Living longer with Michael Rose and Todd Becker

video: https://www.youtube.com/watch?v=GkUEe_UGP0I

LLM-generated summary: Michael Rose, an evolutionary biologist, elucidates how natural selection shapes aging as a progressive decline in fitness traits post-reproduction onset, culminating in a plateau of mortality rates at advanced ages—termed biological immortality—demonstrated via experimental evolution in Drosophila and corroborated by human demography. He refutes reductionist molecular theories, emphasizing manipulable selective forces that delay aging onset and cessation through deferred reproduction, yielding Methuselah flies with tripled lifespans. Dietarily, populations adapt to environments over generations; agricultural ancestries tolerate cereal/legume/dairy diets until ~age 40, after which paleo-mimicking Whole Foods diets optimize late-life vigor, as validated in lifespan assays comparing banana (agricultural proxy) versus applesauce (ancestral) diets. Lifestyle hormesis yields modest gains via reproductive suppression, paling against ancestral shifts, while future longevity leaps hinge on AI-driven omics integration for polygenic interventions, supplanting outdated paradigms.

video description: This episode with Michael Rose will look at longevity from an evolutionary perspective. Michael is an experimental evolutionary biologist who has spent the last several decades running experiments to understand the role that natural selection plays in aging. He's a distinguished professor of Ecology and Evolutionary Biology at UC Irvine, and a great talk at the Ancestral Health Symposium 2018 on Diet, Aging and Evolutionary Mismatch. You can check it out on the AHS YouTube site. In today's episode, our discussion touches on fundamental questions, including: the nature of aging, how evolutionary forces control lifespan, whether aging can stop, the optimal diet and lifestyle for living longer, and how that should be adjusted as you get older. Michael bases his conclusions on decades of experimental research and hard mathematical analysis. It's a wide ranging discussion with some surprising solutions.

Podcast Introduction

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 the 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 is 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.

Michael's Path to Studying Aging

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 but a hero to many who are interested in evolutionary biology. 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. He handed me off to a lecturer in his department in England—for lecturer, 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, of the Royal Society of London. And, you know, 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 in any way. 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 fetuses, chiefly.

I wasn't interested in any of that. 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, 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, 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 some.

Definition of Aging

Right. So you talk about math, and you actually have a book that I thought was very insightful in this, Does Aging Stop? Right? and it's got some math in it and which a little bit of which I can understand but just qualitatively aging kicks in at a certain point right 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 is 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 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.

Gompertz Law of Mortality

And there's a measure of that in terms of the rate at which any cohort would be dying as they get older, right? Which is at some level and then it increases as we get older up to a point?

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 a 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 five or 10 percent every year is dying. 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.

Discovery that Aging Stops

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 humans, 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, James Carey and James Curtsinger, 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 med 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, it abruptly stopped in the last stages of adulthood.

And I remember the day my best colleague, Laurence Mueller, 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 James Curtsinger'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, James Curtsinger 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 Laurence Mueller, 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 Laurence and he said, oh, this is interesting. And I suggested to Laurence 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 immortal, even though they have death rates. For example, 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 hydropolyps 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 know, you and I are aging because of our ages. And, you know, we're 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, 9-0 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 Laurence Mueller 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.

Third Phase of Life: Selective Pressures on Aging

So you've called this phase of late life, you've called it a third phase of life, right? It's a, 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 can you 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 um 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 she, he sees her break, you know, 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 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 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 were 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 it 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 by manipulating this function.

Experimental Evolution: Methuselah Flies

So evolution cares about us very strongly until we start reproducing. Once we been able to reproduce it progressively not immediately progressively loses interest until we so old we're not going to reproduce. It totally loses interest. Now, exactly.

And you've been able to manipulate this and talk about what you've, 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 Ketten who called them Methuselah flies. Okay. Not me.

Secondly, you know, there I 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 Charlesworth, wanted 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 midlife flies, and only letting the eggs laid by flies late 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 reproduce flies, which reproduce 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 we've been, it's easy to double and triple the average lifespan. And as you do that you 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, you know, a hibernation phase. In all the other organisms, like, you know, humans, any mammal, getting to a tripling 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 know, 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.

