AGING IS A SCIENCE: What To Eat & When To Eat To SLOW THE AGING Process | Matt Kaeberlein

So, I'm going to ask is anti-aging total BS or is there something here? It's it's absolutely not total BS. There's there is a real um science of aging that has made I I think immense progress in the last 20 years in understanding what the biology of aging is and I think all of our hopes, everybody in the field hopes that as we continue to gain that understanding, that provides opportunities to actually modify that biology in a way that will increase lifespan and and healthspan. And um there's no question we can do that in laboratory animals. So, it's it's actually pretty depends on the organism, but if we if we talk about rodents, mice is what most people use today, it's uh fairly routine to be able to increase lifespan by 10 to 15%. Some things can do better. So, the the most effective intervention in increasing lifespan in laboratory rodents is caloric restriction. It has been for decades. Um and you know, it can get up to about 60% increase in average lifespan is is the biggest effect that's ever been published. Okay, hold on before we blow past that. So, uh one, just uh caloric restriction for people that don't know, you're just starving these poor little things. And as somebody What do you mean? Because important. So, it's it's actually um more properly referred to as caloric restriction in the absence of malnutrition. So, the idea here is to restrict caloric intake but ensure that all of the vitamins, micronutrients are at appropriate level. So, you it's actually not starvation. And I I actually think that's an important point to clarify. Um but it is, you know, in the case of where 60% lifespan restriction was reported, a significant reduction in total calories of about 60%. It's a it's this weird sort of relationship where 60% reduction? from what they would normally eat if they could eat what they wanted, yes. Okay, so you and I define the word starving very differently. To me, as somebody that did probably Yes. 25% caloric restriction, and that might be generous, maybe it was a little bit less than that, but ballpark math is pretty close to that. Yeah. And it was miserable. Right. I lost a lot of fat, I got lean as hell, I looked awesome, I loved being naked, it was really cool, but my business partners pulled me aside and my wife and said, "You no longer have a personality." Oh, yes. And so, but it was on the back of I'd heard like, "Hey, the one thing that can be replicated across every species caloric restriction." And so, I was like, "Word." Now, to be honest, I was doing it cuz I really wanted to get lean and I just thought that that was going to be the way to do it, but it did not hurt my feelings that I was like, "Oh, and this is going to have life extension benefits." Now, as I've gotten older, gotten more interested in the life extension, but 25% was brutal, and let's say that I'm overestimating and it was more like 20 or 15%, that was so unpleasant. I can't imagine 60%. So, there's a huge amount of nuance to un- to unpack here, right? What One One thing I think we should be clear on is mice aren't people. So, we don't know does 60% in a mouse translate to 60% reduction in calories in people? We don't know. Would 60% lifespan extension in a mouse translate to 60% lifespan extension in people? We don't know. My intuition is probably not. Yeah, why not though? Cuz mine's the same, but I'm way less So, so it it is So, there's a couple of a couple of uh reasons why I I would guess that. One is there seems to be a trend that um the ability from these kinds of simple interventions like caloric restriction to increase lifespan, the magnitude of the effect is shorter in longer-lived organisms. So, you can go So, like in the laboratory, we commonly use yeast, which is single-celled, uh nematode worm called C. elegans, fruit flies, and mice. Those are the four most common. And they live very different absolute lifespans. So, um a nematode will live about a month, fruit flies will live about 3 months, mice in the lab will live about 3 years. And the magnitude of effect you can get from interventions like caloric restriction decreases as you go to the longer-lived organisms. Now, whether that will hold when you go from something like mice to dogs to people, we don't know, but I think it's a reasonable expectation that the percent effect at least probably gets smaller as you go to longer-lived species. There's also some people who argue that um the processes by which humans evolved long lifespan and other long-lived animals to some extent put them into a state that is already you've already kind of gotten the benefits that you would get from caloric restriction. optimized for that already, and so adding to that is not really going to do much. That's really interesting, and I was going to ask you what the hypothesis was there. Uh okay, so that makes a lot of sense. We don't know if it's going to transfer from mice, but we see some early signs that caloric restriction works incredibly well on rodents. Have we seen anything in humans? So, let me take a step back because this is where I think the common perception and the way it gets presented um often doesn't quite match up to what's in the literature. So, it is absolutely true that caloric restriction is the most robust way to increase lifespan in terms of magnitude of effect. It's probably also the intervention that's been tested the most number of times. So, it's it's highly reproducible in a sense that many, many different labs and many, many different settings have shown you can extend lifespan with caloric restriction. What often is not talked about is there appears to be a pretty significant genetic component to whether or not or how big the benefits are going to be. And the best study that's ever been done was a study of 41 different lines of mice. So, these are all genetically inbred but genetically different from each other. And what they saw was that in about 1/3 of the lines, you got this big lifespan extension. About maybe a little bit more than 1/3, you get a big lifespan extension. There's some where there's no effect. And the thing that I find fascinating, and also a cautionary tale, is there's about 25% to 1/3 of the lines where lifespan is actually shortened from from our restriction? Yeah. Whoa. paradigm. This was a 40% restriction in this case. Now, there's lots of limitations to that study. So, I think we we have to say that needs to be redone better. Um but, the same thing has been done in other the all of the other model organisms that I talked about, yeast and worms and fruit flies, and it's pretty similar. There's about 1/3 of genetic backgrounds where there's either no effect or a lifespan shortening effect from a single caloric restriction paradigm. So, and I think this is really important cuz humans, obviously, we're we're genetically different from each other. There it are absolutely going to be people who are harmed by the caloric restriction protocol that you talked about that you tried, 25% restriction. It's not going to benefit everybody. And we don't really have a great understanding at this point of who is likely to benefit, who isn't likely to to benefit. The And And you were talking about loss of body fat, which is really interesting. The one One of the things that seems to correlate in the mouse studies with beneficial effects from caloric restriction, those genotypes that are able to maintain fat when they're calorically restricted seem to be the ones that get the benefit. Better. But, able to maintain fat better. Interesting. The point I was going to make is the other thing that I think is about caloric restriction that's important to appreciate is um humans are weird animals, and there's this whole psychological component to restricting food, right? And it affects some people um in psychologically in ways that I think are maladaptive, right? And And I know many people who have who have played around with different types of caloric restriction and And for some people it works great, but other some other people, you know, um they they really struggle psychologically with uh you know, feeling like they're deprived, sometimes even adopting behaviors that that I'm not a psychologist, I'm not going to diagnose anybody or psychiatrist, but appear to me like eating disorder behaviors, right? And so this this is where again I think we have to be careful about sometimes translating some of what these studies from laboratory animals, mice, which, you know, maybe they develop psychological responses to caloric restriction, but we don't test that in the laboratory, and and they're not given a choice. I think that's part of what leads to the psychological challenge that some people have with food restriction is you're constantly being presented with a choice. Constantly. And so it's a battle for, you know, it's a battle for almost anybody to maintain 25% reduction in calories from what they would normally eat or or even in this case what they would eat if they were trying to be healthy and go 25% lower than that, you're constantly faced with choices to go off of that regimen. And I think that that leads to this sort of internal, you know, mental struggle and um different people react differently to that. So that that's not often talked about, and so that's why again I I get a little bit um worried when people write books saying that everybody should go out and do caloric restriction or intermittent fasting or, you know, whatever. There's not a lot of attention paid to the fact that we know there's a genetic risk, there are some genotypes that aren't going to respond positively to these things, and we know there's a psychological risk to some people. And And so I'm not sure I'm not sure we could we should be recommending one-size-fits-all sort of strategies around nutrition and and diet beyond and I mean you know it. I understand why you're saying that but I at some point people have to do something. And so it's like in the absence of people like you saying look there's no one size fits all but probably eat like this you're going to get the RDA you're going to get people eating the food I guess not the pyramid anymore the my plate or whatever it is. And that's been a disaster. Right. So it's like somebody has to step up with guidelines but really fast going back to the first thing that you were saying. So when I went on that hyper caloric restriction for the reasons you're talking about I said to Lisa my wife uh I'm giving you the keys to when I stop this because I would make an extraordinary anorexic. And and and I say that tongue in cheek but I recognize that about myself. I pride myself on that discipline. It was man it the the the exercise was to manifest that effectively as an eating disorder with optimal nutrition. I was trying to make sure that I had all my bases covered but I was like this is going to be miserable. Yeah. I'm going to be exercising like a fiend eating as little I was eating about 1,500 calories and I would guestimate that my maintenance is roughly 2,000 that's where I came up with the 25%. So it's like it was somewhere in that ballpark. I lost the weight so I know that I was in a deep caloric deficit. I was also eating well but it was like I know I can't trust myself because I had so much body dysmorphia that even though I had six-pack abs and they were very defined and I was leaner than I'd ever been in my entire life I just couldn't stop looking at that lower back fat and I was just like God this is crazy. So anyway I do think that's important but going back now to we're seeing these studies the data's coming out it's super nuanced it's very complicated but people are grabbing onto a narrative. I kind of think they have to and whether that's hey here's my narrative for you to know how to eat or here's my narrative for me to convince somebody to give me a grant so that I can go study this. Yeah. So so yeah, so let me make a couple of comments on that. One is I think um when we talk about nutrition for people, there there's a difference between recommending that people should practice caloric restriction, which let's just be honest, it's not going to work for almost everybody. There are very few people who can actually do the kind of caloric restriction that you did for a prolonged period of time and and you know, stay on it. And this experiment's been done. I've I've actually heard you give this argument before. Your answer's kind of interesting. What do you mean? So uh should we pursue a path where we come up with a pharmaceutical and everybody can take it and great, but it could take 20 years and a hundred billion dollars? Or do we go, "Hey, this is the hard truth. Don't eat these things. Reduce your calories and only the people that are disciplined enough are going to pull it off." Yeah, so that's an interesting question. Um so the couple things I would say about about that specific question and honestly I don't remember what my answer was that I gave before. was we we probably have to consider the you were you weren't like, you know, forget the people that are disciplined, but you were like, "Hey, we need to be thoughtful about the fact that the vast majority of humanity will not be able to do that." That's right. And so if we're trying to You didn't say the words greatest good, but that was like the gist, then we need to be thoughtful at not discarding the path. Because the I would say I had that interviewer's basic stance, which is I need to know what's true. Yeah. And and if what is true is there's a way for me to eat and live that's going to extend my life even if it's hard, I would rather you put your time and attention there versus solving it for people that aren't going to do anything. Got it. So okay, so here's here's what I would say around um caloric restriction. So so I think we need to differentiate between what I would consider healthy nutrition and caloric restriction. So there is absolutely no question in humans that a healthy diet will increase your likelihood of living longer and avoiding disease. a thumb that says what's healthy? Well, here's here's what I would say. I don't think there's a one-size-fits-all, right? So, I think it's unfortunately at this