about those more in depth and what that means but yes i want to i want to kind of this gets me into the controversies and hype because you're talking about like these really robust effects if someone has hiv which is obviously devastating for your for your body and then they take the antivirals and that's really kind of it does have a pretty robust effect on obviously their life expectancy yes you know many different features of health as well as epigenetic aging. So that makes sense. But I've heard people out there talk about reversing their biological age by seven years in, sorry, they reverse their biological age by five years in seven months by doing lifestyle interventions.

47:11Dr. Rhonda Patrick:Is that something that you think could be a real biologic effect? Do you think that could be noise? Do you think it could be cherry picking the best clock to get whatever outcome that they're wanting? Or, I mean, how do you feel about that statement? Yes. So it's a very good question. I think the first thing I would ask, what was their BMI before they started? And many other clinical readouts. So if you start with a person who was obese, had inflammation, diabetes, many of these stressors in their lives, and they really changed everything. And they take their GLP-1 receptor, they suddenly go to the gym and they do everything right, then it would perhaps be possible.

48:07But 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.

48:18Dr. Rhonda Patrick:So you're very unhealthy. You're very unhealthy. And above all, you actually start with an epigenetic age measure, let's say grim age, that shows you are eight years older than you should be. You see, you're 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. And now they say, I changed my diet and now I reversed my age by five 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.

49:07They seem to work in people whose epigenetic age is already accelerated, you know, but not in the people who are very healthy, you know. So, but yeah, so anyways, I would be very skeptical, but I'm open-minded. I'm strictly data-driven, you know, so I would have a long conversation with that person, you know.

49:28Dr. Rhonda Patrick:Yeah, well, you make a really good point, and that is, you know, people that are already accelerating their aging at a faster rate. So they have this age acceleration, right? Their grim age is already, you know, they're going to, it's higher than it's supposed to. Is that correct? Yes, higher. Higher than it's supposed to be. You know, their biological age, their phenol age is higher. Their pace of aging is higher. So they're already age acceleration for whatever reason. They're sedentary, they're obese, they're sedentary and obese, and they smoke. Or perhaps they have vitamin deficiencies. That's another one I've seen, like vitamin D deficiency has been shown to be associated with age acceleration.

50:08Dr. Rhonda Patrick: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, like, you know, if you're already sufficient, taking a vitamin D supplement's not going to slow your aging. Exactly. The thing you're doing, you're already doing it. You're avoiding deficiency.

50:38Dr. Rhonda Patrick:And that's the key, right? Yes. You're trying to stop that. Things that cause the acceleration of aging seem to be easy, more responsive. Exactly. Yeah. 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 Grimmage. I've also heard people say that you can take this DNA Grimmage test and predict the day you're going to die, like within a month. No, no, that's not true. Okay. Now, why is that not true? Yeah. So I want to start out by commenting on insurance companies.

51:19They are in the business of predicting how long you live. If they make an error, it will cost them a fortune. And they are superb at that. And just to emphasize, they look at so much. So they will, above all, look at very traditional readouts, such as what's your blood pressure? What's your medical history? Prior history of cancer, you know, substance abuse. 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 Grimmage add something or Grimmage or another methylation? That's really the question for these companies.

52:03And scientifically speaking, I can say, yes, it adds something, but not that much. you know clearly the life insurance companies have done very well without having a methylation readout but but the exciting thing is methylation adds something but then these companies have to weigh the costs you know because these tests are not cheap they cost several hundred dollars so is it worth it to measure and by the way that's the same question for any consumer is it really worth it to you to measure it. Sorry, the other part of the, you had a second part of the question.

52:41Dr. 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 grimace 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? Yes. I want to tell you that grim age could lead to a prediction of when you die. Let's say age 85. It could. And we know, though, that this estimate is accompanied by a large error bar, plus minus six years. I'm just making it up. So let's say you're a 50-year-old, you measure your grim age, and we apply the math, the mathematical algorithm, which by the way is very complicated for estimating your age at death.

53:43But 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, right? We will say your grim age is 50. And what I want to really explain to anyone who listens is that please do not translate that age estimate in your mind into an estimate when you will die. In other words, if your grim age is 10 years younger than your calendar age, it does not mean you will now live 10 years longer than the average person.

54:47You see, you cannot compare this differential into a lifespan differential. Then what does it mean? Yes. So what does grim age really measure in a mathematical sense? What does it measure? It really measures the instantaneous hazard that you drop dead. I always say to people, it's your risk that you will die in the next year. That's how you need to think of it, you know, compared to a person of the same age and the same sex. So let's start with the 50-year-old. And let's say their grim age is 58, eight 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.

55:43Does 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... You translate that then into an estimate of your lifespan. It's easy to do, but it's a very complicated formula, certainly highly nonlinear. And as I mentioned, associated with a strong arrow bar.

56:11Dr. Rhonda Patrick:Are there companies that have consumer available tests doing that where they're measuring the grim age and then doing that translation to when you will die? Is that something you've seen? No, I have not seen that. And I'm glad because I would have a problem with that on two grounds. I find it on some level perhaps unethical, but I believe in freedom. So if people want to do something, I'm okay with it. My concern is it's scientifically unsound. It really is, you know, for the reasons I mentioned, there's a strong error bar, you know. Right. If you're talking five or six years, either way, that's a pretty big error bar for when you're going to die.

56:53Dr. Rhonda Patrick:But it seems like people are using it more to estimate their biological age, right, in a way. And that's typically what people are usually using. Yes. We use Grimmage, 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. 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.

57:43then you start to have tissue breakdown, right?

57:46Dr. Rhonda Patrick:Stem cell exhaustion, like things that are more downstream of the damage and amplification of that damage. Do these aging clocks, where do they sit on that? Yes, we have gained a lot of insights into aging in general, by the way, and also which 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.

58:43And 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 and also aspects of dna repair you know so that is part of the biology they clearly relate also to changes in what is known as cell composition. So in blood, we have many different blood cells. And some cells are aged, so-called stressed memory T-cells, cytotoxic T-cells that are exhausted. This is actually a technical term, exhausted T-cells from aging. And conversely, they're these naive T-cells.

59:49So 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.

1:00:42You radiate them, any radiation. You induce senescence. The cells can no longer proliferate. And by the way, radiation leads to double-strand breaks. It really very much stresses the cells. And wouldn't it be nice if methylation clocks pick that up? But they don't, you know. So radiation damage, at least for cells—

1:01:08Dr. Rhonda Patrick:They don't pick up double-stranded breaks even? Yes, at least when you induce it by radiation, you know. So we know radiation is very bad for you, but methylation changes do not result directly. 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.

1:01:57It'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. And at least in our hands, we did not see a beneficial effect, at least in vitro. So although I like epigenetic clocks for many studies, but they don't capture the totality of aging. So you really want to complement epigenetic clocks with other readouts.

1:02:41Dr. Rhonda Patrick:That's interesting that they're not, because you mentioned that they do track with the DNA repair process, but not… To some extent. I know I'm giving conflicting messages, but that's the biology. So, there 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. So I think the field really needs to nail that down. Yeah. I mean, well, there's a lot of things that lead to aging. It's a very complicated multifactorial process. When you actually are able to perhaps reverse biological aging, or I guess there's two ways of thinking about it.

1:03:38Dr. Rhonda Patrick:You're slowing age acceleration, right? If you're taking away something that's negatively accelerating aging or negatively affecting your health. But then also, let's say you're, if you can actually somehow slow the aging process, at least on the readout, the clock is showing that you're younger after doing something. Where do you think, do you think that's like inflammation, like these processes that are, that are, that you described that are sort of tracking with these clocks are being affected? So the, you know, mitochondrial function, inflammation, those processes are improving and the clocks are sort of picking that up?

1:04:17Yes and no. I mean, so epigenetic clocks such as Grimmage and Dunedin-Pace and Pheno-H, 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.

1:05:14Just assume you have an intervention where you really replace your bone marrow, you know, or hematopoietic stem cells that produce all of these blood cells. and you just get hematopoietic stem cells with an epigenetic age of zero, 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 do you see there are various interventions that could have a very strong effect, but they just don't touch on that biology you mentioned.

1:06:02Dr. Rhonda Patrick:If it's rejuvenating the blood, is it also perhaps rejuvenating other organs? That's a great hope. So my response is, assume not, because wouldn't it be nice? What have animal studies shown? Have they looked at that? Yes, there have been animal studies, I want to say, in the lab from Vadim Gladyshev at Harvard. And the studies, my reading of the studies is that they have been disappointing. They didn't rejuvenate other organs. If anything, there was a disappointing result that after X number of months, actually, the stem cells had aged. So the body has the memory of the old mouse, and that then aged the blood, really.