Reproduction-Lifespan Tradeoff

So there's this tradeoff between reproduction and aging, right? So delaying reproduction correlates to longer aging, having earlier offspring.

I have to stop you, Todd. I have to stop you. Not immediately. Not immediately. Not immediately. But over generations. Evolutionarily, what you say is true.

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 because 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, you know, 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 of fun. But that has nothing to do with an evolutionary effect.

Got it. It is true that if you castrate 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 trade-off 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.

Evolutionary Mismatch in Diets

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, you 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. 55theses.org—the numerals 55 T-H-E-S-E-S dot 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 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, you know, 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. You know, sodas with sugar, high fructose corn syrup or artificial sweeteners are poison. um 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, who 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, etc.

This is at the core of what an organization like the Ancestral Health Society is all about.

So we clearly not adapted to the modern diet but are we even adapted to the agricultural diet that goes back 10 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, you know, 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 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 agricultural ancestry right is very well adapted to an organic agricultural type of diet, the kind of diet everybody ate before 1870, roughly speaking.

Okay. And this is true if you from a Eurasian background or genetics where there was the whole birth of agriculture.

But if you from Australian Aboriginal background or maybe Pima Indians that might not be true right Exactly. And excellent data have been collected, particularly from Australasia. People who 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. You know, things like type 2 diabetes and cancer and heart disease go from abundant, if not, you know, 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.

Age-Specific Diet Recommendations

So if we're from a European agricultural genetic history, we can tolerate this up, as you said, 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, you know, 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.

Okay. So that, I mean, my great grandmothers were born around and I knew, knew both of them and, um, uh, well, two out of four, around, uh, the 1860s. And, and I knew, knew both of them and, um, uh, well, two out of four, I should say. Um, 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 Laurence Mueller and Cassidy Richter, my co-authors. And Laurence, as usual, did some nice math on that, and the math worked.

Fruit Fly Diet Experiments

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 uh 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 an organic applesauce from Trader Joe literally our Trader Joe emulation of their long ancestral diet which for some of these populations is more than a thousand years ago Okay So sorry I misspoke More than a thousand generations ago.

So you're talking about before the advent of agriculture anywhere in human terms. Okay. 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 and opportunity to adapt. Except if anything, what we'd done in the lab was more rigorous than anything humans had 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. 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, they're 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 got to make that transition.

So bottom line, if you want to optimize your health. Bottom line, we have to become more hardcore as we get older. Is that right?

Exactly correct. Okay Exactly correct All right And what neat is this isn just like an intuition whatever There a mathematical case for it and there an experimental case based on thousands of fruit flies Hundreds of thousands. Hundreds of thousands, repeatable. So what a nice result. I mean, congratulations on that because, first of all, very clever way to demonstrate the hypothesis.

Lifestyle Factors: Movement and Stress Resistance

So let me just check in the remaining time. I want to talk about possibilities for further extending our longevity and health beyond just diet. And just diet and lifestyle diet and lifestyle. So it's also the exercise and the.

Well, it's actually it's actually avoiding sitting. Sitting. OK. It's walking a lot. I don't you know, I don't think you need to be an Olympic athlete. Right.

But it's emulating the patterns of our ancestors from pre-agriculture. I mean, they were hunters and gatherers. They were moving along a lot, right? Even agriculture. So basically, right, people didn't have cars. Right. And almost nobody, even during the agricultural era, went around, you know, with a horse and buggy. That's actually comparatively recent technology.

What Iron Agers 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, you know, 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 total 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 mentioned since we talking about lifestyle you seen a correlation between stress resistance resilience and longevity The longer lived flies or any animal is also more resistant to certain stresses I very interested in hormetic stresses you know to sort of upregulate things. Do you think that there's a case to be made for applying, you know, those hormetic challenges to our life, even cold exposure, fasting, things like this.

I know the world you're talking about. Yeah.

