 Welcome to Ancestral Health Today, evolutionary insights into modern health. Is human lifespan limited to about 100 years or can it be extended significantly? What can you do in practical terms to live longer and maintain good health into old age? What dietary and lifestyle changes will help you live longer? Well, there's a lot that's been written about life extension, but very few scientists have looked seriously at how the forces of evolution affect lifespan and how understanding this might offer ways to extend human life. We'll be discussing this and other topics on this episode of Ancestral Health Today, a podcast providing evolutionary insights into modern health. I'm Todd Becker. We're talking today with Michael Rose. Michael is an experimental evolutionary biologist who spent the last several decades running experiments to understand the role that natural selection plays in aging. He's arrived at some interesting conclusions, including how you should change your diet as you get older and what other factors besides diet promote longevity. He is a distinguished professor of ecology and evolutionary biology at UC Irvine, and he gave a great talk at the Ancestral Health Symposium in 2018 on diet, aging, and evolutionary mismatch. You can check out the AHS YouTube site for his talks. So welcome to the podcast, Michael. Thank you, Todd. It's great to be here. Thank you for the intro. So in today's episode, Michael's going to help us deconstruct how evolution shapes the aging process and how we might take advantage of that understanding to perhaps live longer or at least healthier as individuals, maybe as a species. But Michael, I'd like to start by asking you, what got you interested in studying aging? Because I read in one of your books that you had a sense that aging was a topic that was attracting a lot of hucksters, maybe not a promising area for a young evolutionary biologist, but something got you interested in aging, so tell us about that. So it was suggested to me in the summer of 1975 that I do my doctorate on the evolution of aging. The person who proposed this was John Maynard Smith, not only one of my heroes in the pantheon of evolutionary biologists, a hero to many who are interested in evolutionary biology, a not only a brilliant man, but an extremely gifted communicator, very persuasive. And yet, when I was 20 years old and he suggested I work on the evolution of aging, I immediately scoffed at the idea. And he handed me off to a lecturer in his department in England for lecturer, I think, assistant professor. And Brian Charlesworth then spent nine months writing me letters trying to persuade me to work on the evolution of aging. He verbally sketched arguments in favor of it. He referred to his own work. I was also a fan of Brian Charlesworth then as now. I should also add that both John Maynard Smith and Brian Charlesworth later became members, fellows actually the Royal Society of London, and absolutely brilliant minds. So here I was as a 20-year-old spending more than a year because it wasn't until I was 21 in the fall of 1976 and enrolled as a doctoral student at the University of Sussex that they finally succeeded in persuading me to do my PhD on the evolution of aging. So you should understand that in the mid-1970s, the study of aging was a pretty tiny field among biologists. And not fashionable, trendy, exciting, anyway. It was probably because we're in the middle of a boomer crest, and I'm a mid-boomer. And, you know, being young was everything and being old was nothing. So there was essentially negligible popular interest, aside from a few dubious characters, in the problem of aging. And scientifically, it had not seemed to be making much progress, to be frank. And what progress there was seemed to revolve around the proliferation of cells taken from human bodies and cultured in bovine serum flasks for growth cycles and division cycles. And the whole game was, why did the cells run out of the capacity to divide? So very academic, fundamental studies, right? I mean, in some ways, it's hard to believe now, but 50 years later, from the early 70s. But at the time, this was like really unimpressive and uninteresting work to most biologists, the cell division work, the cell culture work. Now known as the Hayflick Limit Phenomenon, after Leonard Hayflick, who discovered this phenomenon, who was alive the last time. Cells only would divide a certain number of times, right? Yeah, about 60 for the youngest fibroblasts that you could extract from Fetus's chief. I wasn't interested in any of them. I was interested in evolutionary theory. So what really persuaded me was looking at evolutionary theory. What really persuaded me was reading the work of William Hamilton, who did the first really good theoretical, read mathematical treatment of the evolution of aging, and Brian Charlesworth himself, who spent the years from 1970 to 1976 when I showed up in his office doing the best work on the evolutionary genetic equations that determine the evolution of aging. That's what persuaded me because I was very math-oriented, despite being a biologist. Math was my favorite subject area to take courses in, because then most of my biology courses seemed like boring recitations of fact. So it was really math that convinced me. And in particular, William Hamilton in 1966 had contended that the Malthusian parameter was key to