1:06:54Dr. Rhonda Patrick:So did these mice get a hematopoietic stem cell graft? Yes. They did? Yes. Vadim carried out really an elegant set of experiments, various transplantation experiments. And the scientific question is the following. Okay, 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. I thought there was some evidence that if you did some of these transplants where you take young blood and put it into older mice that rejuvenated the brain, for example, or am I, I mean, that's, I don't know if they were measuring using clocks, but they were doing cognitive function and a battery of tests and the cognitive function improved and things like that.

1:08:06No, 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. And so, yes, we know that when an old mouse is exposed to the circulation of a young mouse, it has multiple benefits, cognitive benefits, also muscle benefits. And also, importantly, epigenetic clocks get rejuvenated, many organs. So we know that again from several studies, including from Vadim Bladishev, but others have found that too.

1:09:01So yes, young circulation rejuvenates the liver, the kidney, all of that on the methylation level. But there's a problem. You disconnect these mice, so they are no longer connected. They're no longer exposed to the young circulation. Then things bounce back. The epigenetic age bounces back to that of the recipient mouse. It's very frustrating to all of us who work in the longevity field because that is a very common story. You have a powerful intervention. It actually rejuvenates the organ. The problem is it's transient, you know. But yes.

1:09:42Dr. Rhonda Patrick: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. 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 calorically 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 calorie trial. And I'd love for you to talk about this as a two-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.

1:10:26And I wanted to ask you, were the participants overweight in this trial or were they normal

1:10:34Dr. Rhonda Patrick:weight? Do you know? I don't remember. I know it's a U.S. population, so assume that they are on the chubby side for sure. Okay. Yeah. So in this trial, it was a two-year randomized clinical trial, and there was many clocks that were measured, and it seemed like they had different readouts. Do you want to talk a little bit about the findings? Yes. Yeah. I have a lot to say about weight loss. We should discuss it. But the calorie 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.

1:11:19So there was an ambition that these people would lose more weight than they did. But as everyone knows, it's so hard to adhere to a diet. So the age reduction was on some level very weak, I would say. I apologize. I don't know the number, but I remember it was weak. I mention it because later we should talk about GLP-1 receptor agonists, where the weight loss can be pronounced and there are discrepant findings, actually. But anyways, back to the calorie study. Again, there were multiple blood draws from these people. And so one could evaluate which methylation clocks pick up a beneficial effect.

1:12:07And I was disappointed that Grimm-Age and Pheno-Age did not pick up an effect. But this new clock, a new clock at the time, Dunedin Pace, really picked up an effect, which was reassuring. You know, that reassuring because everything I know about the biology of methylation clocks tells me that they should pick up a reduction in weight if it's strong enough, you know.

1:12:36Dr. Rhonda Patrick:How much weight did they lose? Do you remember? It was pretty, like, not very much. Yeah. It was not impressive to me, at least. So the clock that did pick up the… It was Dunedin and Pace. Dunedin and Pace. And in hindsight, let's discuss why it picked up the effect. Well, it's like a 2 % to 3 % slowing of the rate of aging over the two years. Yes, that's true. Yeah, so it picked it up. And it makes mathematical sense to me because Dunedin Pace, 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, Grimmage was never trained to look at weight loss.

1:13:19It was trained on mortality. so yes Dunedin Pace worked and my reading of Dunedin Pace is that it is good at that biology people losing weight it will pick it up 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, semiglutide.

1:14:17and these people really lost a lot of weight over 33 weeks. And by the way, this study was published in MedArchive. 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 a large sample size, so credible. and they looked at all methylation clocks and suddenly all methylation clocks picked it up, really all, you know. And so that's my thinking, you know, if you have a strong weight loss intervention, you have really a strong reduction in fat, lipolysis, you know, this inflammatory signal is reduced. I think all methylation clocks will pick it up.

1:15:11Dr. Rhonda Patrick:Right, and I think it goes back to this concept that we were discussing earlier, where if your baseline is unhealthy, if you are obese, you are accelerating your aging, right? You're in age acceleration mode, right? So you need to slow it down. And with any clinical trial, you always get a better signal when you're starting with something at a population that's either deficient or unhealthy, and then you're giving something to improve that deficiency or negate it or to, you know, improve their health and you get a more dramatic effect. So we know obesity accelerates aging. We know, you know, that it's associated with, you know, decrease in life expectancy, you know, increase in cardiovascular disease, type 2 diabetes, cancer, right?

1:15:57Dr. Rhonda Patrick:All these diseases of aging. So it's not surprising that you would give someone a drug that does cause rapid weight loss in a short amount of time. So you're going to get a much more robust signal. And you're obviously picking that up with the agent clocks. With the calorie trial, you know, 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 being trained on BMI, wow, that's going to make you sensitive to weight loss for sure. And so the duodenin pace clock, which is measuring the pace of aging, you would imagine would be more sensitive than something that would be.

1:16:40But, you know, my question as a longevity researcher is which clock should a clinician use? You know, if we could briefly talk about multivitamins, the study. Interestingly, here, Grim-Age found an effect, Pheno-Age found an effect based on multivitamin use. But Dunedin-Pace failed. It was not significant, you know. So and you can ask this question now for many interventions. What should be the go-to clock? And, you know, I want to stay clear of this debate because we will never agree, you know. Therefore, I just love it that the field by now simply reports at least five clocks, you know, so the reader can just look at it and be the judge.

1:17:29Dr. Rhonda Patrick:Let's talk about the multivitamin. So this was the COSMOS trial. I've talked a lot about the COSMOS trial in the context of brain aging. So the larger trials, and there was three randomized controlled trials where these older adults were given a standard centrum silver multivitamin every day. And it was 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.

1:18:10Dr. Rhonda Patrick: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 five years compared to the placebo group, which is quite significant. And they did better on a battery of cognition tests. And so that was very, that's very encouraging, you know, and it's something that I do talk about a lot because I feel like it's a very easy, safe intervention that people can take a standard multivitamin.

1:18:45Dr. Rhonda Patrick:These have a variety of vitamins and minerals, trace elements that people are not getting from their diets. And so they're who doesn't want their parents and grandparents to have better brain aging? So my parents are on a multivitamin, right? When it comes to looking at these epigenetic aging clocks, the pheno-aging grim age clocks were the ones that stood out to me. As you mentioned, there was a battery of clocks that were looked at, but it seemed as though they were slowing, or at least, I'm not exactly sure all the calculations that go into this, but 2.7 months to five months, right like they were basically they're they're slowing the aging by roughly that amount yes um which to me is if you think about now this this trial that was done with the aging clocks i think it was like a subset of it of the larger trial was it two years or did they do the 3.6 years for that do you it was yeah i think it was two years two years yeah and and so um to me the question is, now this wasn't, you said the duodenum pace didn't change.

1:19:53No, it changed in the right direction. It just wasn't statistically significant. Oh, I see. No, in the right direction, you know. Maybe a larger sample size would have led to a significant finding. It was definitely in the right direction.

1:20:08Dr. Rhonda Patrick:Well, the question I have for you is if you're changing it by, you know, three to five months within that two-year range, according to the grim age and phenol age clocks, and you're to keep doing that, you know, for years. So now we're talking not just two years, we're talking 20, we're talking 30, 40 years. Yes. How do you think that, do you think that you get this accumulative effect? Yes, I think so. I think so. Maybe to step back, if you tell an 80-year-old that a multivitamin will reduce his or her age by three months, they will roll their eyes. They will say, give me something that reverses my age by 30 years.

1:20:54So 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 age 80. my expectation is that suddenly these three-month benefit they accumulate and suddenly you have a benefit of maybe two and a half years you know it's still not great you know but there is a

1:21:27Dr. Rhonda Patrick:benefit you know so but think of the effort you have to put into just taking a multivitamin right i i think it's pretty great for that amount of effort you know if you're if you're just having to take one vitamin supplement and it's going to delay your brain aging, you know, by 2.1 years just after, you know, in that trial, it was 3.6 year trial, but, you know, that's pretty robust. Five years delaying brain, episodic brain aging. And now we're talking about like globally, like biological aging. If it's slowing it by, let's say on the high end, five months after two years, I don't know. That seems like a pretty great effect if you're just taking a vitamin supplement And for two years, it's doing that.