point um largely information that most people know, right? Like avoiding ultra-processed foods, right? Staying at uh avoiding being obese certainly. I would actually say avoiding being overweight. And I think actually the guide guidelines we've got, you know, for as inaccurate as BMI is for the average person, that's not a terrible place to start. Get your BMI down into what would be called a normal range. Even if it's muscle that's causing the that's what I'm saying. I was saying for the average person. So, this is where again I think we get we need to get nuanced. If if you are a person who appreciates the importance of body composition, if you've had a DEXA for example, and you know with some level of precision what your body composition is, absolutely you can go beyond BMI and say, "Okay, I want to get my body fat down into this range." And then you can even get more nuanced like, you know, is it visceral adipose that you want to get rid of? So, I think it really depends on what the audience is, but um but I think again, you know, as a general rule of thumb, there's not you don't I don't think we should even necessarily try for a one-size-fits-all nutritional strategy because it's it's clear that's that's not going to work Is there so, while there definitely in my experience is no one-size do this, there in my layman's opinion, there is a one-size don't do this. Yeah, so I think that's fair. Yeah, and again, I mean, I think it's it's um hyper-processed. What about sugar? What's your vibe on that? So, my and I think this is I don't think too many people would disagree with the idea that we should avoid high levels of simple carbohydrates. Complex carbohydrates in the forms of vegetables are generally going to be fine for pretty much everybody. I'm not I like I've I've I eat I tend to eat a pretty low-carb diet um because I find for me that works really well. I'm not hungry. I enjoy what I eat. You know, I it's not like I have to think a lot about how much I'm going to eat. Um and it helps me maintain my body weight where I want it to be. But I don't think necessarily that's that works for everybody. And I think, you know, some people have very strong opinions about meat products versus vegetable products. My personal view is I think the science is still a little bit unclear there. And In either direction? In either direction. Well, I think that you can you can certainly make the case that that a diet that's high in plant good quality pit plant-based calories typically is going to be pretty healthy, right? Because you're going to be eating a lot of vegetables. Even fruits, you're going to be eating a lot of fruits. I'm not Again, there you can get a little bit into which fruits are high glycemic, you know, so I think that's that's sort of second level. But but for the average person you probably don't need to worry so much about that. And and really just focus on cutting out the processed foods. I think a whole foods diet is pretty good. Um that and then just paying attention to to how much you're eating. But again, I think the portions more or less take care of themselves if you're really not eating the garbage, right? I think the the the problem, I mean, and again, I kind of feel silly talking about this cuz it's stuff that everybody kind of has already heard before, right? Like this is as somebody that records these kind of episodes all the time, the one of the comments that we get the most is pick a lane. Which is it? Am I supposed to eat meat? Am I supposed to eat vegetables? Like what is it? Yeah. And so I'm actually going to lay out So one of to orient the audience, we're definitely going to get more into what the the influencers are grabbing onto that you think are problematic and then why you're still enthusiastic about this. But I think that it's worth um on this idea of a healthy diet, I'm going to lay out an abstracted from what you chew to what you're trying to achieve level and tell me if you think this is bang on. So, if you're trying to balance performance and longevity, you're going to want to be optimal nutrition is going to be the main thing. So, you have to get your main building blocks, which is largely going to be an amino acid profile so that you can build and maintain the muscle mass that you have, keep that all cause mortality as you get older is so linked to muscle mass. Yeah. So, you're thinking about that. If you're eating a vegan diet, the odds of you being able to get that the right amino acid profile without supplementation is effectively zero. And so, you can do it, but make sure you're thoughtful about your supplements. You can do it through red meat, but red meat or meat in general and I'll assume nose to tail so that you're really getting all of your vitamins, macro, micronutrients. But, that the problem you're going to run into there, and this is going to be a big thrust in this interview, I have to assume knowing what you know, is you're going to turn mTOR on like crazy. And so, if you're living in a world and mTOR for people that haven't heard that, I won't even yet tell you what it stands for, but right now just understand it tells your body to grow. So, if you want to add muscle, whatever, but you can imagine from a longevity perspective, if you're giving your body the impulse to grow forever, you're probably going to end up growing things like tumors and things like that. So, you run into a potential problem. And sort of the quick punchline of where I think your work takes us is you probably have to do something that has some of the same knock-on effects of caloric restriction. And so, you said something that our audience may not yet understand, which is the difference between restricting your calories and not being overweight, yeah, which is going to be an important thing that we'll talk about. But, like if I were to say for people that are like, "Which is the [ __ ] which is it?" It It isn't either. It's you're eating for something. You're eating for an effect. Now, if you think about that effect and you're willing to monitor yourself, you can actually figure out what you as an N of 1 should eat. Yeah, I think that's super super important. So so one thing I would say um uh is that you know, I think again the quest the answer to the question is going to be somewhat different if the goal is to optimize versus you know, just do better than we are now cuz again, I think the average person is so far away from optimal that that's where you can give these sort of general guidelines. The only way you're going to get anywhere close to optimal is by what you said at the end, actually measuring your own response, right? Because there's because again, this goes back to the the point that I made about even something as as blunt a tool as caloric restriction in mice, there's a significant fraction of genetic backgrounds that respond poorly to that in terms of longevity. And that's in a very controlled environment. Those are mice in a laboratory where we control almost everything about their environment. You take humans in the real world and our environment is so complex that that on top of the genetic variation really makes it almost impossible to predict at an individual level what optimal is going to be, which is why you need to measure biomarkers and have some confidence that those biomarkers are actually telling you what you think they're telling you. And that's where I think we're at a really interesting time in the field where we now have a plethora of biomarkers we can measure that we think tell us something about aging, but we don't really know for sure how good a lot of these biomarkers are or how comprehensive they are. And so, you know, when you hear people talking about biological aging clocks or reversing aging, which is a term that I almost despise these days cuz it gets misused so often cuz it's not accurate. I mean, well, let me put it this way. Um there's no evidence that anybody ever in a mouse or a person has taken a biologically old organism and biologically made it young again. That just hasn't been has not been shown to be done. There's no data to support that. that, do you say to yourself, yet? Or you like, this is not Oh, yeah. I don't think So, there's nothing there's no theoretical reason why it shouldn't be possible to reverse biological aging. I feel like there's still so much we don't understand about the complexity of biological aging that it's going to be a long time until we're able to do that. But who knows? I mean, again, this is where you get into how fast is technology going to progress? We don't know. Right. Um but there's so much that we still don't know. You can reboot your life, your health, even your career, anything you want. All you need is discipline. I can teach you the tactics that I learned while growing a billion-dollar business that will allow you to see your goals through. If you want better health, stronger relationships, a more successful career, any of that is possible with the mindset and business programs in Impact Theory University. Join the thousands of students who have already accomplished amazing things. Tap now for a free trial and get started today. Uh my intuition is it is far more complex than even most of the people in the field appreciate. And that the kinds of tools that we're using today, again, are still pretty blunt instruments. And the the one thing that that could change that, and this is still an open question, is whether or not um epigenetic changes are really sort of this this uh primary upstream driver of aging. And we can get into that. That's kind of getting into the weeds a little bit. But there is this popularized concept um that epigenetic changes are are are really the uh primary process of biological aging from which all of the downstream molecular changes, functional declines, diseases of aging derive. If that's correct, and I don't personally think it's correct, but if it's correct, then you could imagine a tech technology, um and and people have developed some technologies to do this, that can reverse those epigenetic changes, and thereby that would reverse much of biological aging. It's a still completely open question, though. I want that to be true. Yeah, I would love it to be true, as well. Partly because it's easy to understand, and so for a layman like me, when I started understanding genetic epigenetic reprogramming, it was the first time I was like, "Oh, wait, I get it." Aging boils down to the dedifferentiation of cells. They're no longer an eye cell, liver cell, heart cell, whatever. They begin to sort of lose, "What am I?" And that is aging. But talking to you, it sounds like it's just that's one piece, maybe, but there's just a whole lot of stuff going on. Yeah, it's pretty interesting, cuz if you go back 10 years now, um you know, there was a pretty famous paper written called the Hallmarks of Aging, where uh several leading scientists in the field put together a collection of nine processes that that that at the time, and I think still today, um seem to be particularly widely shared across the animal kingdom causes of aging or are they just about the biological aging process. So, that's a good question. So, they are, for the most part, um molecular processes that could be causal. So, it's very hard to prove causality, right? But but they could be causal. And they include things like accumulation of senescent cells, which we These are the nine? Yeah, these are the nine. That's one of the nine. DNA damage is one, telomere shortening is one, epigenetic changes is one, mitochondrial dysfunction is one. So, epigenetic changes are one of a collection of hallmarks of aging, and they interact with each other. And I think of it as kind of a network of interacting processes. And so there's two things I would say about that. Nothing has really changed from 2000 I think it was 2012 when that paper was written to today to strongly suggest that epigenetic changes are any more important today than they were then in the science. Again, people have used reprogramming and shown that you can improve some functions in a mouse. And so for your listeners who who who aren't aware, reprogramming is a technology that allows us to change the epigenetic state of an old cell back to what it was when that cell was young or differentiated as you said. Um so people have used reprogramming now in mice and shown you can improve function in a few tissues. You can increase lifespan a little bit. Um but not even to the extent that you can do with rapamycin and nowhere near what you can do with caloric restriction. So those following along, we will get into rapamycin. Yeah yeah yeah, sure. So so the the point being that um we thought epigenetic changes were important when this hallmarks of aging paper was written. We still think they're important, but it's not clear that they are any more important as some of the other processes that that play a role in biological aging. And the real test of that is to take an old mouse, reprogram it, and make it young again. And if somebody can do that, believe me, I'll be on the bandwagon. I hope that happens, but I'm my intuition is it's not going to. And and I've actually starting to think that it's it's probably unlikely you're even going to do as well as you can do with caloric restriction using the epigenetic reprogramming technology. Because I don't think that that epigenetic changes are in fact any more uh important than some of the other factors that we know play a role in biological aging. The last thing I'll say on this is and this is where the field I think unfortunately, has um become a little bit too narrow uh because once these hallmarks of aging were sort of formalized, it created a structure that limited people's thinking. And so, now, even though we know that's not everything about biological aging, it's created this structure that you in order to get a grant funded, you have to frame it in the hallmarks of aging. And so, almost nobody is actually asking, "Well, what else is there? What else might be important? And how do we find those things?" And so, I'm I'm a little bit concerned that that the the field has narrowed its um search in a way that will that's limiting us right now. Eric Weinstein is? The name sounds familiar, but