aging, especially the partial derivatives of the Malthusian parameter. And Charlesworth had shown in fairly explicit models that this was, in fact, the case. Hamilton did sort of the first steps in the mathematical analysis, much like Einstein did with the theories of relativity. And Charlesworth was more like Minkowski, who really did the math right in a way that Einstein couldn't have done on his own. Right. So you talk about math, and you actually have a book that I thought was very insightful in this, does aging stop, right? Yeah. It's got some math in it, which is a little bit of which I can understand, but just qualitatively, aging kicks in at a certain point, which we'll talk about. But before you get into that, how do you define aging? Because it has a very specific definition in your field of evolutionary biology. It's not the same as the man on the street thinks, or the woman on the street thinks of aging as just getting older. It has a specific meaning. So what is the definition of aging? Well, fortunately, my definition of aging, which I offered in 1991 in my book Evolutionary Biology of Aging, is actually widely accepted, even though I think it has its problems now. At that time, I defined it as a persistent decline in the life history characteristics such as survival and reproductive capacities that is sustained despite the provision of excellent conditions, freedom from infection, and so on. So the idea there is it's an endogenous age dependent, meaning as aging goes, as your biological, chronological age goes up, your capacity to survive and reproduce goes down with that age. And there's a measure of that in terms of the rate at which any cohort would be dying as they get older, which is at some level and then it increases as we get older up to a point. So this core phenomenon has been studied by actuaries for approximately 200 years because they've always been very interested in financial wagers on survival and how much they should charge people for life insurance policies. The best and most famous 19th century mathematician who studied this was man called Benjamin Gompertz. And his quantitative estimates of the pattern of exponentially increasing death rates with adult age in humans is referred to as the Gompertz equation or Gompertz's law. Now when you say exponentially increasing death rates, that means every year you get older, a larger probability or a larger percentage of that population dies. So it might be a fraction of a percent and then it's going up and then it's a percent. And then when you get really old, it might be 5 or 10 percent every year is dying, right? Is that what you mean by the increase in death rates? And the really important thing to understand about it intuitively is it's not linear. So your deterioration over each decade gets worse per decade starting at 30 all the way to about 90 in all the demographic data we have access to. So aging seems relatively gentle in your 30s or 40s, but it really becomes a rampaging beast by your 70s and 80s. Now you say there was this work of Hamilton that sketched out some of the forces that were at play here and the implications of that and you followed up on that. So what did you find out about aging? Does it continue to increase exponentially or does it plateau at some point? Okay. So for the first 15 years of my career, my job was to experimentally test and refine the basic ideas of William Hamilton and Brian Charlesworth who developed the core theory for the evolution of aging. And I showed repeatedly that their fundamental ideas were correct but some of their favored minor variations on those ideas some were good and others weren't as good. And I effectively summarized those ideas in my 1991 book, Evolutionary Biology of Aging. And the very next year, two colleagues of mine destroyed our fundamental perception of what goes on in aging not only in laboratory animals but in humans. And what they showed in 1992 was that aging actually stops. There had been some suggestion that this was the case in human demography. In fact, in the late 19th century, there was a beautiful paper published in 1939 about aging coming to a stop demographically in human specifically European populations. In 1939, nobody paid any attention to that. Other things were going on. And it was largely forgotten and ignored until my two colleagues, Jim Carrey and Jim Kurtzinger, published these two studies, one of which was gigantic. It was one of the best studies of aging ever published in a laboratory organism. They both used insects. One meant flies, the other one fruit flies, the same species I work with. And they showed pretty powerfully that after this, you know, exponential explosion of death due to aging in the first part of adulthood that abruptly stopped in the last stages of adulthood. And I remember the day my best colleague Larry Muller summoned me into his office and said, I had to see these papers. And he showed them to me and I was blown away. We were both incredulous. We both thought that something had to be wrong. And we said as much in a letter to the journal they published in Science. But especially Jim Kurtzinger's lab published study after study addressing the possible artifactual explanations for what they were publishing. And they really convinced me by 1994 that, yeah, aging came to a stop. And I was going to myself, what the hell? This just didn't seem to make any