1:22:09Dr. Rhonda Patrick:Well, let's continue on and then combine other things. And we'll get into some of the other trials that do show synergy. But I think it's interesting. The other question is that, and this is where, you know, the COSMOS trials, people, they're looking at everything, right? Cancer, mortality, cardiovascular mortality, all cause mortality. And those didn't really seem to change, at least within the timeframe that was looked at. And so, you know, we see these epigenetic clocks giving us a signal. We see the brain aging effects. And the question is, why are those showing up before? Yeah, I tell you my reading of it.

1:22:45And to me, this whole study was one triumph for epigenetic clocks. And I explained to you why. Assume you knew nothing about multivitamins. You would think that there is a benefit. You know, clearly vitamins are important. It's a trivial tautology. Avoiding deficiencies are important. Especially, you know. So you would say, okay, I administer that to the U.S. 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.

1:23:32Okay, 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?

1:23:45Dr. Rhonda Patrick:It wasn't statistically significant. Yeah, I let you summarize it. But to me, you know, I just looked at it from the point of view as a consumer. Five years ago, you know, I wouldn't take a multivitamin. I looked at the literature. No benefit. I won't take it. now so a person can now make their own judgment you know so what does it mean to me I take it as a wonderful triumph of epigenetic clocks that they did pick up the signal and I call this testing the test you have an intervention where you really think it's gotta move the needle you know And then if a readout doesn't show it, one interpretation is, well, maybe the readout is too crude.

1:24:40Maybe all-cause mortality is a real—I mean, I like it as a readout. I used it for grim age. Don't get me wrong. I like that it's hard and definitive. You can't argue with it. However, people die for a hundred different reasons 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.

1:25:12Dr. 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 globally people are not getting enough of these important vitamins and minerals and trace elements and essential fatty acids from their diet, then it's kind of like an insurance. Like, okay, I'm going to fill some of these nutritional gaps. They won't all get filled because you can't stuff everything in one pill. I mean, you can only get a little bit of some things in there, right? Yes. But I do think that it's, again, I agree with you. I think it is a triumph and it's something that I do think that is safe.

1:25:52Dr. Rhonda Patrick: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 for, you know, looking at these aging clocks. It seems like for the way you're aging as well. Yes. Yeah. So what have you got to lose, you know? Yeah. Let's go back to maybe some of these other vitamins. There's other, I guess, lifestyle interventions as well that I wanted to cover. 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 deficiency gap or you improve your health, lose weight, whatever, then you're going to have a stronger signal, right?

1:26:51Dr. Rhonda Patrick:90 % of Americans don't get enough omega-3 fatty acids. Nobody's eating seafood in the US. It's just, you know, so you're starting with a population that's already, you know, I don't want to say deficient, but they're not getting a sufficient amount of omega-3 fatty acids. And so I think it's probably why it's easy to keep getting this stronger signal because 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. Perhaps it just keeps improving inflammation and then you'll keep seeing an effect.

1:27:27Dr. Rhonda Patrick:But it seems like many, many studies have shown that omega-3 fatty acid, whether it's from food, supplementation, a combination of both, seem to slow epigenetic aging by different clocks. Yes, there has been quite some literature. It started with observational studies that you cannot trust. But last year, we published a study which was very rigorous. This was a study conducted by a Swiss professor, Heike Bischof-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.

1:28:25Average age, I want to say 75, I think, or 73. So older people. And she evaluated famous interventions. Number one, omega-3, one gram, vitamin D. And we should talk about the intervention about vitamin D was tricky. It was high vitamin D versus low vitamin D. It wasn't vitamin D versus no vitamin D. That's a key distinction.

1:28:54Dr. Rhonda Patrick:What was the low? I know the high vitamin D was 2 ,000 IUs. Yes, and the low was 800 IUs. Oh, so it was only double. Yeah, exactly. And that's a limitation because the results for vitamin D were disappointing. No effect on epigenetic clocks, but that's why I hasten to add. Yeah, but we have other randomized controlled trials showing the opposite if you start with the deficiency and add it, and we can talk about that. Okay, so vitamin D. That's true, but yeah. But there was also another disappointing. If you look at the exercise. Yeah, we need to talk about exercise. Yeah. So this was called a home exercise intervention.

1:29:30Now, 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.

1:29:46Dr. Rhonda Patrick:It was resistance training, right? Three times a week. Yes. But it was, I'm telling you, it was mild, mild resistance training. you know but because because um no effect right i was very disappointed did you read that the the starting population 88 like around 88 percent of them already identified as being physically active exactly i mean which is if you were to get a u.s population not a chance like that there's no way you would have had that many people physically active but anyway so that's another people in switzerland hopefully they hike in the mountains they're walking everywhere exactly but that was interesting to me because i'm very interested in in that population people who already do a lot of good things.

1:30:28What can they do to improve their outcomes?

1:30:32Dr. Rhonda Patrick:Great framing of it. Yeah, so I think we already discussed the result. The most credible result was omega-3 on epigenetic clocks. A couple of epigenetic clocks picked it up, Grimmage version 2, PhenoAge, Dunedin-Pace also worked very well in that context. So nice result for omega-3. The other interventions disappointed. By themselves. By themselves. But yes, there was this one treatment arm where people actually used all three beneficial interventions, high dosage vitamin D, omega-3 plus exercise. And according to PhenoH, that treatment arm did the best. So that's the finding that we would have liked to see for all clocks.

1:31:27But it's just the phenol-age pictorial.

1:31:29Dr. Rhonda Patrick:Well, I think there was even a dose-dependent where there was the group that just got the omega-3 and vitamin D, and that also improved more than the omega-3 alone. Yes. And then all three improved the most. So you see this nice dose-dependent effect with adding in these healthy lifestyle interventions, even in an already presumably healthy population, which is exciting. And I have the numbers here. I think it was 3.8 months the biological aging was delayed by 3.8 months. Yeah, over three years. Over three years. Right. Three years of that. And that doesn't sound like a lot again, but they also correlated with some other outcomes, right?

1:32:07Dr. Rhonda Patrick:So I think there was, in all three interventions, yes, it was 3.8 months that delayed the biological aging, but also that was associated with outcomes that were important. 61 % reduced chance of getting metastatic cancer. It was like a 20 % reduction in pre-frailty, which is also nice to see these outcomes correlated with this as well, right? I agree with that. And I can tell you the same study looked at a new concept in the field called intrinsic capacity, which looks at various domains of functioning, frailty, cognition, psychology. Anyways, also intrinsic capacity was improved in that population.

1:32:51Oh, okay. So it's not just the molecular readout, yes.

1:32:54Dr. Rhonda Patrick:I think for me the take-home, again, is something that you mentioned when you have this already healthy. They have to be a healthy population of 88 % with them physically active, right? So, and you take that healthy population, you can still improve, right? You still can improve things. Do you, again, this comes down to the compounding factor, right? So this is three years. And then let's say, okay, well, they're going to start doing this for the rest of their lives. You know, decades, we're talking, well, in this case, they're a little bit older, but people listening to this podcast, maybe in their 30s, maybe in their 20s, in their 40s.

1:33:29It's like, okay, well, I'm going to start training, making sure I'm not vitamin D deficient, getting my omega-3.

1:33:36Dr. Rhonda Patrick:And then you have like, how is that going to compound over time? And I know it's speculation, but it makes sense. That's the way I think about it. I think of it the same way. I wish I could go back in time and tell myself to stop eating chocolates, which really messed me up. So, yeah, good health behaviors, you know, and supplements included, I think, will have benefit, major benefits. When it comes to vitamin D, that's the one that, I mean, this one study was a bit disappointing. But as you mentioned, I mean, comparing 800 IUs to 2 ,000 IUs, I wouldn't imagine to see a big difference there because you're already filling the gap.

1:34:16Dr. Rhonda Patrick:Exactly. And most of the participants had no insufficiency in vitamin D. they really start at normal levels. And we know there have been, in my opinion, so many studies that I've come across and read over the years showing that vitamin D deficiency causes age acceleration, in some cases severe, like three years. And if you correct that deficiency, it'll slow age acceleration, where then you say, you know, reversed aging by, you know not four years or whatever i mean so um i think my take home i know the the one that i like the the most recent one was the the base to the berlin study yes where they took which was the thing that was nice about that was they had a deficient population and then a sufficient population and gave them vitamin d yes and um this was a study in berlin and they followed people for seven years, which was also impressive, was a large population.

1:35:16And you can imagine Berlin is, of course, not blessed by sunshine. So they start out deficient, you know, so it all made sense, you know.