I can't place it very well. dig him. So, he also is a mathematician. For people that don't know, you have a very impressive background in mathematics. Uh and he is saying exactly what you just said about health and anti-aging in uh physics. Yeah. And he was like, "String theory grabbed a hold of people's minds and won't let go. And we now have had 50 years. It's fruitless. It's led to absolutely nothing. But, to be taken seriously and all that, like, everybody's working within that framework." And And his whole thing is like, "Who's going to be the person that is like the young rock and roll researcher that steps outside of that and is not afraid to look crazy and is like, 'No, it's this thing over here.'" Yeah. It's really interesting. Now, as the person who can embody the problem, I will say, "You need an organizing principle." And so, when I do interviews like this, I first write down like what the person's theory is, and then I try to understand So, one, it shows me that I understand where you're coming from. Like, I could I might be wrong in some unacceptable percentage, but I could reiterate to you right now what I think your thesis is. The reason I do that is I want to know what the predictions are. And I'm trying to do that so that I categorize like what's going on. So, for instance, you give me nine hallmarks of aging. My immediate question is is there an underlying cause? Uh, yeah. Like, is there one thing that then manifests as these nine things? Because that gets interesting. Now, it might be a categorical error on my part or anybody else's part to try to bunch everything into the hallmarks of aging, but for instance, when I think about aging, even your own thesis has to do with inflammation. And so, it becomes a question of is this all like is this a game of inflammation? Like if I can turn off inflammation, does that like what we don't know what that is, but like if I identified that sort of switch of on inflammation off inflammation, if I could somehow and obviously inflammation's a good thing, so you don't want to eradicate it, but if I could turn that switch off whenever it wasn't doing the job that we want it to do, would that stop aging? So, anyway, I I don't need you to take that question seriously. My thing needs to be a framework. Well, I think that's a good good question. So, So, first thing I would say is no, changing or turning off inflammation or optimizing inflammation, maybe that's a better way to say it, would not stop aging, I don't believe. So, you So, you asked a I think a very interesting question that that not very many people in the field actually I think spend enough time thinking about and and we don't know the answer, but we've got some clues, which is is there an underlying principle that is biological aging? Is there Can we actually boil it down to one thing, right? And we don't know the answer. There are as I alluded to this, there are absolutely links between the hallmarks of aging. You can draw it as a network diagram and make make connections where we have evidence to support those connections. I think the best evidence that there is a something fundamental about the biology of aging is in every animal or organism where we've looked, we can identify single genes that significantly increase lifespan and seem to improve what we call health span or delay the functional decline. and I can edit some things. There are people trying that. Yes. Interesting. Yes. And we can do it in mice. Like again, this is fairly routine. Well, there's there many. So so one of the cool things so so So I'll answer your question in a in in two ways. Um one is sort of from my own personal background. I started in this field in 1998 as a uh first-year graduate student. Um and that was a really cool time to be in the field because it was when the field sort of switched over from being observational to molecular and mechanistic. And one of the things that allowed that to happen were the creation of tools where you could suddenly do very detailed genetic, molecular, biochemical experiments in simple model organisms. So again, I I talked about yeast and nematodes and fruit flies where you where they they they age so quickly, you can do it in time frame that's amenable to discovery. At the same time, people created these things called genome-wide libraries where you could look across the entire genome at either gene deletion or gene knockdown and look for mutants that gave you whatever phenotype you were interested in. Now, I was interested in lifespan cuz I study aging. So you suddenly had the ability to look at 5,000, 10,000 genes and in a very unbiased way ask which ones increase lifespan when you mutate them. And so that led to the observation there are hundreds of genes that when you mutate them in simple organisms will increase lifespan. Now, the effects are usually pretty small on the order of 10% to 30%. I would say a 40% effect from a single gene is is very large. That's towards the upper end of what we've seen. unifying characteristic to these genes? So they affect they affect they affect the hallmarks of aging. That's kind of how the hallmarks of aging actually evolve is because as we learned about mechanisms So is it like all hundreds of them slot into these nine things? I don't think you could ever say all cuz there's so much we don't understand and this this gets a little bit to how science happens, right? I mean, you know, I let's So one of the things I did early early-ish in my career was one of these genome-wide screens and we identified hundreds of genes, but you don't go study all 300 of them. You pick a few, one of which was mTOR, so we'll come back to mTOR I'm sure. Um you pick a few and those are the ones you study and those are the ones that you figure out the mechanism. So there's still a lot of undiscovered country out there for things that people have never really followed up on. But but to answer your question, yes, in general you can point to certain pathways or networks that seem to be particularly important and work across the evolutionary tree, right? So and I think that's what That's again where a lot of the attention has been paid. If a gene in yeast that affects lifespan only in yeast, that's not so interesting. But if it also affects lifespan in worms and fruit flies and mice, then we start to think, okay, maybe that's going to be really relevant in the real world. And so those are things like um growth hormone signaling, insulin-like growth factor one, IGF-1, insulin signaling, mTOR, um and things in that network. FoxO is another uh factor in that that interacts in that network. So So So those are sort of to me form in my own mind a a picture of an interacting set of very important factors that seem to modulate the biology of aging, which would be represented to some extent by those hallmarks of aging. And the way I think about it is there are certain nodes in that network that are particularly amenable to intervention in a way that will increase lifespan and healthspan. And that's where something like mTOR comes in to play. Just turns out that and for reasons that I don't understand, but I speculate have to do with the network architecture, that particular node, when you tweak it, has big effects throughout the the network that that then lead to our observation that you can increase lifespan and healthspan. And another thing that makes certain nodes more favorable is that you've got a a a range in which you can play before you push things the other direction. So, again, all these things are going to have the potential not only to increase lifespan. So, if you think about a certain gene, there's an optimal expression level of that gene for lifespan. None of our genes are intentionally optimized for lifespan, which is probably why it's so easy to find genes that affect lifespan. Um Uh but some genes, so that means you can you can get it to the optimal, which would be increasing lifespan, but if you go outside that range, you're going to go the other direction. And you're going to shorten lifespan. And and it's much harder or much easier to break a system than it is to make a system function better. So, all of these things, you have to be careful, cuz if you tweak them the wrong way, you're actually going to go to place we don't want to go. Um Have you ever asked the question did nature have a reason for making sure that we die? Yeah, I mean, it's an interesting question, and there are different people who have different thoughts on this. So, the uh the the the the collection of people who argue that nature did evolve us to die, fall into the camp that that would be called programmed aging. The idea there is there is an evolutionary evolutionarily selected program that causes us to age and die. And you can come up with speculative reasons why that might be beneficial. There are some cases where that seems to be the case. So, salmon are sort of a classic example, right? Where they have evolved after reproduction to undergo this rapid senescence process and die. Um leafs are another one. So, leaf senescence is another one, where annually, leafs will go through this senescence process and So, that's that clearly happens in select cases. My personal view is that there's a much much easier argument and sort of going by Occam's razor, right? Let's just take the easiest explanation that works. There's a much easier argument that what what aging really is is an absence of selection. So once we do our job, we from an evolutionary perspective, we pass our genetic information on to the next generation and we get them far enough that they're going to be okay. Natural selection doesn't really care about us from at that point. So it's a it's a selection shadow. There's no benefit from an evolutionary perspective to slowing aging at that point and making us live longer aside from the little bit of added benefit from further reproduction, but most of the work is done early on and then the the the benefit that comes from slowing aging and increasing lifespan falls off pretty quickly. And so that so the idea would be that that biological aging to some extent is an accident of evolution. It's an absence of selection. And you know, these are fun sort of conversations to have, but you can't really test them experimentally and so I tend to I I like to have the conversation when people start arguing about it. I I tend to tune out cuz I'm like this isn't interesting anymore. But you know, people love to argue so All right. Well, I want to use a a specific example to highlight some of the things you're talking about. So rapamycin. Yeah. Rapamycin tied to mTOR. Um give us a brief history. So you're doing the dog aging project. The punchline is let's see if we can extend their life and health span by giving them rapamycin. As far as I know, that's the only while you're tracking other things, that's the only intervention. That's the only clinical trial as part of the dog aging project. Okay. So why why did you think rapamycin would be the right thing to try as a clinical intervention to extend the life of dogs? Right. So I mentioned caloric restriction was the most effective way to increase lifespan intervention-wise in a in mice. Rapamycin's the second most effective and again seems to be the most reproducible. So, there's a huge body of literature showing that genetically turning down mTOR can increase lifespan in yeast and worms and fruit flies and mice. And then there's another body of literature showing that pharmacologically turning down mTOR, and that's what rapamycin does. It's an inhibitor of mTOR, can increase lifespan in all of those organisms. So, and it's been done by many many different labs. And so, personally, I have a lot of confidence in in that body of work because it's not one lab showing this one time and then everybody gets excited about it and and then, you know, it may or may not be real. This has been reproduced over and over and over again. Um and then in mice, there's a couple of features of rapamycin that are particularly, I think, um relevant for potential to have an impact outside of the laboratory. One is, um you can start the treatment in middle age. And really, that was first that that was first demonstrated with rapamycin. I think but that was done in 2009. Um before that, I think most people, myself included, would have been would have would have speculated that it would be very hard in an old animal to actually have a significant impact on lifespan and healthspan. But that was shown with rapamycin, you get almost the same effect starting at about the mouse equivalent of a 60-year-old person as you do starting at young age. And so, from a we can talk about maybe why that's happening, but from a from a from a translational perspective, that all of a sudden starts to become pretty exciting cuz you can it's much easier to imagine a drug that you would start giving to people in their 60s, 70s, 80s versus something that they start taking as teenagers, right? So, so so that was and that also told us, I think, something fundamentally important about the biology of aging Like what? that that it it um that there's some plasticity there, right? That at least at a functional level, you can actually reverse some of the functional declines that go along with aging. Okay, so this is the one I want to push on. So, I am scandalized scandalized by one of the findings I've heard you talk about. So, you talk about rapamycin and the effects on um oral cavity degeneration just to lump it all into one thing. That Okay, fair enough if rapamycin happens which again is shocking for people that understand mTOR is about growing rapamycin therefore if it's inhibiting that would lead most people to predict that you would get muscle loss if you're taking rapamycin. That seems pretty logical, but it doesn't. It actually seems to lean that it might do the exact opposite. And so, you can grow bone back in your teeth. None of this is scandalous once you accept that even though it's counterintuitive All right, I'm waiting to see what's scandalous. How the hell does it impact the oral microbiome? I don't understand that. That's bacteria in my mouth. What the hell does something that inhibits mTOR have to do with whether bacteria can thrive or not? I