sense. And in fact, Jim Kurtzinger was not shy about pointing out that this posed a challenge to the conventional theories for the evolution of aging. And I agreed with him. It did. But as often happens in my collaborations with Larry Muller, I thought about it and thought about it and thought about it. And I came up with a crude idea for which I did some very crude mathematics. And I showed the math to Larry. And he said, oh, this is interesting. And I suggested to Larry that he do some simulations to test whether or not my math was in fact correct. And he did those simulations and my math worked. And what he and I realized between 1994 and 1996 was that, in fact, the evolutionary theory of aging always had, as one of its corollaries, or corollaries, that aging would actually end up stopping at sufficiently late ages under the appropriate environmental conditions. And we published that work. Yeah. Yeah. So yeah, I guess before we get into this a little bit, I just want to again clarify that by aging, you don't mean that we stop, that we become immortal. What you mean is that the rate at which we deteriorate flattens, right? So we get older, we get chronologically older and people die every year. So we're not immortal, but the rate at which people are dying off. That's what you mean by aging, right? I now have to be a little nitpicky. Okay. The term biologically immortal has existed for a long time. It does not mean a zero death rate. It means your death rate is no longer increasing with age. With age, right. Okay. In some species like juniper shrubs, trembling aspen trees, fissile sea anemones, which are animals for those who don't know. And all these are multicellular organisms. They don't age at all. They are biologically. They divide, right? Yeah. And we say they are biologically immortal even though they have death rates. For example, a hydra, fissile hydra. In that case, not only do they not have an increasing death rate, their death rate is so low. A colleague of mine, Danielle Martinez has been able to keep individual hydra polyps alive in aquaria for decades. And in nature, this is an animal that is very easily killed. And of course dies all the time from being eaten. But if you keep them under ideal conditions in an aquarium, they'll just go on living. Now, here's where I'm going to go back to the question of aging, stopping. So by my definition, you and I are aging because of our ages. And we're a very demonstrably aging because we're pushing 70. Yeah. And with the wrinkles and gray hair to prove it. But the 1939 data from Greenwood and Irwin, who first really showed the cessation of demographic aging in humans, that suggests that in Europeans before the 1930s, that they stopped aging around the age of 90, 90 years of age. And after that point, yes, we would call them biologically immortal. But they're not supernaturally immortal. They're not young again. They just stopped getting worse. And that's the result that my colleagues showed in 1992. And that's the result which Larry Muller and I explained in terms of evolutionary theory using explicit math based simulations. And then starting in the mid 90s, we spent another 15 years working on the evolution of biological immortality. After the cessation of aging. And to me, this is one of the most stunning facts about aging that has been established over the last 30 years of research that actually aging comes to an end. And to my mind, that meant two things. Firstly, to make it stop as soon as possible. And secondly, to make it stop in the highest possible state of health as possible. So you've called this phase of late life. You've called it a third phase of life, right? So you're seeing very little aging then at a certain age around the age of reproduction. And you can explain why that is. It speeds up. And then you see this third phase where it's plateauing again. So you've said that this is due to certain selective pressures. Can you explain why aging kicks in at sort of this age of reproduction and then why it stops? Okay. So since we can only use words and not math. I can't even show a diagram, though I did show diagrams in my ancestral health society talk in 2018. I will resort to a metaphor. Which is Rhett Butler's relationship with Scarlett O'Hara in the book and the film Gone with the Wind. And when they first meet, Rhett Butler falls for Scarlett O'Hara. But he immediately realizes she's a coquette. That's the European term for what Americans sometimes call a tease. Okay. And first he watches her from a distance. And he sees her break the heart of young men over and over again. And finally he moves in and tries to have a relationship with her. Which of course she makes as difficult as possible. But they do marry. And then she makes their marriage very hard. And by the end of the film and the novel, he just gives up on her. And you sort of see the much of the arc of the movie being the contrast in Rhett Butler's mind between desire and exasperation. So mathematically we can show that natural selection cares very much about you as an organism evolving as a species, as a population. Up until the age at which you start reproducing. Which is sort of when we meet the young Scarlett O'Hara, who I think is supposed to be like 18 or 19. And then it progressively loses interest in you as you go through your reproductive years. Until finally it has effectively no interest