1:35:27Dr. Rhonda Patrick:Yeah, reverse aging, if you're deficient and feel that sufficiency, but the people that were not deficient, actually, there was no effect, which is, again, what you expect. It's not about this is a magic supplement that's slowing aging. It's not doing that. It's helping people that are deficient correct their deficiency. And that's why there's so much, even in the scientific literature with vitamin D, for example, if you're looking at outcomes, it's the same thing. And it drives me nuts when studies don't measure their baseline levels, or if they only measure 10 % of the population and then use that to extrapolate like everyone else.

1:36:03Dr. Rhonda Patrick:You can't do that. There's so many, you know, and there's gene snips that are affecting vitamin D. There's other micronutrients. Magnesium really affects vitamin D. You need magnesium to convert vitamin D3 into, you know, the steroid hormone. So there's so many different things that are affecting your vitamin D. If you don't measure it before and after, it's hard to really make a statement that it did what it did or didn't do what it was supposed to. Yes. Okay. So I want to... We should talk about exercise yeah we can go into exercise oh no but follow your script sorry oh no no we we were i was we were talking about calorie restriction and i just wanted to mention dietary patterns in general you know because you mentioned weight loss and we've talked a little bit about it with the glp1 obviously if you lose weight yes it's probably a big confounder with all some of these dietary pattern trials right like if you're getting someone who's overweight and these participants are overweight and you're putting them on a healthy diet or a Mediterranean diet or something like this, and they lose weight on all the diets, then how much of what you're seeing is due to that weight loss, right?

1:37:12Exactly.

1:37:13Dr. Rhonda Patrick:So do you want to talk about that? It was like the direct trial. Is that what it was called? Yeah. I need to tell you, I don't know too much about it, but I want to explain some properties of grim age that I'm aware of. So grim age very much correlates with what is known as carotenoid levels in the blood. So what are those? So, you know, let's maybe back off and think of nutritional studies. Many people have so-called food questionnaires where they evaluate the diet of participants. And from all I know from analyzing data is that these food questionnaires often don't reflect reality. I don't remember what I ate for breakfast.

1:37:59Dr. Rhonda Patrick:Well, I didn't eat breakfast today, but. Yeah, I mean, and people always know what they should answer, you know, but so that may bias their memory. They will say, oh yeah, I ate X servings of broccoli, but it just doesn't reflect reality. But fortunately, they're blood tests. You can measure the so-called carotenoid levels in the blood and have an objective readout of fruit-vegetable consumption. And the striking finding in postmenopausal women from the Women's Health Initiative was that this measure of vegetable intake has a strong correlation with grim age and other epigenetic clocks. Strong meaning maybe minus 0.3.

1:38:45So it's, to me, a very strong effect, which really changed my behavior. By now, I really eat a lot of vegetables.

1:38:52Dr. Rhonda Patrick:Can you translate that to like months? Like what would minus 0.3? Yeah, sorry. I could translate it, but... Or just an estimate. Yeah, no, let me put it this way. Smoking has a correlation of 0.4. So if you smoke a lot, it increases your age. Vegetable consumption, minus 0.3. So it's actually... Wow. Yeah, I was very surprised. So in this... Sorry, I add one more statistic. Exercise. The correlation would be 0.1. So do you see, so vegetable intake has a much stronger effect. I mean, orders of magnitude, stronger effect on Grimm age and these methylation clocks than, for example, exercise. 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?

1:39:47Yeah, you know, I never looked into that, but I feel that would be such a worthwhile research study. What I can tell you is this vegetable association is 100 % accurate, but now teasing it apart, what is it, you know, to be seen?

1:40:02Dr. Rhonda Patrick:Probably so many things. I mean, you've got the fiber matrix, you're getting vegetables, especially greens. And if you're talking about carotenoids, lutein, zeaxanthin, these are carotenoids that are in greens. And interesting, there's been a lot of studies coming out looking at blood levels of lutein and 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, improved brain aging in general.

1:40:43All right.

1:40:44Dr. Rhonda Patrick:And there's 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

1:40:56Dr. Rhonda Patrick:basically, I would say, buffering oxidative stress and singlet oxygen, for example, if you're talking about in the eye. But it's interesting that vegetable intake can have such a profound effect. And there was a vegan trial too, I think. Also, there was a trial looking at people that are eating a lot of vegetables versus like a healthy omnivore trial. And I I think the vegan trial, they also had to slow their epigenetic aging more. But there's always weight loss as a confounding factor because they were eating fewer calories. But that's really interesting that there's a minus 0.3. That is pretty strong.

1:41:30You gave me that reference point of smoking being, you said it was, wait, smoking was 0.4. Okay, smoking 0.4, maybe 0.45. So it's an increase correlation. Exercise 0.1.

1:41:46Dr. Rhonda Patrick:Okay. And we can talk later about exercise, but very weak effect. In order to see an effect of exercise, you really need to study many thousands of people. With vegetable intake, the effect is so strong, you probably see an effect when you analyze a couple of hundred people. But regarding the question vegan versus carnivores, I honestly have not seen convincing data. Omnivore. Omnivore, yeah. Carnivore would be the extreme opposite. That's true. Yeah, let me rephrase it. So I have not seen any evidence that people who, let's say, eat a lot of red meat age much faster than people who are vegans.

1:42:36And we looked again in the Women's Health Initiative. I mean, there was a hint, I want to say, when we analyzed 3 ,000 women and then women who ate red meat, it was barely noticeable that red meat was ever so slightly increasing epigenetic age, but it was truly negligible. So what I can tell you is I eat so much meat. Hopefully it's not bad for me. You eat meat and vegetables. I eat meat and vegetables. I try to be easy on the carbs. I eat carbs, but I try to reduce them.

1:43:08Dr. Rhonda Patrick:Well, vegetables are carbohydrates. They're just complex carbohydrates, not simple. So you're not eating the simple carbohydrates. Yeah, exactly. Yeah. That vegetable stuff is interesting. There's so much in vegetables with the micronutrients and the phytochemicals, right? That's another thing in them. The fiber. I mean, there's a lot of things going on here. Somebody should really tease that apart. What kind of vegetables should be eaten? And dosages. Lots of exciting PhD dissertations could be written on that topic. Exercise. Yes. So let's talk about that. There's a trial that you sent me that was pretty convincing, and it was a new one in 2025, showing that six months of cycling, it seemed to slow epigenetic aging or grim age, right?

1:44:02Dr. Rhonda Patrick:Grim age by 7.4 months. Yes. Maybe I'll frame it like that. So there have been very nice studies on the effect of exercise on grim age and phenage and other clocks. And so what do I mean by nice? Studies where they use one way or another a wearable to really measure your step count and activity. So it's a very rigorous readout of your physical activity. And the studies were also convincing because they were large scale studies. many thousands of people, and in different countries, Japan, Germany, US. And the finding is the following. Yes, if you move more, yes, your epigenetic clocks pick up a small effect.

1:44:52And I mentioned earlier correlation minus 0.1. What it means, you need to study 3 ,000 people, then you will see a statistically significant effect of step count, as an example. But I've been deeply dissatisfied with that finding because we all know exercise is what they call the poly pill. You know, it touches so many systems and it's very beneficial. So I would have loved to see a strong effect on blood methylation, but the literature shows weak effect.

1:45:25Dr. Rhonda Patrick:And what about muscle methylation? Yeah, so people have built clocks for muscle. so literally human muscle biopsies. I don't know what to tell you. Some people claim they see an effect, but I just am not yet convinced. It is disappointing. I would say it's disappointing. So then there's this study that was published by first author I can remember, Van Damme. I think differently spelled from the actor, But anyways, and this intervention was very different because it didn't look at step count or what we discussed earlier than home exercise intervention. That was the next level intervention. It was putting people on a bicycle and they now bicycled four and a half hours a week.

1:46:23Now, for the health nuts out there, that's not much. But to me, this is daunting. So if you forced me to bicycle four and a half hour a week, I would struggle with that. Why? We are all busy people. But anyways, the people who adhered to that trial, they had strong effects on VO2 max.

1:46:45Dr. Rhonda Patrick:20%. 20 % and many other readouts. So they didn't fake it. So they really saw physiologic benefits. And then sure enough, suddenly the clocks worked. So PC Grimmage, as an example, we keep talking about PC. PC means principal component-based Grimmage. That's a version of Grimmage that's even more robust than the original, robust in the sense of test-retest variability. It's a very reproducible measure. So anyways, it picked up a seven-month reduction in Grimmage, which again dwarfs everything we just discussed. And that was a six-month intervention. These people were younger, though. I want to say they were between 30 and 65, basically a population that you can put under such a stringent regimen.