can't wrap my head around it. Really good question. There's actually So, so the real answer is we don't know for sure, but I think there's a pretty good speculative answer that that's probably correct which is that the reason you get the remodeling of the oral microbiome is because of because rapamycin is rejuvenating to some extent immune function. So, most people don't realize this, right? But there's a huge interaction inhibiting mTOR rejuvenate Okay, oh wait, can I guess? Okay, I'm These are all your ideas. I want everyone to be very clear, but I think I understand. So, one of the things that I've heard you say is you have senescent cells. Some percentage of aging is you get these cells that become senescent. Senescent means that they realize they're dysfunctional so they don't keep replicating, but they kick around still and they give off an inflammatory signal of some kind and so, you get these autoimmune responses where because of these senescent factors the immune system is going after them. So, now you have this increased inflammation, a certain type of inflammation called sterile inflammation, meaning there's no bacteria present that's causing it. Let me just So, this is interesting cuz I had a conversation with somebody the other day about this these terms. Cuz I tend to use them interchangeably, chronic inflammation, sterile inflammation. All sterile inflammation really is is autoimmunity. It just means your immune system reacting against yourself as opposed to a pathogen. So, again, I think I think to be clear, that's part of what's happening to the immune system with aging is the chronic signals given off by these senescent cells, which then it's not only causing your immune system to act against self. It it kind of hyperactivates the immune system in general. The outcome of that is that you get higher levels of auto autoimmunity. Senescent cells probably aren't the only thing causing that. Just to close that loop, if I'm taking rapamycin, it goes in either addresses those cells in some way, it somehow lowers the inflammation. It shuts off what people call the senescence-associated secretory phenotype, which is mostly this inflammatory signal. It's Rapamycin's one of the most potent interventions we know at shutting down the the stuff that senescent cells are giving off. That stuff, I like We understand some mechanisms, but again, it's you know, it's um it doesn't really matter. The what matters is that it shuts the cells off. But there's an important question for me in there, which is if that's the mechanism, is it rejuvenating the immune system or just giving it a break? Probably both. So, here's the way I think about it. And again, I've I've tried a few times to to learn enough immunology to to at least, you know, be able to talk to immunologists and I fail miserably every time. So, I've come up with a very simple way that I think about this. So, we know that what happened one of the things that happens during aging is people talk about a decline in immune function. And that's true. We are more susceptible to pathogens, we are less likely our immune system is less likely to catch cancers early, so there's this thing called immune surveillance of cancer, which is why I think most cancers are strongly age associated cuz as we get older, our immune system is less able to catch those cancers and kill them early. So then they become tumors, then they metastasize, and that's that's when it becomes a problem. So immune function does decline towards some of the things it's it's supposed to do, but there's this other thing that happens, which is this increase in the immune system doing what it's not supposed to do, which is autoimmunity or sterile inflammation. And I think what rapamycin does is it it's almost like a reset. I I don't know that it actually brings up the the stuff that's that's declined with age, but I think it knocks down this sterile inflammation to the point where the system can reestablish homeostasis. So functionally, it's a rejuvenation. And that's where again I think you know, terms are important and and we need to try to be precise in the words that we use. I think it's okay to say that that we know things like rapamycin, again at least in mice, can reverse some of the functional declines that go along with aging. It can also reverse some of the tissue pathologies that go along with aging. Did it reverse aging? No, it didn't make an old mouse into a young mouse again. That the best again we've been able to do with rapamycin is around 30%. way? Well, that's where it it depends a little bit on what level of resolution you want to you want to get to. Um I I can't answer this with 100% certainty because nobody's ever done it, but I am pretty sure that if you dug deeply, you would still find accumulated damage in pretty much any tissue that you look at in a mouse that's been treated with rapamycin. Mhm. So it depends a little bit on how what you look at and how how deeply you you look. And how you define it. So like when I think about anti-aging, what people really want, they want to go backwards, they want to feel better, they want to be able to contract muscles harder, add muscles easier, look better, tighter skin, that kind of stuff. Like there's a very specific set of things that they're looking for. I mean, this is what the question, right? What does So, exercise does all of those things, right? Does exercise reverse aging? If you give your muscles get big enough. Yeah, it's harder on the face. right? This is Yeah, no, you're right, but it depends a little bit on what you're what you're looking at. This is that's that's all I mean, it's a really good example cuz that's exactly the point I was making. I was making it cuz I, you know, I'm a scientist from the molecular perspective, but it's the same thing. It depends on what which which phenotypes you're asking about. You can find some where absolutely rapamycin reverses it. If you keep looking, you're going to find others where it doesn't. And I think exercise does the same thing, right? Certainly functionally, you can al- almost anybody from where you're at now, you can functionally improve your body through exercise. Facts. So, is that reversing aging? Again, it depends a little bit on how you want to define it. fun way to look at it. Okay, so very important to get our terms right. Definitely when I say, um, reversing aging, I don't mean optimizing for where you're at now. It's a fun framing, and that actually is more motivating to actually work out harder. Uh, but when I think about what I'm really hoping happens is that we get back to, and I imagine it will be the nine elements of aging or indicators of aging, um, but also there's hormonal profiles, there's all kinds of things that lead your body to not only do those things, but to do them either more efficiently, faster, better, whatever. Um, there is something, and I've heard you I can't remember the stat that you threw out. Oh, no, it was you were talking to Peter. Uh, Peter Attia. Peter Attia's kid was on his scooter, whatever, he falls down, mashes his face, gets up, blood everywhere. Peter's like, "How fast can I get to the hospital?" And he said like a week later he had like a minor mark left on And he was like, "If that had happened to me at my age," he's like, "the scar of mine will last for a year or more." Yeah. And there is some like I don't know how we define that, if it's just efficiency, if it's that the system isn't bogged down by the damages that you're talking about. But there there's a a way to classify youth that we're trying to get back to. Whatever that bundle of things is, we're trying to get back to that. Now, I am this is how we started the episode. I'm one of the people that really, one because I want to live as long as I can, have the greatest health span possible. I want to make sure I want this stuff to be real. So, I have like this vested incentive, meaning I don't want to die, Yeah. that this becomes real. So, I get very emotionally invested. I get very excited. I recently had a guest on the show, his name is Brian Johnson. And he I don't think he would call himself a scientist, but he's been very successful, and so he's able to throw a lot of money at his body. And so, he spends something like $2 million a year trying to reverse reverse aging. Now, this gets into measure what matters. Are the clocks real? Are they not? Are we looking at the right things? But when I sat across from him, he looks like an elf from the Lord of the Rings. And so, he looks great. And I had interviewed him probably 5 years earlier, and he looks better now than he did then. Now, that doesn't mean he's reverse aging. Um but how do we begin to like parse out like you believe in this enough that you're doing a gigantic trial, you've dedicated a huge portion of your professional life to seeing if it works in dogs, presumably not just for dogs, but for humans. And so, what should we be measuring? And what like path are we actually going to go down? Because Brian has a blueprint protocol that I'm about to do. And based on this discussion, it's like either I go, maybe we're not able to measure the right things yet, maybe, you know, it's it's the hype has gotten a little ahead of itself, or maybe it's worth a shot. So, I again, I think this is a there's a there's a ton that we could talk about to unpack here and it it again is is super nuanced, but um so one thing I would say is I'm I'm not so sure that exercises and and nutrition are fundamentally different from rapamycin. Exercise hits the hallmarks of aging, right? It affects biological aging. So so I don't put those in different buckets. I actually think about them in my own mind as um different ways to tweak that that network and and again, this gets back to I think that there are certain interventions and ultimately probably combinations of interventions that get us closer to tweaking that network in an in a way that optimizes functionality or health or vitality or youthfulness, right? I'm again, and I'm also not so sure that at least in my own head I have a bundle of things that I would say I associate with youth that are fundamentally different from what I would put more in the bucket of sort of overall health span or healthy longevity. I mean, being able to function at a high level the way that you want to um fits into both buckets. The wound healing is an interesting one because absolutely, there is an age-related decline in wound heal our ability to heal from wounds. It's very individual, not everybody experiences it at the same rate and you can modify it by knocking down inflammation, right? So and you can do that by fasting, for example. So these things are are tied together. I'm not sure that it's fundamentally different rapamycin is in in any in any sense fundamentally different from some of the things that we can do with non-pharmaceutical approaches. It's just that most people can't do them in a in a consistent way. So the blueprint, I think is really interesting. Um So so my take is that I I probably 90% of that is just diet and exercise and and 10% of it is everything else and there are a couple things I would say. First of all, I think I mean I think I I I I think I have a lot of respect for the intensity and level of detail at which he's approaching this, right? I mean I think that that's great. I um I do worry a little bit about the markers being used. I don't think I don't think that they are necessarily telling us about biological age or biological aging in any comprehensive way. Are you guys checking markers in the dog or you just like let's just see how long it lives? we are. We are. So, we are looking at the epigenetic changes that happen in blood. We're looking at metabolome in the blood, microbiome, fecal microbiome. People have built clocks off all of those things. We're also looking as as best we can at functional measures. So, you know, activity levels, cognitive function, heart function, neurological function. Um and lifespan. So, I think you can start to paint a picture when you put all of those things together if you're seeing the arrow going in the right direction for most of them that you've you've had an impact on the biology of aging. Some of these are exploratory though. Like I talked about the epigenetic metabolome microbiome. Those are not things where people should have a high degree of confidence that they're actually measuring biological aging. And in my view, I'm much more interested in functional outcomes and disease. You know, if I can if I can not have any diseases and be able to lift as much weight as I want and do the things I want to do, I'm I'm much happier about that than if my biological age test tells me that I'm 35, right? Or vice versa. So, I'm So, I again I don't I don't put a lot of faith in those those tools at this point. I think they're something to steer by or maybe the average person does, I don't know, cuz maybe in your field you don't, but like at some point, and I think I'm speaking for Brian, and that is a mistake. He should speak for himself. But if I had to guess, he's like, I need something I can look at to see if this intervention that will only play out over the next 50 years, am I going in the right direction or not? I agree with that. I think the problem is you're not going to know until it plays out. So it's sort of a best guess. directionally you don't know this. Well, it depends on the test, right? So I think there are there are certain certain blood-based parameters that we know with certainty are highly correlated with specific diseases and with mortality over time, right? So, you know, if you have a high level of blood glucose or HbA1c, right? That that's a bad thing, and it's it's you're likely at higher risk for diabetes and early mortality. Same thing with lipid profiles that are outside of the the normal range. So those are biomarkers, right? They're you know, no different in that sense from the epigenetic clocks. It's just that we have a lot more evidence behind them telling you that yeah, this is kind of where you want to be. We aren't going to know on the epigenetic clocks for a while. So most of these clocks have been built off of in humans have been built off epidemiological studies spanning 