in you at all. It doesn't care whether you live or die. And that arc of increasing indifference in natural selection is what tunes your aging. And I've shown this in experiments dating back to the 1970s when you and I are both young. Remember those days? Yes. And because in the lab you can tune when this happens. You can tune when reproduction starts. You can tune when it ends. And when you do that, you change the timing of the start of aging. And it turns out you also change the timing of the end of aging. So you can expand and contract the window of aging. You can shift aging to a later age. You can bring it to an earlier age. And you can do the same thing for when it ends. It's all completely manipulable by tuning the forces of natural selection. And I will comment as I do at book length in the book I'm finishing this month with my graduate student, Kenneth Arnold, that this basically shows that all the cell molecular theories are wrong and that the fundamental key to aging is this mathematical force of natural selection. Because it's phenomenally easy to completely retune everything about aging but it's by manipulating this function. So evolution cares about us very strongly until we start reproducing. Once we've been able to reproduce it progressively, not immediately, progressively loses interest until we're so old we're not going to reproduce. It totally loses interest. Exactly. And you've been able to manipulate this and talk about as an example what you've done with your fruit flies where you've actually created a cohort of what you call Methuselah flies that are long-lived. How did you do that? Well, firstly it was Kathy Keaton who called them Methuselah flies. Okay. Not me. Secondly, there was a graduate student working on the evolutionary genetics of aging doing a bunch of experiments that nobody cares about very much but my doctoral advisor, Brian Charles, would want me to do. And then I realized one day, sitting at the University of Sussex Library, you know, if it really is the force of natural selection and the timing of when reproduction starts, then it's a very simple experiment to be done which is to change the pattern of the force of natural selection in the lab with my fruit flies because they're easy to control in terms of when they get to contribute to the next generation. This is different from sex. It's when you actually contribute to the next generation. It's very much analogous to my then life as a graduate student when in theory I could have all the sex I wanted but if I actually produced a baby, my life would be screwed. So basically this was done by discarding all the eggs produced by young to middle life or early middle life flies and only letting the eggs laid by flies laid in their middle age contribute to the next generation and do that generation after generation and after just 12 generations, when I compared those delayed reproduction flies to normally reproduced flies which we produce early, the delayed reproduction flies had evolved in just 12 generations, a 10% increase in lifespan. And this has now been done by myself and others over decades ever since and it's easy to double and triple the average lifespan and as you do that, you're doubling and tripling the maximum lifespan. So just think of the case of tripling average lifespan in the United States that would take it over 200 years. Think of tripling the maximum lifespan that would take it from about 120 years to about 360 years. That is dead easy to do using evolutionary experimentation or experimental evolution as I like to call it. It's damnably hard to do it in any animal that doesn't have a metabolic arresting stage, a hibernation phase. In all the other organisms like humans, any mammal, getting to a troubling of average and maximum lifespan, no one's done it. But of course we've done it because in our opinion, we evolutionary biologists who work in aging, we know what we're doing because everything we do rests on a very powerful mathematical theory. You've heard of E equals MC squared, same concept in parallel. You have some very powerful equations, you can do amazing things. We have very powerful equations, they work every time as long as their suppositions are met. In our opinion, and I've been arguing this for more than 40 years, we know what we are doing with aging, they don't. And the proof of the pudding is that it's dead easy for us to produce much longer-lived animals. So this is trade-off between reproduction and aging, right? So delaying reproduction correlates to longer aging, having earlier offspring. I have to stop you, Todd. Not immediately. Not immediately. But over generations. Evolutionarily. So it's not something that's going to show up in a single generation. So if we as humans were to delay having offspring, that's not going to have any effect on us as it takes a selection process over generations for this to kick in. Now, however, by correlation, do you find that just looking at cohorts that in families that have long intergenerational periods that they also tend to be long-lived or do you not see that correlation? And I'm looking at even in humans or other animals. Not experimentally, but just by observation. I'm not aware of any well-founded analysis of that type. Okay. I'll just comment that my grandfather, my maternal grandfather waited until 50 to get married and have children and he lived to be 100. Okay. An