1:47:45Dr. Rhonda Patrick:Well, they're young and middle-aged. Yes. So I would argue, Steve, that this is 10 ,000 steps. That stuff is like, okay, it's better than nothing. but if you really want to move the aging i mean like you got to go more than that and and this is the kind of stuff i mean that that we talk about on the podcast i mean i've had ben levine on he is a rock star in the cardiovascular exercise physiology world and he's done multiple randomized controlled trials but he did one that was a two-year study in 50 year olds they were about 50 year olds and they had never been physically active but they didn't have any other diseases put them on a two-year trial where they were working out, exercising about five, on average, five hours a week, doing a lot of cycling.

1:48:31Dr. Rhonda Patrick:They were doing some high-intensity interval training in there, a little bit of resistance training, but a lot of it was aerobic. And they improved their VO2 max. And their heart structure, so he looks at like the structural aging of the heart. As we age, our heart gets smaller with age. It gets stiffer. And they improve the structure of their hearts by, it was like, if you, basically it looked like they reversed aging by about 20 years. Their hearts, you know, got bigger and they were more flexible and it looked more like a 30 year old, even though they were 52 at the end of the trial. And so I would argue that, you know, doing, really taking time to exercise every day, something and, and more than just walking, you know, is very powerful for longevity and for, you know, slowing age acceleration.

1:49:23Dr. Rhonda Patrick:And so it is really nice to see this new trial because I have also been very disappointed in, you know, some of the data, but no one's really doing these kinds of studies where they're saying, hey, again, it's like getting a stronger signal. Let's not just walk. Let's not just do 10 ,000 steps, let's push them to improve their VO2 max by 20 % and see what that does to their aging clocks, right? Yes. Now we know. You know, I mean, this study didn't have a control arm. We should mention that, you know. But I certainly was impressed by that. And it's hard to argue against exercise, you know. Yeah.

1:50:02Dr. Rhonda Patrick:I mean, there's so many studies showing it improves outcomes, right? Cancer mortality, cardiovascular mortality, all-cause mortality. It improves. brain aging, Alzheimer's disease risk is lowered, everything, like all these age-related diseases, frailty, you know, you're stronger, you're more capable, you're healthier, your heart's working better, your lungs are working better, it's improving organ function. So we know it's good for aging, for sure. And so it's nice to see that, I mean, there might be a real threshold to pick it up with this epigenetic clocks where you have to kind of put in the effort.

1:50:36Exactly. And so are you going to put in more effort now? Yeah, I will try. Yeah, definitely. You know, hopefully there'll be more studies.

1:50:46Dr. Rhonda Patrick: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, you know, because I want to see a 10-minute hit, you know, every day. Like, how is intensity affecting it? How is volume, duration? I mean, there's so many things to look at. You know, we need to develop exercise in a pill for people who have lost mobility. It's never going to happen. What do you tell someone who is in a wheelchair? What do you tell to an 85-year-old? You know, so we need to develop interventions that still rejuvenate them. It's low aging.

1:51:26Dr. Rhonda Patrick: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 look at an epigenetic agent clock. So 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 like getting on a stationary bike and, you know, doing about 100 watts. So you're for 20 minutes and then comparing that to like a 20-minute sauna and you get a lot of the similar benefits.

1:52:02Dr. Rhonda Patrick:You get improvements in blood pressure, improvements in your resting heart rate. You get, you know, again, 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, you know, Steve, like I don't, I mean, maybe we'll, get that, but it seems like... Yeah, I'm joking. Yeah, I know. We need something. It seems like a moonshot. I want to briefly comment on body temperature. There has been a very elegant study in mice. So it turns out if you stimulate certain neurons in the brain, the pre-optic nerve, I think, you can actually lower the body temperature of a mouse.

1:52:49And there There was a team in Harvard, Zinisa of Ratin, who did just that in the mice. And he lowered the body temperature of the mice, I want to say, by three degrees Celsius, some order of magnitude. And then he just looked at their methylation clocks, multiple organs. And guess what? Very strong effect. So the mice whose body temperature was lowered, they really aged substantially more slowly than a control mouse. To me, that was very interesting.

1:53:22Dr. Rhonda Patrick:Well, their metabolism has probably slowed. Inflammation, because if you're going colder, vasoconstriction also happens, I would assume. Yes. I mean, so inflammation maybe. It's interesting, you know, so I just want to mention. So the benefits of sauna and all of that are undisputed, you know, but I just want to mention that maybe lowering your core body temperature by a degree or so could be beneficial. Who knows? During hibernation, animals that hibernate? Yeah, same thing. There have been a couple of studies that suggest that there's a slowing of aging. We did such a study at UCLA. We looked at marmots in Colorado, I think.

1:54:12And sure enough, during hibernation, the methylation clocks didn't advance. you know so yeah so interesting it is it's interesting i think i think that things kind of

1:54:22Dr. Rhonda Patrick:just you know just i think people need to realize that just normal metabolism normal neuro you know fear firing of you know cognitive function and you know neurotransmitter firing away all this stuff is producing damage you know so if you're just in if you're just in this slow everything down um i say cold i associate the cold with slowing it down um but at least in the hibernation state for sure everything slowed down and so that would kind of make sense that you're kind of just slowing the whole process yeah yeah makes sense so um sleep is something that you and i were discussing off camera where there's just not a lot of evidence we all know sleep is good for us we'd like to see more evidence i mean there may be some observational studies but there are lots of confounders there.

1:55:10Yes. So I worked with a team at UCLA, Judith Carroll, and she looked at sleep disturbances in the Women's Health Initiative and other cohorts. And sure enough, people who report severe sleep disruptions, these people exhibited increased epigenetic age. No surprise here. I mean, it was an observational study. I know that people are looking at that, especially now we have these wonderful tools for tracking sleeping. So 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.

1:56:01Dr. Rhonda Patrick:Yeah, I think we know that sleep deprivation, chronic sleep deprivation increases inflammation, changes your appetite, people gain weight too. I mean, so there's all the reasons why it would accelerate aging and that would make sense. But yeah, I don't know that there's enough evidence looking at the specific stages of sleep and there's a lot to tease apart there and, you know, a lot more research to be done in that area. Yes. But another area that's very exciting has to do with our mental health and our social relationships. Yes. Right? I mean, that's... This was the biggest surprise to me in the last six months, perhaps.

1:56:37So I need to tell you, I'm not a social scientist. I don't study behavior. I really am not, you know. So anyways, there was a researcher at Harvard, Laura Kaczynski. I butcher her last name, but she is a very rigorous scientist, and she wanted to evaluate what she calls, I think, social cumulative advantage, which is a measure of how connected you are in the community, your social behavior, your friends, your community. Anyways, how does that affect biologic aging? And this is similar to the vitamin study we just said. It's got to have an effect, right? I mean, so we all know loneliness is the big killer in the elderly at the level of smoking, right?

1:57:35You don't want to be lonely and socially deprived. So anyways, she did a very rigorous study, large sample size, and she evaluated everything a researcher would evaluate. So what am I talking about? You want to evaluate cortisol levels, various hormones that measure stress. You want to measure inflammatory markers, you know, IL-6 and various other readouts of inflammation. But fortunately, she had enough research funding, apparently, to measure methylation. Because I say that because if I had been a researcher, I would have focused on urine and blood. for measuring hormones and inflammation. And for methylation, I would have advised that don't even measure it because I just don't think you pick that up.

1:58:31And why do I say that? Why would your connectivity, your friends, your relationship with your spouse and your family, why would that translate to changes on the DNA molecule in blood? 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 Grimmage, again, picked it up. People who are blessed, really, by having wonderful family relations, community, just this social advantage. Sure enough, their grim age was reduced. So it really taught me something.

1:59:30Dr. Rhonda Patrick:Do you know how much it was reduced? Do you remember? No. You know, my problem is I only ever look at p-values. I'm a statistician. I know everyone always wants to know how many months, but I just go by p-value. You know, there's a lot of things here. I had Arthur Brooks on, and he talks about the science of happiness. He's amazing, by the way. If you don't follow him on X, you should. He's got really great, you know, 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.

2:00:05Dr. Rhonda Patrick:yes but you know if you think about the flip side of that the loneliness and not having those social relationships there's also the possibility that the relationships were unhealthy and so people separated from that you know there's so there's stress probably that's involved in that equation yeah too um loneliness itself has been shown to increase stress you know as as was picked up on this this study and others but um there's a lot of i think nuance there with respect to you know if you're someone that has a lot of social relationships um versus someone that doesn't and like a lot of times you look at the people that don't there's usually some trauma too right and that definitely would cause a stress or that's a stressor i couldn't agree more if you're in a toxic relationship get out right of course you know right don't tolerate abuse i mean just for sure you know but those things probably make leave their mark on the epigenome that stress Yeah, I need to tell you, I always like studies that actually show the opposite from what I report.