10, 20, 30 years. And so there's there's and so you can you can show that you can identify patterns that are in that context predictive of 3, 5, 10-year mortality risk, right? What you can't show is that that's going to be relevant for you or me or any other individual. And what's often not appreciated is many of those samples were taken 20 years ago in a specific population whose environment has changed dramatically. Just think about our environment 20 years ago, right? So are those same parameters going to be relevant in our environment today? We don't really know. So this is where I think we just have to have So it depends a little bit on your your level of So so, much certainty do you need? If you're If you're just looking for what's the best out there, and let me take a take a best guess based on what we know today, I kind of like what what what he's doing in terms of the the comprehensive biomarker. So, but I but I I love the the sort of sharing of data. I think that absolutely the approach of, you know, measure, intervene, measure again, intervene, measure again. That's exactly what we should be doing. That's the only way you ever get to personalized interventions. So, I think that's that's uh uh really commendable. Um all right. So, if we're going to do measure, intervene, measure, intervene, uh and what do you care what, in terms of your own life outcome, what do you care most about? Your kids doing well? What what's that thing? Like your deepest like I need this to happen and I will have been a good man. It'll make sense in a second. So, So, what do I need to have happen for me to be a good man? So, it's a funny question. So, absolutely, I mean, I think I I would love for my uh probably the most important thing is that my kids grow up and be good people. Okay, perfect. Let's take that. Okay. For for this, we'll get to the bottom in a minute. So, if you live to 150, your kids will have just a glorious life and they'll live even longer and it'll all be amazing. But, it's all contingent on you making it to 150, which is it's that's a lot, right? So, oldest person on record 123, something like that? Yeah, some people argue whether that was even fudged a little bit, but yes, 122 plus a few months. You're going to have to figure something out and you're going to be doing this test, intervene, test, intervene. What would you, with your deep body knowledge and access to a gazillion people, what would you test? The truth is, hitting your career goals is not easy. You have to be willing to go the extra mile to stand out and do hard things better than anybody else. But, there are 10 steps I want to take you through that will 100x your efficiency so you can crush your goals and get back more time into your day. You'll not only get control of your time, you'll learn how to use that momentum to take on your next big goal. To help you do this, I've created a list of the 10 most impactful things that any high achiever needs to dominate. And you can download it for free by clicking the link in today's description. All right, my friend, back to today's episode. It would probably include all of the the current biological aging clocks. So here's a So you would use them. Here's the way I would frame it though. We don't know what they mean. So it would be more So so if again, you got to play the long game, right? So if we're talking me living to 150, I got to go another 98 plus years, right? Okay. That puts it in perspective. So actually there's a there's a cool uh visual I'll tell you about in a minute if if we if I remember. So um uh so so you got to so you got to recognize you want to capture as much data as you can because you're going to need to learn from it. Even if it's not telling you what what you hope it is today, you've got to capture it now so you can learn from it as you go. going to be looking for patterns. Absolutely. Yeah. So I think you would want to use what we currently know about the hallmarks of aging. And all of these biological aging tests are built off of that framework, right? They measure aspects of the hallmarks. Would you be measuring adipose tissue? Absolutely. So body composition would would be part of the story. Um certainly as comprehensive a blood panel as as I could get. And actually I think that's an area where people in in my field haven't paid as much attention. There there's There've been a couple of um blood-based clocks built off of, you know, clinical typical clinical measures. Um PhenoAge I think was the first first one. Because they don't know what to look for. No, because it's not as interesting as epigenetics. This is This is where shiny object, you know, comes into play. Where are they getting the epigenetic read then? I thought it was in the blood. Are they taking it from there? I'm talking about the standard clinical stuff that you would get from a you know, CBC chem and you maybe other stuff. not turning those results into a clock. So, then one has been built with with the like 10 or 12 blood markers. Um but but there's a whole bunch of blood diagnostics that you can do that that are outside of the standard panel that most general practitioners do that tell you important stuff about your health, right? Vitamin deficiencies. Like I recently found out I'm vitamin D deficient. Not shocking, I live in Seattle, but I take a vitamin D pill and I'm still vitamin D deficient. Hormonal panels, like comprehensive hormonal panels. That's gotten to the point where, you know, there are a larger number of people who get them, but still the majority of people in their 50s, 60s, 70s never get a a comprehensive hormonal panel, right? Would you do hormonal replacement therapy? Not to derail, but Um so so I I I I would if it was appropriate and I do believe that um hormone replacement therapy has gotten a bad rap. So, you know, um based on the literature that's out there, I think the the aversion to hormone replacement therapy it for both men and women for different reasons um doesn't make a lot of sense when you actually look at the data. But there is this culture that, you know, has evolved that that somehow docs that that practice hormone replacement therapy are doing sort of shotty medicine or whatever, right? And I I I don't agree with that at all. So, I think absolutely there's there are certainly people who who when you're when you're clinically, you know, outside the reference range, then it's then it's clearly appropriate. But I don't see a lot of logic behind the idea that it doesn't make sense to try to maintain at least the key sex hormones at youthful levels, right? And so But we don't have a lot of data either way. We don't have a lot of data showing that if you do that that it's necessarily beneficial other than people anecdotally report that they feel better and they can function better and for men they can maintain muscle mass better and and for women, um, you know, I think treating the symptoms of menopause can have huge benefit for certain women. So, I'm generally, um, pretty positive on hormone replacement therapy, but I also recognize there is there is a point where it can be abused, right? I think there are certainly a fair number of men out there who just want to take testosterone cuz they, you know, they they don't want to watch what they eat, and they want to want to have big muscles, right? So, um, and I don't again, I don't know I don't know how dangerous that is cuz I just don't think we have a lot of data yet on them. Not fair. Okay, so, I don't want to pin you down too hard, but I'd love to get your top three or four clocks, assuming that's what you're looking at, that you would really pay attention to cuz I'm looking at things like the average person still thinks they need to be checking their cholesterol. Is that a marker? Like, should we really be looking at that? If you're going to hit 150, that's important. Yes. So, there's two things I would say. So, I and you can put kind of put these in the bins of, um, not dying and biological aging, right? So, rule number one of living a healthy long life is don't die. Yep. And so, you need to measure things like your cholesterol. I would I would say the standard blood panel for lipids is not good enough. You want to get your cholesterol peak sizes. You want to look at things like LP little A and apoB. You probably heard Peter talk about those, independent risk factors for cardiovascular disease. You want to go get a carotid scan, right? You know, or calcium CT scan, where you can actually look at the plaques. So, these are all things you might maybe want to get a whole body MRI. And I don't not saying everybody should get a whole body MRI, but, you know, if you can afford it, and it's not a big deal, Are you worried about the radioactive dye? Well, I didn't do it for that reason. So, here's the thing, right? Again, there's a there is a small risk from from radiation, but if you've got a pre-existing cancer that you can catch early that that's going to kill you. So, again, you kind of have to If money were no object, how frequently would you do that? Oh, that's Yeah, that's probably above my pay grade. I haven't really I haven't I'll just be honest and say I haven't really thought carefully about the risk reward and looked into the the total exposure. So, I would certainly say probably not more than once every few years. Um but uh but I don't I don't I I haven't spent a lot of time thinking about it. But I I put all of those things in the bin of, you know, don't die. And so, you've got you've got you've got to have a set of diagnostics that are going to tell you as early as possible if there's a problem, something that's going to kill you. Or, you know, and and I I say that sort of jokingly because it it it makes sense, right? But but it's also important from a health health span perspective is don't get sick, right? So, one of the things that that we've done in, you know, modern medicine is we've gotten very good at keeping people alive with one, two, three, four age-related diseases. But living that way is very different than living without any age-related diseases. And so, you want to make sure you you maintain, you know, your health as long as possible. And so, I think these same diagnostics can help you catch age-related disease, like metabolic disease, early and then modify appropriately. And that may involve prescription drugs, it may involve lifestyle changes. So, so I think that sort of comprehensive baselining is super important. Um and then the biological age test again, I you know, I hesitate to point to any I'm not going to point to any of the specific commercial um ones. But as a as general classes, like you can you can you can develop you can use existing clocks and they're they keep coming out on on comprehensive blood chemistry. So, the clinical stuff, which you're going to measure over here anyways. Um epigenetic profiling is is the most common and that's where people get a little bit confused because there are literally probably dozens of different epigenetic clocks now. But they all come from the same technology. So, you can measure the epigenetic marks in your blood um comprehensively and then apply different clocks. And that's what a lot of the companies are are doing is just applying different clocks. So, from a measurement perspective, it doesn't matter. You just get the most comprehensive epigenetic profile that you can get from blood. Um there's a couple others. There's a uh uh blood glycans, which are a different kind of chemical moiety in the blood that are thought to reflect biological age or some aspect of biological age. Um uh And then I think you'd want to you'd want to think about doing some what we would call sort of exploratory endpoints. So, um high-dimensional proteomics and metabolomics. That just means measuring proteins. So, Got it. That sounded super fancy. Yeah, I know. It's like it's a fancy word. No, so it's it's um you know, old technology that has gotten got a lot lot better um where you basically quantify, you know, thousands of proteins in your blood um at any given time. And and metabolomics is a is a it's it's a different kind of technology, but conceptually the same. You're looking at the level of hundreds sometimes thousands, depending on you on how you do it, of metabolites in the blood. Which come from your microbiome, right? They get absorbed. They come all over the place. So, they come from your own cells. Some of them come from the microbiome. Yeah. Interesting. What what what cells kick off metabolites? All your cells are constantly giving out all all sorts of organic uh molecules. Yeah. And those are all they all fall under metabolites. Yes. Learned something new. mean there's there's there's proteins, there's metabolites, and RNA, and then you can get to a little bit more exotic stuff. But those are the big three. So, you can also measure um RNA from blood, uh which tells you about gene expression. So, all of these things can be measured with with tools that are available today in in pretty high dimensionality. The problem is, again, we're still very early in building the clocks from them. But the earlier you get your own samples, you can always go back to that data. So, once you've measured it and digitized it, it's always there, right? And so, as the clocks get better, you can look backwards in time and see the state that you were in back then and be informed by how that state changed based on what you were doing in the intervening time. So, let me give you an example of why I am uh a little bit worried that that that the epigenetic clocks have gotten ahead of themselves. So, there's an emerging I think pretty significant question about what the epigenetic clocks have been measuring that has yet to be resolved, but but it's there there's emerging evidence um from a couple of different labs that one of the major signals that comes out of these epigenetic clocks is the composition of the types of immune cells in your blood at a given point in time. So, there are multiple types of different immune cells in our in our blood and they all have their own type-specific epigenetic profile. But, when you're measuring these epigenetic clocks, what you're measuring really is a you know, uh all of that at the same time on top of