anecdote. But that is nothing to do with an evolutionary effect. Got it. It is true that if you cast straight men whether it's boys or adults, they live longer on average. Yeah. Very few people are willing to volunteer for the experiment. There's also data. That at least speaks to some energetic tradeoff between energy you put into reproduction versus into yourself, right? Or is that not true? Yeah. So I've had six children and I have personal experience of the debilitation, distraction, and deflation results from years of childcare. There you go. No, so this is very interesting, but I want to turn to another topic that's of great interest to people in this ancestral health community. And that is your studies on diet. And you've done some really interesting experiments, and your students that you talked about in Bozeman, where you were able to basically look at the effect of different ancestral or sort of agricultural or more contemporary diets, the effect that had on longevity. Can you explain the setup of that and what you learned? Okay. So a full explanation is provided at my website, 55thesis, the numerals 55thes.org. And we've also published on this recently, and you can find that on my Google Scholar page, Michael R. Rose. Having said that, I would just like to do the baby steps version today. Okay. Natural selection does not adapt populations regardless of environment. Natural selection leads to the adaptation of populations to the environment in which natural selection has been acting, in which natural selection has been acting for many generations. Okay. You don't get adapted to living off of nasty modern diets, the kind we've had for less than 150 years, in the five to six generations we've had in that environment. So many of the foods that billions of people now consume on a regular basis are basically toxic. Sodas with sugar, high-fructose corn syrup, or artificial sweeteners are poison. Seed-derived oils like sunflower oil, safflower oil, canola oil, and so on. Completely novel nutrients. Those were not foods before 1870. Okay. So, you know, on a modern diet, meaning a modern, what I call industrial diet, or the center aisles of your typical supermarket, they're laden with poisons that have been carefully crafted for us to want to eat, because they have a high salt, sugar, and fat content. They are deliberately engineered by food scientists, we should be called mass murderers, to get us to purchase the products, regardless of the fact they will then slowly kill us by giving us type 2 diabetes, hypertension, heart disease, some degree of Alzheimer's disease, cancer, et cetera. This is at the core of what an organization like the Ancestral Health Society is all about. So, we're not adapted to the modern diet, but are we even adapted to the agricultural diet that goes back 10,000 years? So, more than 95% of the population on Earth has ancestry in which their ancestors ate some type of agricultural diet, especially consuming foods, where a lot of the carbohydrates come from giant grass species, rice, corn, all the cereal species that we use, and a lot of protein from soybeans and other legumes cultivated ubiquitously, products derived from the udders of cows, which are fantastic for young calves, and so on. This is a diet that I don't think any population on Earth has consumed as the bulk of its diet for more than 20,000 years. 20,000 years is a reasonable number of generations. It's hundreds of generations. So, I do think that people with agricultural ancestry, especially very long agricultural ancestry like almost all Eurasian populations, in terms of their ancestry, are well adapted to that diet up until the age of 30 or 40 years of age. And here's where, again, the mathematics of the evolution of aging come into play, because it's a very deep but only recently noticed corollary, or corollary, of that theory that the speed at which populations adapt to an environmental change scales with those same forces of natural selection I was talking about before, which is to say people before the start of reproduction and right after the start of reproduction, in human terms you could think the ages of zero to 30 years of age, that whole group with ancestral ancestry, ancestral ancestors, agricultural ancestry, is very well adapted to an organic agricultural type of diet. The kind of diet everybody ate before 1870, roughly speaking. And this is true if you're from a Eurasian background or genetics where there was the whole birth of agriculture, but if you're from a Australian Aboriginal background or maybe Pima Indians, that would not be true, right? Exactly, and excellent data have been collected, particularly from Australasia. People have fully indigenous genomes, no agricultural ancestry at all. You give them agricultural foods and it makes them sick. Even when they're young. Yeah, even when they're five years old, 10 years old, 20 years old. And they develop chronic debilitating diseases at a terrifying rate. But people with backgrounds in medicine and anthropology realized decades ago that if you switch them back to a crude approximation of their ancestral diet, they should get much better. And that has now been done many times with those populations. And the health improvements they get are dramatic. Things like type 2 diabetes and cancer and heart disease go from abundant, if not epidemic, to relatively rare, as they