2:01:08I want studies that show that people who are terribly stressed and depressed and don't sleep well, that they don't age too fast, you know. Have you seen that study? So I'm always happy when a sleep study shows only a weak effect, you know, because I'm rooting for these people, you know. But I'm not sure. So let me say something about the elderly. Again, loneliness is the big killer in old age. And unfortunately, geriatric patients are often isolated. You know, many of their friends have died. And what to do about it? And there have been very nice studies in Japan, of course, where they deploy various robots, you know, to entertain people.

2:01:59The robots are coming. The robots are coming, the companions, you know, and maybe to a Western audience, this is culturally a little bit alienating. But I look at it as an opportunity because maybe this AI revolution, you know, and then upcoming robotics will give us companions, at least to fill this urgent need to engage a geriatric patient. I just think it's better if they interact with something as opposed to just sitting in a chair, you know.

2:02:34Dr. Rhonda Patrick:Yeah. Ideally, their kids would come visit them, but I guess, you know, that's not always the case. It's just not realistic. You know, many of these jobs that deal with geriatric patients are underpaid. There's a shortage, you know. So we need to think of creative ways of addressing really this need, you know. Well, let's talk about, I want to talk about. And 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.

2:03:20Dr. Rhonda Patrick:And this is obviously used at the level of research quite nicely. But it's also that's something that's available to the consumer. And I think a lot of people that are listening to this, we do have researchers listening, but we also have just people interested in their health and interested in living healthy. And everyone's coming from a different starting point. Some people are overweight and obese. And the thing they have to focus on is weight loss. That's like focus on that. And then everything else can come after, right? Some people are smokers and they need to focus on quitting smoking. Some people are not sleeping and they need to sleep.

2:03:54Dr. Rhonda Patrick:Some people are not exercising and they need to exercise, right? Vitamins, minerals, all these things come into the equation. Some people want to do all of it. They want to do everything they can. They really want to feel as good as they can, age as good as they can, and give themselves the potential that they have to age the best way they can. And I'm definitely one of those people. I know a lot of listeners are in that category. And so I think the excitement for them is they want to go out and perhaps try to experiment with some of these tools that are available to them and get a baseline test of their DNA grim age or something and see what their biological age is and do they have room for improvement and can they start to improve things and then see that improvement?

2:04:35Dr. Rhonda Patrick:What would you say to those people like in terms of like, first of all, finding a reliable test? Do they have to go out and do a couple of tests to make sure you're getting the same age at baseline to make sure it's a reliable test at first? and is it something that you think people can use? Let's say they find a reliable test. They establish that they got close to the same age a couple of times. Then can they perhaps start doing the cycling for six months and improving their VO2 max and then also in addition to measuring their, either they measure their VO2 max or they measure an estimation of that, which is probably a lot more accessible to people.

2:05:13Dr. Rhonda Patrick: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 grimmage and other, perhaps, you know, tests of these epigenetic aging clocks in there. Yeah. Well, I would say several things. First of all, unfortunately, these tests are expensive. They cost several hundred dollars. And I always say, you don't need to measure anything on yourself to know that you should stop smoking and exercise and eat vegetables, you know. But interestingly, longevity doctors always tell me that an epigenetic clock measure leads to better adherence.

2:06:02Because I, you know, I go to conferences and then longevity doctors approach me and they thank me for developing epigenetic clocks. And I ask them, well, what are they good for in your practice? And that's what they say is 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, you know, to really offer that, I think.

2:06:51But I mention it because companies will work on that. And what it then leads to is a different clock. So when you go out there and you look at different providers, they may offer clocks that have been less characterized in the literature. I'm not saying these clocks are worse in any way. It's just there's not the same level of literature. We discussed earlier today there are these five clocks that everyone uses, why they all use a particular technology, the so-called Illumina array. and also do need and pays. 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?

2:07:47Whereas if you lower the cost, you don't have these legacy data. So less characterized.

2:07:52Dr. 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 Grimm age? Does it have to say Pheno age? The duoden and PACE? How does someone navigate that world and try to find the most reliable test to use? Yeah, I want to tell you that overall, my reading of the community is that there are several good providers of tests, really, you know, because the beauty of this Illumina array is that it follows a very standardized protocol, you know, and many years of research went into how to pre-process the data, how to optimize the signal versus technical noise, you know, so that has been standardized.

2:08:54So I think as long as you go to a lab that has experience with generating this data, you're in really good shape.

2:09:04Dr. Rhonda Patrick:And why would people not want to go out and use the Horvath epigenetic agent clock for their biological age? No, you know, 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. Anyways, various famous proteins 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.

2:09:53It'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.

2:10:07Dr. Rhonda Patrick:And those are consumer available as well? That's already available to the consumer. So you may end up with a report, 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. How would you do that? You know, there are webpages. You upload the data to a webpage and it outputs the results. Like what webpage? Yeah. I started a non-profit foundation. It's called Epigenetic Clock Foundation. I know they have a calculator where people upload data and they get an output.

2:10:58But I just want to emphasize there are many other outlets, you know, so you can do some Google searches on who offers that.

2:11:08Dr. Rhonda Patrick:Well, I've kind of not, I think based on our last conversation and my skepticism on, you know, using these clocks on the individual level and then trusting what's consumer available, 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'm going to do some experiments, but we didn't have enough time, two 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 and 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.

2:11:52Dr. Rhonda Patrick:Because, again, I'm already healthy and I do take a lot of supplements already. 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? Right. And then probably presumably don't want to measure it when you're sick.

2:12:38Yeah, 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 Grimmage that was used in the Cosmos multivitamin study. Anyway, these are very reproducible. And to give you a number, let's say you measured that marker two days apart. You measure PC Grimmage on Monday and then another measure on Wednesday and nothing has happened. I would expect a technical variation of maybe four or five months, perhaps, or two months. It's a few months, you know.

2:13:28And so this is just technical variance, you know.

2:13:38But other clocks, Dunedin Pace is slightly less robust, but also very high technical reproducibility. However, if you use different types of clocks, you will get different measures. So if you take Grimmage and then compare it to what people call Horvath pan-tissue clock, you may get very discrepant results because they measure different aspects of biology. The Horvath pan-tissue clock is very good for stem cell biology, hematopoietic stem cells, precursors of leukemia, that type of biology. Just not good for mortality risk.

2:14:24Dr. 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, you know, which clock is best? So are we talking about, like, if you're wanting to look at the duodenum pace and the pace of your aging versus your DNA grim age, right? I mean, what is, maybe you kind of need both almost. Absolutely. I would look at both, you know. I really would. It's a bit like the example of a biochemical test when you go to a doctor, you know.

2:15:07Do 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 methyl hormone.

2:15:21Dr. Rhonda Patrick:But you would predict, and this is something that, again, with some of these trials we're seeing, the duodendin pace is picked up, but then the grim age is not, or vice versa. And the question then becomes how these clocks are, I don't know, trained and developed and what they're more sensitive to. And that's another thing. So if you are someone that loses a lot of weight, then you would, you know, both would pick it up. But presumably the one that's trained more on BMI would be more sensitive. Yes. Remember the exercise study that we discussed, four and a half hours of bicycling. Grimmage was better than Dunedin Pace, you know.

2:16:02And so we -

2:16:03Dr. Rhonda Patrick:Inflammation, right? Does grimmage pick up inflammation? Yes. Yes. But, you know, we are really learning about these clocks, you know, because all of them were built with AI machine learning models. And we are trying to understand what perturbs them, you know, what kind of interventions touch them. And ultimately, what the field needs to develop is what we discussed earlier, surrogate endpoints for a clinical trial. Because when you do a clinical trial, you need to tell the regulator, what is the primary readout? You can tell them, I look at 10 clocks. And the very fortunate situation is that there's a biomarker consortium, biomarker of aging consortium, that really rigorously evaluates all of these clocks.

2:16:59and also substantial research funding goes into that field. There was an announcement by ARPA-H to study interventions but also to develop then biomarkers for tracking longevity interventions. And so I'm very hopeful actually that the science will advance that next time you and I talk, I can tell you this clock is the primary readout.

2:17:27Dr. 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 get them better? Yes, absolutely. And maybe to give you some perspective. So, Ake Lu in the lab published Grimmage 2019, way before ChatGPT, before anything. And now it's 2026 and Grimmage still seems to be the best mortality predictor. To me, that's deeply frustrating because I want to see step changes in these biomarkers. And I'm sure it can be achieved. Now, the good news is people have already published new clocks based on AI. You know, they do use large language models.