each other, right? Um and all of those cells are probably aging. Your body's whole body's aging, but um you can get changes in the composition of the immune cells, like what percent are, you know, different types of immune cells at a given time, very quickly. You You get an infection, the composition of your immune system is going to be very different than it was before you got that infection. And then it's going to change as you clear out that infection. That I would speculate will greatly change these epigenetic clocks and make it look like you are aging rapidly or reversing aging rapidly. No, what you really did was you got infected, you had the appropriate response, and you cleared that in infection. And so, they are they have been built um to predict usually mortality based on samples that were available. And those usually come from blood samples that were collected across thousands of people as part of these large epidemiological studies. The problem is we don't always understand what the potential artifacts are involved in building these kinds of tools. Um because we haven't really thought carefully about what the what the population was that samples came from. And so we may find out that most of what these early phase epigenetic clocks were really telling us about were immune status. Right? How healthy is your immune system? Which is a part of biological aging, but it's probably not the whole thing. And so um it and they may actually be telling us more about whether you have a pathogen or how well your immune system is functioning or how inflamed you are at that given snapshot in time. This is what And I I actually I actually think that there's going to be some truth to this because to me that's how you explain the sort of very rapid changes in these clocks that some people have claimed, right? Some people have claimed that they can reverse their epigenetic age by 10 years in in a period of a couple of months. Um or 5 years in a period of a couple of months. And biologically it just doesn't make a lot of sense. I mean it's possible. Can't rule it out, but it's it it does make a lot of sense that you can remodel your immune system in that time frame. Because it's such a high turnover system. Right. Makes sense. Um That's one thing I will give Brian credit for is he said, "If somebody's really asking me my biological age, I have hundreds of ages. It's tissue dependent and everything's going to be different and some are harder to measure than others." and there is still this open question of do all tissues age at the same rate? No, they don't. They're all There's a some coordinating principle that's causing all of our tissues to age, but you look at the the female ovary. I mean that's a really good example of a place where aging is greatly accelerated, right? Yeah. Um so so clearly no, they don't all age at the same rate. You may hate this question cuz it's just speculation, but do you have any guess why women stop being able to reproduce so young? Is it that they're getting too frail? They're more likely to pass on genetic mutations? Like you have to assume that evolution tried it where women stayed fertile forever. Yeah, that's a good that's a good question. This is getting a little bit outside my area of expertise. I think um I think there's certainly this school of thought that that menopause is evolved. Like it was selected for specifically. Um and and actually you know what you said is kind of interesting which is that evolution must have tried it. So it certainly in our close primate ancestors they don't undergo a similar kind of menopause. Um and so I think it's likely that it was an evolved trait as we went down the the hominid lineage. Why it evolved I think you know that that's again it's it's become speculative but it it you know there is speculation around the um the idea that and certainly there's evidence that egg quality declines with age that you're much more likely to get um severe birth defects and uh things like that as as a woman is older. And so um it's probably easier to evolve ovarian senescence than it is to try to evolve mechanisms that would fix that that problem of egg quality going down. I don't find that super satisfying. It it's just a little bit hard for me to think about how you get enough um selective pressure to evolve a process specifically for senescence of the ovary just for that. But I don't have the real answers. I don't know. I mean like you said it's it's very speculative and and I don't I don't know that we have a good answer. But I do think what what I do think is more interesting and more clear is that that process in women of ovarian senescence and menopause then has add-on effects throughout the rest of the body, right? That accelerate aging we think. I guess I should be a little careful. Accelerate the onset of aging phenotypes in other other parts of the body. Interesting. And so, these again, these tissues and organs are all talking to each other. And I don't think that's at all selected. I think it's a it's a byproduct though of the whole process of of menopause. Um and then just to to give you one more sort of tidbit, which I think is pretty cool. Going back to rapamycin, one of the places where it's been pretty surprising to me to see is in mice, you can actually reverse ovarian degeneration with rapamycin. So, that's another place where rapamycin has a regenerative process. Will the rat start ovulating again? What? So, you can you can take a mouse out of being they're infertile, they're postmenopausal, and bring them back into uh estrus? I should be careful. Mice don't go through menopause. They go through a I don't remember the word. There's a different word for it. So, it's it's it's a different biological process in a sense, but they do become infertile. And I should be a little careful cuz I don't think any of these papers have been published yet. This is all from what I've heard at meetings. So, but yes, I've seen data shown at meetings where they show that the mice that got rapamycin are able to reproduce. Mice that didn't get rapamycin are no longer able to reproduce. Okay, so now This is late onset, so. Now we have to start cuz I I'm getting excited again about rapamycin. Um I've gotten very excited about metformin and was like, I'm not going to take this. The number of people that not everyone, so I'll leave everyone to speculate, but the number of people that I've had on the show that off camera are like, yeah, you should take metformin. And I know a guy that's a very high-level surgeon and he was like, oh yeah, you should take metformin. I take metformin. And I'm just like, I am always tense about taking exogenous substances. Sure. And just cuz who knows the balance? Like take vitamin D. I'm just convinced that the sun falling on your skin does more than just trigger the production of vitamin D. So, Mike, if you're avoiding the sun and supplementing vitamin D, the odds that you're getting exactly what you need are basically zero. So, Sure. I'm a little sketched out. So, I didn't take Metformin. And now it's starting to come out, well, maybe Metformin isn't as good for you as we originally thought. So, as I get excited about Rapamycin, Yeah, yeah. No, I think that's I think it's a totally legitimate uh perspective and and I I maybe don't go quite that far, but uh but I'm pretty skeptical of supplements and I've been public about that for for that reason. Like it's like there's not a ton of evidence most of the time and you never know what the consequences might be. So, one thing I'll say about Rapamycin is Rapamycin's interesting cuz it started with a bad reputation cuz of the way it was clinically developed. So, if you go to almost any physician who doesn't know anything about Rapamycin, they're going to look up the side effect list and they're going to be like, this is an organ transplant drug. You shouldn't take this. Why would you take this, right? So, it started from the bad reputation place. Um do you want to talk about Metformin? Cuz Metformin is pretty interesting. So, so I'm I I'm I'm definitely in the camp that uh people who don't have glucose homeostasis uh challenges probably shouldn't take Metformin for aging. So, the evidence there in mice is actually pretty weak. Metformin does either does not increase lifespan in mice or it increases lifespan by like 5%. So, you know, caloric restriction, Rapamycin, Metformin in terms of magnitude of effect. And in the one study where it it was tested and it showed that 5% extension of lifespan, they tested two doses. This isn't talked about, but the other dose shortened lifespan by 10%. So, the evidence that Metformin really is a potent longevity drug, not so great. Um now, certainly in people, it's a very good anti- diabetes drug and there's a a bit of evidence that now has turned out I think there's been contradictory evidence. There was There was an initial paper that showed that diabetics taking Metformin, they lived much longer than diabetics not taking Metformin, and maybe even a little longer than non-diabetics not taking Metformin. That's the data that gets pointed to in people as the best evidence that Metformin might have an impact on longevity in humans. That sense is not replicated at least in one other study. I don't know I don't know what the answer is there. But um But did you ever take Metformin? No, I've never taken that. So there was something there enough that made you go, "Mm, probably not." But rapamycin, I've heard you do take at least occasionally. Yeah. Yes, that's right. The other thing I want to say about Metformin though, because most people don't appreciate this, and I didn't actually know this until recently, is that um in men, a significant fraction of men taking Metformin, it actually has a negative impact on testosterone. And it's not clear to me whether that's reversible or not. Whoa. So yeah, so I would just think about that in the whole context of science. the mechanism? No, here's the problem with Metformin, nobody knows the mechanism. It's a super dirty drug. So it's Dirty meaning it it impacts a lot of things. bunch of stuff, yeah. So it's talked about as an AMPK kinase activator, definitely as a mitochondrial inhibitor, so it inhibits the electron transport chain, probably has 10 or 12 other targets. So we don't really know exactly how Metformin's working, and we don't know if it's the same target for the different effects of Metformin. So anyways, that that's why I wouldn't take it. Um uh So rapamycin um has a much better track record in terms of actually reproducibly and robustly impacting the biology of aging. And it's not just lifespan. So we talked a lot about lifespan, but you know, as we've alluded to in mice, at least, you can either delay functional declines, or in at least four different organs and tissues now reverse those functional declines giving it to mice in older age. Wow. So, the potential upside I see from rapamycin, again, purely speculative that it's going to work in people the same way, but the potential upside is so much greater than it is for metformin just based on the preclinical work that that goes in the, you know, risk-reward, that goes in the potential reward pile. So, then the question is, what are the real risks? And um we've gotten a lot more data in the last 5 years on what the risk profile of sort of non-organ transplant lower-dose rapamycin looks like. And we haven't published it yet, but um we hopefully will be in the next we'll probably submit it in the next couple of weeks. We did a survey-based study of about 330 333 people who've been using rapamycin off-label. We compared them to about 150 kind of age-matched demographically matched people who've never used rapamycin and looked at a whole bunch of stuff. And so, it looks like the side effects from from, you know, off-label use of rapamycin, the the ones that are real are mouth sores for about 10% of the people. That's a known side effect of rapamycin. Mhm. Um and then it probably does increase risk of bacterial infection by maybe twofold. So, you can look at that and be like, "Oh my god." Or you can look at it and be like, "Two times a small number is a small number, right?" So, but it probably does increase risk of infection by about twofold, bacterial infection. Interesting. Is it a Okay, so going back to we're lowering the immune response. Got it. Here's the thing though, it actually seems to enhance resistance to viral infections cuz it turns up antiviral gene expression through mechanisms that aren't understood. Okay. That that's come out of some clinical trials, and that seems to be in our group. And one of the things we looked at in our group was COVID-19. So, this was actually, you know, fortuitous timing that we had just come through this whole COVID-19 pandemic, and so we were able to ask people, you know, are you vaccinated? Did you get infected? If you did get infected, what was your infection like? Was it mild, so less than a week, more than a week, or did you have to go to the hospital? And then, are you still experiencing symptoms or did you experience symptoms that look like long COVID? Okay? And here's the thing where again, these are all fairly small numbers. I told you the size of the group, right? But so it's not like I want to put a a huge amount of certainty behind this, but but but I've been in this business long enough to kind of look at data and I know what looks like questionable and what I think is probably real. The one thing I think that's probably real that came out of this is the the people who took rapamycin continuously, so before, during, and after their COVID-19 infection, had a much lower risk of anything other than a mild infection. Woah. So, almost nobody had a moderate infection and none of them had a severe infection, had to go to the hospital. None of them got long COVID. Am I just not remembering people talking about this or are you like a lone voice in the wilderness on this? I I'm telling you some unpublished data right now. There have been people talking about rapamycin for COVID. Um it hasn't gotten as much attention as it probably should. Huh. Um one one place where where people I think they tried to do a clinical trial and it just never got off the ground was for for severe