make that transition to their ancestral diet. Because those populations never adapted to a cereals, dairy, legume-based diet. So from a European agricultural genetic history we can tolerate this up until the age of 30 or 40. But what about when you're our age in your 60s? Are we under that same evolutionary influence or is there a different principle in play here? It's the same principle again. It's the forces of natural selection. It's over for us. Okay. There hasn't been enough time. So should we switch our diets to even something earlier? So a simple way to put this verbally would be to say everybody up until the age of 30 should follow Michael Pollan's advice and not eat anything your grandmother wouldn't have eaten. In my case, my great-grandmother wouldn't have eaten as a young woman. Okay? So that, I mean, my great-grandmothers were born around the 1860s. And I knew both of them. And, well, two out of four, I should say. And, you know, they were young people in a world that didn't know seed oils, that didn't know high-fructose corn syrup, of course, that didn't have heavily processed foods, that cooked with lard and tallow and so on. Okay? So up until the age of 30-ish, I think that's great. So up until the age of 30, be moderately ancestral. And then in my opinion, over the age of 40 or 50, you got to be hardcore ancestral and go back more than 20,000 years to what I call a Whole Foods of Trader Joe's Approximation to an ancestral diet. So I basically had that insight in 2010, 13 years ago, when I was working on the book Does Aging Stop with Larry Muller and Cassie Russer, my co-authors. And Larry, as usual, did some nice math on that and the math worked. And then, as my lab usually does, we take, you know, very well-founded mathematics and we do strong inference experiments. So I took our flies, which were harvested from apple orchards in Massachusetts in the mid-70s. They were then given our standard diet for more than 40 years, which consisted of banana food. And on banana food, you know, they do really well, especially when they're young. If you compare the banana food diet with my flies to a completely different diet, which they could have been adapted to based on oranges, but they were never given, they do systematically better on the banana food. So the orange food diet we tried is our really quite benign emulation of a supermarket diet or an industrial foods diet. But then we used a third kind of diet, which featured mushy apples, which was our literal, we bought them at Organic Applesauce from Trader Joe's, literally our Trader Joe's emulation of their and long ancestral diet, which for some of these populations was more than a thousand years ago. So, sorry, I misspoke, more than a thousand generations ago. So you're talking about before the advent of agriculture anywhere, in human terms. Because they have so many more generations per year than we do. So inadvertently, my lab had done an emulation of human history, totally parallel in numbers of generations, an opportunity to adapt, except if anything what we'd done in the lab was more rigorous than anything humans have done. And what we found was that earlier ages, very early ages, like that zero to 30 years of age in humans, our fruit flies did, on the banana food, did as well or better than they did on the ancestral apple diet. So this is the agricultural equivalent versus the paleo for the first part of their life, right? But if you look at later ages, much later ages, on the applesauce diet, the flies on the applesauce diet are far superior to the flies on the banana diet. And if you look at one of our measures of functional health, the aging of the flies on a diet they have not seen in some cases for a thousand generations, was very gentle, very gentle, whereas the flies on their agricultural banana-type diet, their long adopted, you know, hundreds to thousands of generations diet, their aging was relatively precipitous. So if you want to be healthy, first you eat a moderately ancestral diet, and then you eat a scientifically accurate paleo diet after some time in Middle Ages, somewhere between 30 and 50, you've got to make that transition. If you want to optimize your health. Bottom line, we have to become more hardcore as we get older, is that right? Exactly correct. Exactly correct. And what's neat is this isn't just like an intuition, whatever. There's a mathematical case for it, and there's an experimental case based on thousands of fruit flies. Hundreds of thousands. It's repeatable. So what a nice result. Congratulations on that, because first of all, a very clever way to demonstrate the hypothesis. So let me just, in the remaining time, I want to talk about possibilities for further extending our longevity and health beyond just diet. Well, just diet and lifestyle? Diet and lifestyle. The exercise and the... Well, it's actually avoiding sitting. Sitting, okay. It's walking a lot. I don't think you need to be an Olympic athlete. But it's emulating the patterns of our ancestors from pre-agriculture. They were hunters and gatherers. They were moving a lot. Even agriculture. So basically, people didn't have cars. And almost nobody, even during the agricultural era, went around with the horse and buggy. That's actually comparatively recent technology. What our ancestors did was walk one hell of a lot. And that was true in agricultural societies as it