2:18:22one person Lucas published what he called Grimmage version 3 but they 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 grim age. Why? Because we need even better clocks for clinical trials. Yeah.

2:18:58Dr. Rhonda Patrick:I think since we're talking about new technology and, you know, it's something that I'm super interested in, as you know, that is, and it's just this concept that goes back to the Yamanaka factors and basically the birth of these induced prepotent stem cells, right? I mean, Chinya Yamanaka won the Nobel Prize in, was it, 2006 for discovering you could add four transcription factor proteins. These, for people listening, are a type of protein that can, you know, change the way several different genes are expressed, activated, deactivated. and he could add them to any cell, old cell, a skin cell from an 80-year-old, and revert that cell to a pluripotent stem cell state, which is so cool and fascinating.

2:19:54Dr. Rhonda Patrick:And you could just sit there and think about that for hours and all the things that it means and how it happens and just on and on. So I think we talked a little bit about this in our last conversation, which is You know, what happens to the epigenome when you reset it from like an older, more differentiated type of cell like the skin to a stem cell? And it seems like the epigenome changes, right? For sure. So back in 2013, I published the Pan Tissue Clock. Figure five in that paper showed Yamanaka factors reversed the age to a prenatal state. So you take a skin cell from a 50-year-old and the epigenetic age of an induced pluripotent stem cells is a negative number, meaning prenatal.

2:20:47And of course, so many people have worked on the idea then to apply these Yamanaka factors briefly and briefly interrupted reprogramming. There are many names in that field, Juan Carlos Belmonte, Manuel Serrano, but so many more have worked on. David Sinclair famously, who now has a clinical trial for optic nerve regeneration based on that idea. Yeah, but the idea being, so apply these factors or a subset of these factors to rejuvenate organs. And why interrupt?

2:21:31Dr. Rhonda Patrick:Rejuvenate, but keep their identity. They're not going to become a stem cell. Exactly, because you don't ever want that a skin cell forgets that it's a skin cell or a liver cell, that it's a liver cell. And why is that dangerous? Cancer. That's a great danger. And there have been substantial developments. So on the one hand, I mentioned the study from David Sinclair, where he now administers adeno-associated virus and 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 a bated breath. Will that succeed?

2:22:22It would be a triumph for the whole field. There have been extensive characterizations in mice. So which kind of organs benefit if you target them and also in vitro. So we understand quite a lot. But what companies struggle with is where exactly do you deploy it? For what kind of condition? Always keeping in mind to ensure safety. Yeah.

2:22:53Dr. Rhonda Patrick:And there's questions in my mind that are even more mechanistic, you know, just because that interests me, which is, you know, if you're taking an old cell that has these hallmarks of aging, there's like 12 of them now, right? You're talking about mitochondrial dysfunction. You know, inflammation is now even a hallmark. It used to be just this amplifier that still is an amplifier. But, you know, you have your proteostasis isn't working right. So your proteins are not folding properly and they're also being not degraded properly. You've got DNA damage, nuclear damage, genome instability, all these things that happen with age in older cells.

2:23:37Dr. Rhonda Patrick:and if you're going to change, if you're basically just going to change the way the gene expression pattern is in the epigenome, so to speak. Yes. Like, how does that get rid of all this damage? And what doesn't it get rid of? Yeah, apparently it doesn't get rid of all types of damage. And the obvious damage is, of course, various somatic mutations in the DNA. if 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. Right, imagine that. 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.

2:24:31So certain cytosines that do not get completely reversed. It's so interesting.

2:24:39Dr. Rhonda Patrick:Do mitochondria get healthier? Yes. So mitochondria oxidative phosphorylation. What about mitochondrial DNA? Yeah, sorry. I forgot. So mitochondria get healthier. Yes. Stem cells get rejuvenated? Do they just start working better? I mean, what? I want to draw on attention because most of our conversation was about epigenetic clocks. And now we talk about other readers. Yes. It's important to distinguish because methylation clocks do detect a benefit of interrupted reprogramming in certain organs, but not all. I just want to alert people to. Which organs do they not or what should they do? do you talk?

2:25:28I know I remember, I'm trying to think of old publications, but I remember in skin, there was a strong effect, I want to say, also muscle, you know, it's just not all organs. And now I'm talking about interrupted reprogramming, because as we said, if you go all the way, you will find an effect, you know, but I, I mentioned it because when it comes to that intervention, you really want to measure many readouts that we discussed, you know, so above all, organ function test, you know, so depending on the target organ, you need to really establish that it works well. As an example, if you study the liver, really measure the liver functioning, you know, or kidney, you know, that just show functional restoration.

2:26:19On a molecular level, there have been very detailed functions of gene transcription that indicate that the gene expression reverses, reverts back to a more youthful profile. But there's a problem with that statement that many people may not appreciate, which is, It's actually very difficult to build clocks based on gene expression. So what does it mean that gene expression is rejuvenated? The field has struggled with that for many, many years. But I can mention, so people look at so-called mesenchymal markers. So some of you may have heard epithelial mesenchymal transitions. So cells change their phenotype as we age, in part due to inflammatory signals.

2:27:20So an epithelial cell forgets that it's an epithelial cell. It thinks it's a mesenchymal cell. But anyway, so that's a readout. Inflammatory markers. We mentioned oxidative phosphorylation. So various readouts that convince a researcher, okay, the cell seems to be younger.

2:27:43Dr. Rhonda Patrick:If we talk about the extreme case of making an induced pluripotent stem cell, do the somatic mutations persist in that as well? Yes. That's disappointing. Because you cannot touch it, right? It's a DNA is changed. Yeah, I mean, it's just, we got to solve that problem. No, but you need to ask a different question perhaps that has a hopeful answer perhaps, which is do somatic mutations actually matter? Now, to be clear, cancer is often due to somatic mutations. So if you say, does cancer matter? Of course it does. But what happens as we age, all cells in your body accumulate somatic mutations. They really do.

2:28:30And the question is, does that actually translate to biologic aging?

2:28:39Dr. Rhonda Patrick:Doesn't it depend where the mutations are? Of course. 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 are somatic mutations 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.

2:29:24Yeah.

2:29:24Dr. Rhonda Patrick:I mean, if you're getting somatic mutations in regulatory parts of the genes or even, you know, parts that are promoter or whatever, I mean, you'd think that you start to have dysfunction 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, I mean, obviously, if you get more and more of these mutations, then the chance of you having it in a part that matters goes up, right? For sure. Sure. I mean, just to be clear, we don't want it. The question is, how bad are they? Let me turn it around and ask a question to you and the audience.

2:30:04Imagine you had a way to completely stop somatic mutation. You have the perfect therapy. Would you stop aging?

2:30:13Dr. 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. Yeah, and also coming back to DNA repair, right? So let's say you have ways to improve DNA repair. I'm asking the question because my answer is the following. I think if you stopped all sorts of, if you completely stopped somatic mutations, I think you would still age. I don't have definitive proof, but that's where I'm at, you know. For me, a lot of aging… But would you age slower? Yeah, no question. It has a benefit. You would still age. You would still age for sure.

2:31:00It's not…

2:31:01Dr. Rhonda Patrick:But you would. Because aging happens at all levels. We mentioned the epigenome today a lot, but also the transcriptome and the proteome. Proteins aggregate. And that protein aggregation may have nothing to do with somatic mutations or even methylation. And so, I mean, 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? All the damage. So there's 12 hallmarks, right? That's why, I mean, obviously genome stability is just one. So if you take care of that, you've still got 11 more to take care of. You're still going to be aging.

2:31:45Dr. Rhonda Patrick:So if you were to clean up all 12, then what happens? But you know, I liked our earlier discussion about, let's say, organ transplantation, because I'm looking for a miracle intervention. I'm making something up. Imagine somebody has a pill that really prevents sarcopenia. You keep your muscle strength. Could it be that this benefits so many organs and suddenly we increase healthspan by five 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.

2:32:35Dr. 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 mean, I would imagine if you just improved muscle function with age that you would have an effect. I'm with you on that, you know. Yeah. But let's now again talk about the 85-year-old. So, let's say we have such a pill. we give them this intervention and you really even restore muscle functioning, will they suddenly live five years longer? I hope they will, but I'm just saying these are the interventions that are exciting to me.

2:33:18But what about their cardiovascular disease risk?