COVID infections when you get the cytokine storm, using rapamycin to knock that down. But Joan Mannick did a clinical trial. She did two clinical trials with a drug called everolimus, which is a derivative of rapamycin. So, for this conversation, you can just think of it as like rapamycin. It works exactly the same way. Where they showed that you could improve flu vaccine response in healthy elderly people through a six weeks of everolimus. Before during or after? Uh before the vaccine. So, short-term treatment and then you give them the vaccine, then you get a better response to the vaccine. know how long it lasts? No. Cuz if these these trials were all just one-offs. Yeah. But it kind of makes sense with the mouse rejuvenation part, right? So you you you you restore homeostasis and then you give the vaccine, you're going to do better than if you give the vaccine when you've got too much self and not enough, you know, appropriate response. So that part makes sense. What was interesting there was was they went back after the fact and looked at um number of infections those people got in the next, I think it was either 6 months or year. And it didn't protect against everything, but the people who got the mTOR inhibitor had um lower risk of subsequent flu vac flu infection or coronavirus infection. This was done in 2019. So this was before COVID-19. Nobody knew about COVID-19, but that was one of the particular viruses where it seemed to have this protective effect. So basically, it may have a protective effect against your sort of basic cold. Viral, yes. Viral, yeah. I assume most colds are viral. What I think of as a traditional head cold. Right. That's huge. Uh this is an organ transplant drug though. So is this This is one of those if I go to my doctor, "Hey, prescribe me rapamycin." He's going to be like, "Dude, no." First of all, he's not even going to know what rapamycin is cuz it's called sirolimus in the clinical world. Sirolimus? Same drug, two different words. Yeah. So but yes, if you went to him and said, "You know, I I want to start taking sirolimus." Um if he knows anything about it, he he would probably say, "You know, there's a long list of side effects. It's risky. It's going to suppress your immune system. Why would you want to do that?" And you know, I'm going again, as I said, I think it probably is a real effect. It's not It's not a strong immune suppression, but it probably does slightly increase risk of bacterial infections, which is why some people have started cycling. Like they'll take rapamycin for 6 weeks or 10 weeks and then stop for several months and then start again and um and I I I I kind of I kind of like that approach. First of all, I should say I'm not suggesting anybody start taking rapamycin. I'm not an MD. This is not I'm sure you have a disclaimer, but but I need to I want to be careful because I I I'm I'm very um, excited about the data that we've got so far, but I also want to be clear that we don't know that this is going to work for everybody. We don't know it's going to slow aging. Um, and and we're still figuring out what the side effects are. So, I'm certainly not suggesting people should run out and start taking rapamycin. Um, but it kind of makes sense that you would get that slight uptick in risk of bacterial infection um, because you're knocking down inflammation. And I think I think that's how most of the beneficial effects of rapamycin that people experience where you they and I've had several people tell me like I feel so much better after taking it. I think it's really the people who have high levels of sterile inflammation. They're the ones who notice the effects. Um, so but it's not probably not going to benefit everybody in that context cuz we're And and the other thing I think I think I should say is, you know, rapamycin is not so different from fasting. Fasting hits mTOR, rapamycin hits mTOR, fasting knocks down inflammation, rapamycin knocks down inflammation. So, they overlap a lot in their biological effects. They're not identical, but they overlap a lot in their biological effects. Um, but people don't always appreciate that that also means that most of the side effects from rapamycin are also side effects from fasting. But we think about dietary interventions as you know, safe and pharmaceuticals as dangerous and you know, there's this disconnect. That is my rough analysis. Yeah, like if I can get the exact same effects, am I better off just doing the fasting? Sometimes. Yeah, fasting again is a dirty drug. Rapamycin is a clean drug, right? So, fasting hits thousands of metabolic pathways. Rapamycin is pretty specific. But what does that mean, you know, in terms of benefit and risk reward and all of that. I don't know. Very interesting. Very interesting. So, I want to close the loop on this idea. You've talked about homeostasis as one of the things you can look at for whether you're prime condition, youthful condition, whatever you want to think about how rapidly are you able to get back to baseline. Is there I mean, do you just look at that in terms of like colds, cuts, scrapes, like Yeah. exercising till your heart rate back to normal again? don't I mean, I don't think there's a right answer to that question. I think, you know, this idea of resilience has gained a lot of attention in the field as a as a phenotype of aging or in some ways it's a biomarker, right? How quickly are you able to return to baseline? I think there are lots of different ways you can you can look at it. In some ways it probably depends a little bit on your bias. Again, I tend to put a lot more faith in functional measures like wound healing because that's important. I mean, that is, you know, that that that's that's important to your quality of life, but it's also telling you something about your likelihood if you get a serious wound of being able to recover from it, right? So, so I think I think those are good measures. I think you can look at you can look at at performance measures like, you know, heart rate variability and things like that or recovery from exercise. Those are probably telling you the same type of information. I just don't think I don't I don't know if we have enough if we have as much data on those kinds of measures and how they're integrating into the biology of aging. I mean, clearly they're integrated. I just don't know if we have as much data on on that. Um So, I yeah, so I I don't I guess I don't know how to answer your question in in great detail other than to say that I think there are you you could look at, you know, I guess to some extent glucose response is is kind of a similar kind of metric. So, you know, when you you could do a glucose tolerance test and actually that's probably not a bad idea. We're going back to the kind of what would you measure? I think a glucose tolerance test is kind of that kind that sort of a measure where you greatly perturb the system and then you look at how quickly is it able to respond? That's another measure of resilience of your your metabolic system. Yeah, that's why I found this interesting. I'd never heard anybody talk about homeostasis as a big signal to you. And, you know, also just thinking about long COVID as potentially one of these where it's it is a mechanism of not being able to get back to homeostasis. wish I knew what was hap- I mean, I obviously lots of people wish they knew what was happening with long COVID, right? But my I speculate that it is a sort of again chronic inflammatory reaction to the initial infection. And so, to me it makes sense that rapamycin and other things like rapamycin might have beneficial effects there. Yeah, this is why getting to the underlying um What is what is the organizing principle of this thing that's happening? So, what are the the nine hallmarks of aging have in common? What are driving the I actually cuz you said it in that context, I want to come back to something you said before which is that, you know, one of my sort of guiding principles is is around inflammation. And that's kind of true. I mean, I think in in mammals this increase in chronic and or sterile inflammation is driving a lot of the functional declines that go along with aging. But, I have to say, you know, I was very late to the inflammation game and I actually don't think that's the fundamental feature of biological aging. And the reason why I don't is, you know, I I talked earlier about how mTOR and rapamycin came initially out of studies in invertebrate models in yeast and C. elegans and fruit flies. Yeast don't have an immune system. They're a single-celled organism. Yet, rapamycin works there, mTOR works there. C. elegans have an extremely rudimentary innate immune system. But, but not a lot of evidence that that inflammation is driving much around aging in those organisms. And yet mTOR inhibition works there. Rapamycin works there. So, it's hard it's possible that rapamycin and mTOR evolved to affect aging by completely different mechanisms in mammals than it did in invertebrates. But that's to my mind very difficult to to credit. I think it's much more likely that there's an underlying principle that's shared in all of these species for how mTOR and rapamycin are affecting aging. And it just turns out that this increase in sterile inflammation is a downstream consequence of mTOR hyperactivation that leads to many of the the at least the functional and health declines that that we notice the most. The aches and pains that go along with aging. The debilitating changes that go along with aging. And probably the increased risk of cancer at least to some extent because your immune system isn't clearing the cancers anymore. The reason I think that kind of thinking is so important, having an organizing principle, is it allows you to create a narrative, which I'll say is just another word for hypothesis. I think things are working in this way. And for my non-scientifically minded people, once you have the hypothesis, it'll make predictions. So, if this is true, then this also has to be true. And now I can go test that thing. I have found that really useful in my life. For one, make sure I understand somebody. Oh, if you're saying this and it predicts this, did it? Yes. Okay, cool. Then I actually understand. And then two, how I filter what I try and what I don't try because hey, it'll make a prediction that either if if this is true and that's true, not interested. But you're now starting to get some of the answers to these predictions with the dogs. And so, I know the study's not done yet, but I've heard you say that you are starting to get some pretty interesting insights out of what's happened. So, so what I can tell you and and I mean, it's been frustratingly slow to get to this point. What I can tell you is we've done two short-term clinical trials that gave some preliminary results that are encouraging, right? So, the the the things that seem rock solid is we really have no evidence for any significant side effects uh from rapamycin in dogs, which is important for a clinical trial in people's pets, right? I think of this very much like a pediatric clinical trial. Um, so you really want to make sure that it's safe. The The other things that are in potentially interesting in terms of improvements, um, uh we found some evidence for a reversal of age-related heart decline, a specific component of the heart or chamber of the heart, the left ventricle. We were able to measure potential improvements. And that was based on mouse work. So, we we basically measured exactly the same parameters. it. Well, because we had a we had a hypothesis, right? That it that that if this is conserved, if it works in mice, then it will work in dogs, right? And so, that's why we measured that. Um, uh and the evidence looked like it did. So, you know, a small study, short term, but but it looked um looked pretty real. And then the other things that I think are interesting is in both of the the the short-term trials, the owners, and they were blinded, this is double-blind placebo-controlled, self-reported that their dogs were more active. And so, that makes sense. Again, you know, the the way I think about this is dogs, just like people, as we get older, you get a you get you get you get more uh sterile inflammation, autoimmunity that leads to a lot of the aches and pains in joints. Rheumatoid arthritis is an autoimmune disorder, right? And so, if rapamycin is sort of generally tamping that down, you might see that as a decline in pain, which would then be translated to an increase in activity in an old dog. So, that's speculative, but it kind of fits with and it also fits with you know what I know from my own personal experiences and from talking to lots of people about rapamycin in humans. So, that seems like it's probably real. Um the one thing I will say though is because it's owner reported, we really want to get the quantitative activity monitors. So, like you know little collar trackers that where we can actually look at activity. Yeah, yeah, yeah. Yeah, but uh but I you know I felt I I felt pretty good about the quality of the owner reported data that we've gotten not just for the rapamycin trial, but in the larger dog aging project. It seems more accurate than I than I would have thought um going in. People pay a lot of attention to their dogs and and can actually report the data. Yeah, no I heard you mention that for some people cuz you always refer to them as companion. Yeah, pet and companion are sort of interchangeable. It's just that the word pet, you know, has sort of a connotation that that some people don't appreciate and so companion is is probably a better word. The only reason I don't use that word all the time is because some people when I say companion dog think of service dogs. That's exactly what I thought. Yeah. But then when I heard you clarify that you know a lot of people think of their pet companion animal as one of their children and I was like oh yeah, that's me. And that's when I realized oh you just you're just giving it warm name to pet dog. Right. Got it. And so that is I'm really intrigued and if this ends up and I'm assuming you did it on dogs because it's just such a faster life cycle you can learn more than if you're trying to do it on