was true in hunter-gatherers. Hunter-gatherers probably ran more often than agricultural populations. But it was a relatively small fraction of the population that ran a lot, which was the best male hunters in a little band of hunters. So there would be the runners, the trackers, et cetera, et cetera. So the runners could go way ahead and the trackers would follow once the hunters might have initially done some damage or found the prey that they're looking for. The idea that are... And I'll give you one very important fact, which was only recently discovered. The amount of metabolic expenditure hardly varies among human populations, whether they're hunter-gatherers, agriculturalists or modern-day industrialists. I think the key to that is a very large fraction of our total metabolic expenditures on our brains. Now, you've mentioned, since we're talking about lifestyle, you've seen a correlation between stress resistance, resilience, and longevity. The longer-lived flies of any animal is also more resistant to certain stresses. I'm very interested in in hormetic stresses, you know, to sort of up-regulate things. You think that there's a case to be made for applying those chattelos-hormetic challenges to our life, even cold exposure, fasting, things like this. I know the world you're talking about. It's based on the relationship between stress resistance and aging for 40 years. That long-antidated ancestral diet research. And we have, must be 100 publications on the relationship between stress resistance and aging. Roughly. The key to that story is that if you stress the body of an animal to increase stress resistance, which we have done multiple times. And by we, I'm talking about teams of hundreds of scientists at UC Irvine. Basically, what you're doing is you're partially or completely shutting down reproduction. And that gives you a side benefit of enhanced health and function. So this is like, so caloric restriction is the famous example of this. You can think of it as hormesis like, you know, cold stress or whatever. Anything that you do that reduces the costs of reproduction, tends to give some benefit to survival and aging patterns to the extent to which the animal has a greater quantitative scale of variation in reproduction. So if you do this in mice which have spectacular physiological mobilization for reproduction on a scale that boggles my mind as a biologist. Their bodies the bodies of female mice are radically altered to sustain these and if you give them lots of food and you have them fertilized lots and lots of pregnancies to produce hundreds of offspring at the limit. That's why you can get a 50% increase in rodent life spans very predictably from caloric restriction and sometimes more specialized dietary restriction. You can get similar effects from regularly stressing or pushing them to be more athletic. They're not as strong. When you do that in fruit flies which we did for decades you also get an enhancement in stress resistance by restricting diet. You get a crash in reproductive capacity and you get a 10 to 15% increase in lifespan. Interesting. Together with a colleague from UCLA Jay Phelan we did a quantitative study with the best data we could find which are from Japan on extremes of nutritional variation between sumo wrestlers who eat vast numbers of calories and the Okinawan population which in the 20th century was chronically calorically stressed. The corresponding benefits to humans from caloric restriction are order of magnitude smaller than you get with rodents and people have done some experiments with primate nutrition which are all tangled up with the qualitative nature of the diet and so on. It's perfectly clear from those experiments that you just don't get the kind of massive enhancements in a lifespan from caloric restriction to the primates that you do with rodents. Nonetheless it is a general principle that if you can shut down your investment physiologically in reproduction you get at least a small benefit in terms of lifespan. Jay Phelan loves food and his point of view is he's not interested in living a year and a half longer than he would take of becoming relatively emaciated, infertile and grumpy all the time due to lack of food. So let's talk about Let me just make a very important comparison. Our research suggests however that the benefits of the qualitative change of going more and more ancestral in your diet will be much greater than the benefits from hormesis, caloric restriction and cold shock Okay, that makes sense. So you've said that a lot of the early theories of aging were flawed because they were very reductionistic and looked at just one factor like oxidative stress or very simplistic and also the people who have tried to look at life extension they're looking for some magic compound and one of your arguments is that the genes involved in lifespan and longevity there's not one or two genes, there's hundreds there's a lot of it's a complex system the transcriptomics the metabolomics are very complex so likely I have to stop you here to make a very important qualification That might have been an argument 40 years ago, now it's a demonstrable fact so because of this complexity we're not going to find these magic bullets right? but you've also, I've seen you've talked about maybe using AI to really understand this complex system and tease out some a path forward in terms of some