2:33:20Dr. Rhonda Patrick:I mean, if it's true that people's organs age at different rates and there is individual variation there, So, you know, maybe my heart is aging faster than yours. Maybe you are more susceptible to your brain aging more. I don't know. Like, if that is true, I mean. It is true. It is, right? I mean, that's. We know that even from methylation clocks, yeah. That even within a person and, you know, obviously their diet and their lifestyle, everything's like should be the same, affecting the same organs, the same, but it doesn't, right? Yes. Either it doesn't or there's other things that are happening that we don't quite understand.

2:34:01But where was I going with this?

2:34:05Dr. Rhonda Patrick:Yeah, that basically if our organs are aging at different rates, then, you know, obviously the muscle would only affect the people that are going to die from their falls or whatever. You know, I don't know. I think it's an interesting question in terms of like what organs are aging faster in you. And there's biomarkers that can help you understand that risk, but the aging clocks, that is something that people can now go and test, right? Yes, that's where the field is at. And now I'm talking about the biomarker field in general. So people have developed protein markers of various organs, which is the obvious thing.

2:34:47Organs secrete various proteins or 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 are optimized. There's room for improvement, perhaps, to be seen. But that's how I envision really medicine 2.0, preventative medicine. You measure many readouts of organ function. You diagnose that something is going the wrong way. And then you target it. You restore it. Precision medicine, really.

2:35:26Dr. Rhonda Patrick:I even, you know, I've done my gene array before and looked at, there's like all these different companies that are able to go and look at your SNPs or even your whole genome. And even those tests, when you get the raw data back and sort of look at them, you'll have genes that say, oh, you're predisposed to coronary heart disease. Or, you know, so they're already sort of targeting organs or neurodegenerative disease like Alzheimer's disease. We know there are even genes that are involved in predisposing you to certain diseases that are based on your organs. And so it makes sense that the methylation patterns would also play a role in that because they play a role in gene function.

2:36:05Yeah. 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 that people know these associations are absolutely minute, more often than not. I mean, they are famous association, APOE4 for Alzheimer's. They're a strong association. But I just want you to know that if you have a genetic risk for a certain cardiovascular disease, These effects are absolutely minute and they are dwarfed by you just walking your 10 ,000 steps.

2:36:49Yes, yes. I agree. However, interestingly, methylation is a far stronger signal than SNPs. So epigenetics, order of magnitude more informative than genetics.

2:37:06Dr. Rhonda Patrick:So looking at the epigenetic, organ-specific epigenetic clocks even. Yes, it's just you can't compare it. I'm a health nut. I spent many hundreds of dollars on various tests. Many tests have no use. But I haven't spent money on a 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. Right, yes.

2:37:52You're not doomed if you have a bad prognosis based on genetics. Exactly, absolutely not.

2:37:59Dr. Rhonda Patrick:I mean, there's a lot of people that have APOE4 that do not have Alzheimer's disease. And there's a lot of people with Alzheimer's disease that do not have an APOE4 allele. So it's not a hopeful message. 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.

2:38:41Is there anything else that we need to discuss that we didn't get to so much? No, I think we covered everything. That was a real pleasure.

2:38:50Dr. Rhonda Patrick:Have you done any of these biological tests on yourself? Yes, for sure. Do you like the results? Yeah, I do. You know, so I remember a phenol age result a couple of, maybe half a year ago. I was 13 years younger, if I remember that. I like that. So I'm actually doing well on various biologic tests. How old are you? I'm 58 right now. Oh, you're 58. Wow, you look great. Yeah. No, I don't. I look horrible. Thank you, but I look horrible. Have you done the organ-specific one? Not yet, you know, so, yeah. Okay. Again, I'm trying all sorts of health behaviors. I actually don't need any readouts for motivation.

2:39:37I'm a bit of a health nut. So what's your routine?

2:39:41Dr. Rhonda Patrick:What do you eat? What's your health nut routine, your supplements? I go with validated interventions. We talk about omega-3, multivitamin, creatine I take a lot. By the way, I love your podcast. I learn a lot from you. Thank 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. Are you sleeping better? Do you sleep better? I think so, yeah. But by the way, I love placebo effects. They always work. I love placebo effects. Nothing wrong with that, you know.

2:40:24Dr. Rhonda Patrick:I don't like nocebo effects, but I love placebo effects. That's right. Yeah, so the reason why I mention it, I think it worked, you know, but I don't have hard data on that. Do you take vitamin D? Yes. Vitamin D. And you eat a lot of vegetables. Exercise, how does that come in? Yeah, I do. Every day, 30 minutes, you know, not too much. No, that's great. I follow routines. Yeah. I mean, exercise needs to be a routine. It needs to be part of your personal hygiene. Yes. I also take medications against high glucose. I'm actually a pre-diabetic because of my decades of eating hundreds of grams of chocolate each day.

2:41:08So I take something called acarbose. Does that have any effect on aging, acarbose? I have no idea.

2:41:21So anyways, I take statins. I take ezetimibe, you know, so various interventions where there's very credible evidence, you know, that they move the needle. I'm always impressed by people who swallow 120 pills, but it's not me. I take a lot, but not 120. Do you take ubiquinol if you're taking a statin?

2:41:44Dr. Rhonda Patrick:You might want to think about that because statins target the melvanite 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. So, taking CoQ10. I say ubiquinol. It's the reduced form. Ubiquinone also does the trick. But you might want to look into that as well. Thanks. I knew I would learn something from visiting you. Well, do. Well, Steve, thank you so much for all your contributions to the aging field.

2:42:22Dr. Rhonda Patrick:Thank you. the ones that you continue to make. People can look up your publications, many, many, many publications. Where else, you're on X, what's your... I have a handle, prof underscore 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. Thank you. Thank you so much, Steve. I really appreciate that. Is there anywhere else you want to direct people to besides your Twitter and your publications?

2:43:12No. Stay young. Try not to be stressed too much, you know, and enjoy life.

2:43:19Dr. 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. I need to tell you, the hopeful message about stress is that short-term stress does not seem to affect epigenetic clocks. Psychological stress. So I always love that. But repeat it. Short-term, is that repeatedly or just like? So there is some literature that really severe psychological stress. We're talking now childhood sexual abuse, perhaps even PTSD. that affects 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.

2:44:02Like being worried about a podcast. That's right. Grant deadlines. Exactly. So I've never seen evidence that this has a strong effect. Well, don't stress too hard. That's the bottom line.

2:44:14Dr. Rhonda Patrick:Thank you so much for this conversation. It was a pleasure. I want to thank Dr. Steve Horvath for joining me today. and for giving us such a clear, rigorous, and nuanced tour through one of the most important frontiers in aging science. Steve is one of those rare scientists whose work did not just contribute to a field. He helped define it. If you haven't already, you should follow Dr. Horvath on X, formerly Twitter. His handle is at P-R-O-F underscore H-O-R-V-A-T-H. That's at prof underscore Horvath. He regularly posts interesting papers, updates, and insights on aging biology, epigenetic clocks, rejuvenation, and where the field is heading.

2:44:55Dr. Rhonda Patrick:Highly suggest you follow him. And for everyone listening, we've also put together detailed show notes for this episode. You can find them at foundmyfitness.com forward slash episodes, E-P-I-S-O-D-E-S. At the bottom of the show notes, we've included a brief consumer guide on biological age testing that includes what to look for, why the clock that you're using matters, and which clock you should use if you're interested in things like mortality risk versus disease risk versus metabolic health versus the rate of aging. I also just want to take a brief moment to thank you for supporting this show.

2:45:30Dr. Rhonda Patrick:Found My Fitness is ad-free. That means we don't take any sponsorships, we don't interrupt these conversations with ads, and we don't shape our content around commercial interest. The goal is to keep the episodes as evidence-based, as rigorous, and as independent as possible. And that independence is only possible because of listeners like you and your support. If you value these long-form, deeply researched conversations, one of the most meaningful ways to support our work is by becoming a Found My Fitness premium member. The premium membership gives you access to the aliquot. This is our members-only podcast where we go deeper into practical evidence-based protocols and emerging science.

2:46:10Dr. Rhonda Patrick:Recent episodes include how to prevent and recover from jet lag, how to slow joint degeneration, and how to protect immune function with age. You'll also get access to a monthly live and recorded Q &A with me, and you'll get sent a curated science digest twice a month. Your support helps us continue producing ad-free, unbiased, evidence-based content on health, fitness, and aging, and it directly sustains the research and production that go into every single episode. There are hundreds of hours that go into this. You can help us support the show and sign up to become a premium member at foundmyfitness.com forward slash premium.

2:46:51Dr. Rhonda Patrick:Again, that's foundmyfitness.com forward slash premium, P-R-E-M-I-U-M. Thank you so much for listening, and thank you for supporting Found My Fitness. Talk to you soon. Thank you.