humans. Uh but And because dogs share our environment. So, again, if you think about what we know in a laboratory is in this very sterile controlled environment and whereas companion dogs, with the exception of food and even depends on the depends on the household, sometimes even the food, they share pretty much every aspect of the human environment. So, it's a it's a way to capture environmental complexity. The other is the genetic diversity. So, dogs are sort of unique in this um uh breed structure that humans have have created, right? Through selection. We've got purebred breeds, but then on top of that, we've got this this um mixed-breed genetic architecture, which is very interesting and and powerful, but can match to some extent the diversity of the human population. So, you know, I don't know if we're going to be powered enough to really get to true sort of personalized outcomes in our trial, but in the larger dog aging project, where we have 44,000 dogs now, we actually do have enough power to actually say, "Okay, in these in these breeds, you know, there is this genetic component to this aging process or to this interaction between aging and diet and things like that." It's incredible. Want to talk about obesity. So, you made a really interesting distinction between whether caloric restriction is actually the thing that's having the benefit or if it's just not being fat. Yeah. Talk to me about fat as an organ. Why does that hypothesis spring to mind? So, so I think I think the question of whether in laboratory animals, where we know caloric restriction can extend lifespan, is purely an anti-obesity uh response is a valid response because of the way that we maintain animals in the laboratory. They do become obese with age. They are overfed. Um and I've heard people criticize that by saying, "Well, that means it's not going to work in humans." Well, look around. I mean, you know, So, so I don't think that's a good argument for for saying that caloric restriction is not going to work in in humans. I do think it is an an important question whether uh obesity is just on the same spectrum with respect to biological aging. In other words, is is, you know, are we going if from This is very simple. I don't believe it's true, but let's just make it simple. You know, if you're calorically restricted, you're aging the slowest. If you're at a normal weight, you're aging at a rate in the middle. and if you're obese you're aging in an accelerated way. I think conceptually there's probably some truth to that and in fact we see that obesity is associated with, you know, higher risk for a whole bunch of different aging disorders. faster? If this is accurate, are you aging faster because you're just eating more things and you're asking your body to process it? Or is it actively holding the fat, whether it's the hormonal signal that fat kicks off or it's the compression of the organs? I mean it's probably it's it's certainly some of it is that. Some of it is driven by adipose itself, right? We know that adipose gives off uh inflammatory signal. Coming keep coming back to inflammation. That's what I'm saying. It's all about inflammation right? So so absolutely uh the fat itself can contribute. I think also the you know you you I think you were alluding to this the the physical um effect of gravity, just being heavier, wears down your your joints and your organs and so I think that probably plays a role as well. Um that's something we don't really think about in the biology of aging very much is the impact of of gravity on our bodies, right? And and that's actually maybe important. It might mean that some of the stuff we do, if we reverse biological aging, is only going to be so effective cuz we're not going to change gravity unless we go with Elon and go to Mars, right? You know? So so uh so that probably is important in the context of adipose though. There is this physical component there. Um but I don't think that's all of it. I mean I think so I think some of it uh is probably just from enhanced metabolism and the impact of that enhanced metabolism on other tissues and organs, on your liver, you know, which is kind of the first pass for all this stuff, on your kidneys, which have to detoxify all the stuff you're taking in, on your circulatory system. So that all is going to affect the aging of the rest of your body not only because of of the adipose itself. Super interesting. Yeah, that's one of the things when I think about our modern diet and I think about organizing principles. So, what's the underlying cause and effect? Yeah. Um we're God, is it we're we're extending life but not health span or is this the first generation that's going to live less time? Either way, it's Remains to be seen. Yeah, no, it really remains to be seen what's going to happen to life expectancy going forward. But yeah, I mean, obviously a huge swath of the population in pretty much every developed country is unhealthy. Oh, so you're not sure? And I don't So, so a couple things I would say, I don't think you can argue that we have been successful at keeping sick people alive longer. I think you can have a debate about how much of the life expectancy over the last 30 years is better health and how much of it is poor health. But I think it's clear a significant fraction is poor health. And then you put on top of that these cultural and societal forces which have led the vast majority of people to eat an unhealthy diet and become sedentary and that's just, you know, compounding the whole thing. And yeah, I it's you know, it's we'll see where it goes. I mean, I I think I'm not super optimistic that medicine is going to be the solution. Um you know, I think we've we've had a couple of exciting developments in anti-obesity drugs and we'll see how effective they are over the long term and whether they're are they using? Is it ever able to, you know, be be used widely, right? Um so, there's a few. So, I think I think the the newest ones are actually mostly inhibiting appetite. So, they kind of make you nauseous. So, you don't want to just don't want to eat. Yeah. The thing I've heard though and I haven't read the study. So, so don't don't don't quote Well, I guess you can't quote me on this. I'm going to say it. We will quote you as you say don't quote us. Fair. We get it. So, I have read though that there's now some concerns about rebound. So, when people come off the drugs, you know, they rebound. And And that that we know about this from yo-yo dieting and all that. in the brain? You know, this is where I'm going to I would I would rapidly get outside of my area of expertise if I started commenting too too deeply on this. I think there is absolutely uh uh effects of many of the highly processed foods and high-calorie foods that are easily available today on the brain that reinforce this process. I don't think anybody really would argue with that. Is it a formal addiction or not? You know, that's a word that I think triggers some people, and so I don't I don't know that that's important, but clearly um there are changes in brain chemistry associated with eating certain foods that reinforce that behavior and contribute to the obesity epidemic around around the world. And I mean, look, some of these things were developed for that purpose, right? I mean, some of these these companies that that created these foods put a lot of research into figuring out how to you know this how do we impact this What's it called? The bliss number or something. Yeah, this this scale, right? You know, to make the brain fire. So, I think there might be something else going on as well. So, I'll throw I'm just not I don't have a scientific pedigree to protect, so I'll just pontificate. Um I think that part of what might be going on is your microbiome is adjusting to what you eat. It's sending neurochemical signals to your brain of like crave this, crave this, crave this. And then on top of that I have heard I don't know if this is going to pan out or not, but I have heard from somebody They believe it. And they are very much a scientist in FDA trials right now, and they believe that they have a mechanism by which you can adjust the hypothalamus's basically weight fat set point. Set point, yeah. So that the amount of fat the body wants adjusts. And that his hypothesis is you have a set point. Your body wants, I don't know if you want to put in percentage, pounds, whatever, I don't know. But it has some amount of fat that it wants on your body. And you can diet all you want. You'll lose the fat. But as soon as you stop dieting, it goes right back or more. And until you adjust that set point, all you can hope to do is is yo-yo. Yeah. That's interesting. Now, if you combine that with the microbiome screaming out for things and you've got the set point, you're going to rocket to that. So So, yeah. So, I mean, I think there's there's certainly some truth to the whole set point idea. And I don't know I don't know what you're referring to, so I don't I can't comment on likelihood that that's going to be successful. Couple things to say. So, I think the microbiome is is link is super interesting. And definitely there's some evidence that that for exactly what you said, which is that the the diet you eat remodels the microbiome. And then the microbiome indeed is sending signals throughout your body, not just to the brain, throughout your body in these metabolites that we talked about before. So, they get in your circulatory system. And that that probably does play some role in the I don't know whether you want to want to call it habituation or changes in brain chemistry, you know, whatever the process is that's reinforcing this desire to continue to eat that way. Is it a big role? Is it a small role? I don't think we know enough at this point to know. But it it it almost certainly is is important. And the microbiome interacts with your immune system. So, again, the the gut is I think the largest immune organ in the body, right? Because of these interactions with the microbiome. And so, that's probably also driving a lot of the changes in immune function that that happen as well in response to these these, you know, low-quality diets that lead to obesity. So, again, it's all interconnected and the signaling is um complicated. Yes, it is. Yeah, super complicated, but so interesting. All right, as somebody that's going to deploy this stuff, I always find it very interesting to see where people are in terms of if they have kids, which I know you at least have one. You learn real fast what people really believe in. So, what how do you feed your kids? Uh would you have them supplement anything? Like how does that play out? Yeah, so so we have always uh let me not say always. So, when the kids were very young, I will admit we did take them to McDonald's once in a while, but we haven't done that for years. We've And this is What about not going to McDonald's? No. Interesting. Oh, no. But we never did it all the time. So, so I I should say this is this is more my wife than me because she was she first of all was much smarter about diet than I was but earlier. So, she she was telling me things that I now am, you know, saying out loud, right? Or about 10 years before I actually started practicing them. And so so she really was the one that drove this. But but we were pretty healthy. So, she uh made a strong effort to ensure that, you know, we mostly whole foods, uh lots of vegetables, um and um but we're not perfect and we never have tried to be perfect. And again, I think there's this, you know, this is where I think it becomes very individual. And and and I think that some people can function in a very rigid sort of lifestyle and that works for them, but I think most people can't. And so I I we have never tried to say, "Oh, you can never have a hamburger, cheeseburger, whatever. You can never have candy." But try to make sure that the day-to-day sort of uh normal uh life at home is a healthy one. Supplements, um I Vitamin D we give to our younger son because he is also vitamin D deficient. Um and probably a a multivitamin and that's about it. is and one who isn't? Well, uh our oldest one has never No, our oldest one I don't know if he's ever been tested to be honest with you. Our youngest one got tested. Our youngest one got tested. Our oldest one is out of the house now, so it's a little bit different situation then. But How old were you when you had them? Um He was born in 2002 and I'm going to be 52. So, yeah. Wow. 2002 sounds like oh, a couple weeks ago. Yeah, I know, right? Crazy that yeah, that's a 21-year-old. Whoa. Uh but but you know, we're not super big on supplements. So, so my wife takes a multivitamin. I don't. I I Actually, I've been thinking about this. I need to go get a comprehensive vitamin uh panel. I don't think I'm going to be deficient in anything, but I need to find out. But I don't I I don't like the idea of mega-dosing. So, you know, finding the right balance for vitamins is important. And so I want to figure out where I'm at and then figure out what if anything I need to supplement other than vitamin D, which I already know. So interesting, man. I really like the way that you approach things. Where can people follow you? So, um I would suggest that people follow me at the Dog Aging Project, which I've got my shirt on. dogagingproject.org. And I'll also make a plug if anybody out there has a dog, any age, any kind, any size, consider participating in the Dog Aging Project. We are You said it is from home? Yeah, absolutely. Go to the website, nominate your dog, and uh you can complete the survey. And um it's the largest open science project for uh canines in the world. And our goal is to increase health and longevity for pet dogs. So, if you have a dog, I'm sure you think that's a worthwhile goal and I'd encourage you to participate in the project. Yes, I do. That's awesome. All right, guys. If you haven't already, be sure to subscribe. And until next time, my friends, be legendary. Take care. Peace. Click here now to learn how to reset your age, look younger, and live forever. And he said, "I thought I was going to fail, but do you see what I'm seeing?" And I said, "Yeah, I see it." "What are you seeing?" I said, "The future."