interventions so what do you think it's going to take based on this approach and how soon can this happen where we can actually make big strides forward in longevity what are your ideas there for the future? once again I will say that the biggest stride you can make is going more ancestral in your diet and lifestyle but that's not going to get us to age 200 is it? not at all that's incremental we will get the first step in getting to age 200 will be the use of machine learning and the full scale of omic information genomics, transcriptomics, metabolomics together with really good clinical data on tens of thousands to millions of humans right now in terms of the data that we can get from people at reasonable cost the current practice of medicine is barbaric it's like surgeons not washing their hands before going to surgery after 1900 the germ theory of disease was really well established and you know, microbiologists were progressively taking over medical instruction so continuing to go see a doctor who vaguely remembers the lecture from medical school about the importance of free radicals and the doctor tells you to take you know more vitamin E because it's an antioxidant or eat more blueberries because they have some antioxidant properties that's barbaric antiquated, useless destructive what not only needs to but I think absolutely will happen over the next 10 years is the integration of large scale omic data machine learning combining the omic data with clinical data and a radical transformation of medicine which will proceed as fast as the resistance of physicians allows it to which is the same problem that faced the microbiologists all through the 19th century physicians then were happy to let their patients die by the hundreds of thousands to millions and have to change their minds as long as they didn't have to learn anything new as long as they didn't have to accept microbiology in our time almost all physicians are trained with cell molecular reductionism as the foundation of their medical education they're not willing to absorb the evolutionary biology of aging they're not willing to absorb the ideas of diet and lifestyle properly construed they're not willing to exceed to the recommendations of machine learning off of genomic information because none of it makes sense to them because they were all trained in the 20th century paradigm of genes with large effect causing major diseases which is in fact true 5 to 10% of the time right but if you want to so if you really want to push the limits we have to use this AI and omics approach are you yourself participating and helping drive some of that research are you persuading people are you running trials where is this okay so I'm retiring this year as a university professor over the last 15 years we've been working very hard to integrate omic data detailed functional data machine learning together with my colleague Larry Muller and our graduate students in the lab with Drosophila why are you doing this with Drosophila because the stuff we've done over the last 15 years could not have been done in humans over 15 years exactly many more generations out of the flies and look obviously we can do things with flies you'd not be allowed to do with humans so it's very very clear what we need to do over the next 10 to 15 years from what we've done in my lab over the last 15 years and I've been publicly arguing for that I think I gave my first public talk about that in around 2012 2013 when we were first starting on this and then I gave a more assertive talk on that around 2017 and I'm going to be giving a couple more talks about that this year this is what we have to do next with people basically a human emulation of what we've been doing with fruit flies over 15 years you can see our publications on my google scholar page Michael R. Rose that's been our our other focus actually it's been more time consuming in the ancestral diet thing because it's a lot harder and a lot more expensive Michael this is just fantastic and so exciting so you've mentioned the google scholar page can you let us know any other places people should go to see your work would that be the best start well you could basically get a hugely expanded version of this conversation at the website 55thes.org 55thes it's modeled on Martin Luther King Martin Luther sorry Martin Luther's 95thes which he aimed at the Catholic Church my 55thes are aimed at cell molecular reductionism the leading cause of death in our time great and you mentioned a book that's going to be coming out can you say more about that I have a book which does the same job as the website except it shows data it shows the math it's called conceptual breakthroughs in the evolutionary biology of aging Arnold excuse me A, R, N, O, L, D and Rose coming this summer from Elsevier fantastic we'll be looking for that thank you so much for a wide ranging discussion and you obviously have been working on this for 40 or 50 years and it still is the gift that keeps on giving and so I encourage everybody to look at Michael's work really really interesting thank you so much for this enjoyable conversation thank you Todd so much alright take care thanks for joining us on this episode of ancestral health today we hope you enjoyed our discussion on how evolutionary insights can inform modern health practices be sure to subscribe to our podcast to catch future episodes