Hormesis, Caloric Restriction, and Stress Resistance

So we have worked on the relationship between stress resistance and aging for 40 years. That long antedated ancestral diet research. And we have must be 100 publications on the relationship between stress resistance and aging, roughly.

So the key to that story is that if you stress the body of an animal or you make it evolve increased stress resistance, which we have done multiple times. And by we, I'm talking about teams of hundreds of scientists at UC Irvine. um 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 a famous example of this um you can think of it as hormesis or like 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 are, the bodies of female mice are radically altered to sustain pregnancies. 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 lifespans 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 percent 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 is 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 an 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 with 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 not interested in living a year and a half longer for the sake of becoming relatively emaciated infertile and grumpy all the time through the lack of food

So let 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, cold shock, and so on. Okay, that makes sense.

Complexity of Aging and Future Directions with AI/Omics

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, you know, 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. OK. Yeah. That might have been an argument 40 years ago. Now it's a demonstrable fact. Demonstrable fact. So because of this complexity, we're not going to find these magic bullets, right? Correct.

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. Secondly, however. But that's not going to get us to age 200, is it? Not at all. Okay. So how do we get to age 200? That's incremental. Yeah.

We will get the first step in getting to age 200 will be the use of AI or 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 like surgeons not washing their hands before going to surgery after 1900, when 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 was 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, so long as they didn't 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 accede to the recommendations of machine learning off of genomic information, because none of it make 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 five to 10% of the time. Right.

But 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 have been working very hard to integrate omic data, detailed functional data, and machine learning, together with my colleague Laurence Mueller and our graduate students, in the lab with Drosophila.

All right. We say, well, 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. You get many, many, 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 and nor should you.

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 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 other focus. Actually, it's been more time consuming than the ancestral diet thing because it's a lot harder and a lot more expensive.

Conclusion and Resources

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 place to start?

You can basically get a hugely expanded version of this conversation at the website, 55theses.org, 55theses. It's modeled on Martin Luther's 95 theses, which he aimed at the Catholic Church. My 55 theses 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. All right. 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.

Insights

• Selective Indifference Arc: Natural selection maximizes fitness pre- and early-reproduction (high selection gradient), wanes progressively post-reproduction (Malthusian parameter derivatives decline), yielding age-specific aging; experimentally tunable via deferred reproduction in Drosophila, tripling lifespan in generations.
• Aging Cessation (Biological Immortality): Gompertzian exponential mortality plateaus late-life (~age 90 humans, post-adulthood flies) as selection vanishes; predicted by theory (Hamilton-Charlesworth models), validated via simulations and demography (Greenwood-Irwin 1939; Carey/Curtsinger 1992).
• Evolutionary Mismatch in Diet: Adaptation lags environments by generations; agricultural Eurasians tolerate post-1870 organics ~age 40 (high early-life selection), but require pre-agricultural paleo thereafter (low late-life selection); fly assays (applesauce > banana late-life) emulate human history.
• Reproduction-Survival Tradeoff: Hormesis/CR/stress resistance extends life modestly by suppressing reproduction (10-50% rodents, <10% flies/humans); superior to single-molecules, inferior to ancestral shifts.
• Polygenic Complexity: Aging polygenic (hundreds loci), no magic bullets; AI/omics (genomics+transcriptomics+metabolomics+clinical) for predictive interventions, emulating fly successes (15-year lab pipeline scalable to humans in 10 years).

Transcription errors?

• "Kathy Keaton" → Likely "Kathy Ketten" or lab-specific nickname; uncertain, retained as "Kathy Ketten" based on phonetic fit and Rose lab history (possibly "Kathy Buckingham" or similar; best guess: lab member who named strains).
• "fissile sea anemones" / "fissile hydra" → "fissiparous" (asexual reproduction via fission); misheard as "fissile".
• "Iron Sisters" → Likely "Iron Agers" (Iron Age peoples); contextual walking reference.
• "Bozeman" → Ancestral Health Symposium location (2018 talk).
• Dates/papers: "1939" paper by Greenwood & Irwin?

See also

• longevity