 Hello, I'm Canadian so I'm not good at yelling so if you can't hear me in the back, you know wave throw things No garments How do I I guess I guess I advance with this yes Better one than this because this one sucks completely So this talk I've been here for the whole meeting and and It's as bad And this talk is not going to be like any of the other talks. I've seen I'm an experimental evolutionary biologist and Worse than that everything that I really have worked on over the decades has been derived from mathematical theory So I don't really believe in stories I don't really believe in You know nice images. I like data. I like math What can I say? And a big problem facing all of you is that Dating back to the 1960s storytelling has been dominated and This is going to be all science I've hidden most of the math And preparing this talk with Grant Rutledge who really should be giving this talk, but he's jet-lagged out of his brain from trip to Japan We decided to eliminate all the math, but we do have sort of cartoony math And I will try to cartoon my way Through the math for you, but then we're going to get into gigantic experimental Studies with lots of data and not on people but on fruit flies And that is because at the core of what your society is based on are some very deep scientific issues Which have not been systematically addressed using strong inference science in my opinion to date ever and this is a Follow-on to Grant's preliminary presentation of these kinds of results. I think two years ago to four or five people so we have more data and More firm conclusions about the relationship between paleo ideas Organic agricultural ideas, and that's what I'm trying to accomplish So to go into a little more detail than than Brett did a traditional evolutionary evolutionary point of view which tends to dominate Pop thinking about evolution we can actually blame on Charles Darwin And that's the idea that evolution proceeds with great gradualness over long periods of time like hundreds of thousands two millions of years and in that context It's a natural conclusion to infer that our best possible diet is the one we had For at least a million years prior to the advent of agriculture Which is to say a paleo hunter-gatherer regime Beautifully embodied in this image here Though probably we didn't really look like that So that I think is the intuitive basis for a lot of what many people who come to these meetings believe To be very concrete. I believe that view myself in the 1970s Before I started to look at data from experimental evolution studies. I Bought into the then conventional wisdom of Darwinism That indeed evolution proceeded very slowly and we probably weren't very adapted to agricultural diets or lifestyles But starting in 1980 we got a revolution and evolutionary biology Which most people outside of the field have not heard about Which is that evolution can actually act with great speed? And I was one of the people behind that revolution It gave rise to a field called experimental evolution and I have a book called that with a co-author and many contributors and according to this Body of thinking and a large amount of data much of which I've published in fact We should be well adapted to the use of organic agricultural foods. That means diets from before 1850 Because at least Eurasian populations have had those for thousands of years and That's hundreds of generations and we've shown in the lab with flies that you can accomplish amazing things in about a hundred generations sometimes less than that sometimes 40 generations That's the basis for Marlene Zook's critique of many of your beliefs In her book paleo fantasy and she points to some examples of this from research and evolutionary biology Including a famous human example, which is the adaptation of Tibetan populations to high altitudes So to this point in time. We're really dealing with verbal contention and Starting in 2010 my lab and colleagues there principally Grant Rutledge whose date I'm going to be showing today have developed a mathematically based alternative to both sides on this debate and Starting with Grant Rutledge's doctoral research we have done experiments to test these core ideas and at the core is How fast can populations adapt to a recent but not entirely novel diet that is to say Like the neolithic transition of agriculture Now the foundation of our reasoning is this very profound result which is not Intuitive gestalt its hardcore math to arrive from basic first principles of evolutionary theory and This result has a name Hamilton's forces of natural selection. This is the force of natural selection acting on your ability to survive and What the math shows which is here sketched is that before the first age of reproduction little b The force of natural selection is phenomenally strong and much for intuition about what natural selection can do is derive from the results you get when natural selection is very strong but once reproduction starts in a population the Math shows that the force steadily falls Until sometime around the last age of reproduction in a population when it hits zero Some people think that aging should start here But actually the theory suggests it should start sometime after the start of reproduction In a population that doesn't mean when you first had fun in high school, or I hope not junior high It means what goes on in a population and how it subsequently evolves Now I have made my living off of this equation since 1976 and What I was the first to show very clearly in the 1970s is that if you change the timing of the force of natural selection if you change When reproduction starts you can make aging evolve in other words The master control of aging is not the damn telomeres It's not the free radicals It's the force of natural selection if natural selection pays attention to the problem It can do anything it wants with aging including producing immortal non-aging organisms, which it does frequently Here's the basic idea your normal lab culture regime for fruit flies and many other organisms Including mice is to start the next generation almost as soon as you have adults and Produce the next generation and discard the adults. This is what I use the called trailer park trash reproduction Until I sort of got a little more woke and a little more sympathetic to the plight of the American working classes But that's just an arbitrary thing you can do in a lab. You can actually change when Reproduction occurs and here we have under the heading delayed breeding regime C in green the Typical med school graduate school reproductive pattern which does include sex All the way through undergraduate years graduate school postdoc Tenure track in the case the academic version or for the medical school your undergraduate degree medical school Internship residency getting your feed-in underneath you in your first practice and then finally you reproduce in your your late 30s And it doesn't really matter that much whether you're male or female That's the only sane way to approach graduate education is putting off your reproduction So the the math that I just cartooned for you implies that given a reasonable amount of evolutionary time in These organisms aging should start soon and in these organisms aging should only start later Okay, because you're delaying the first time of reproduction and We've since done this experiment many times as have others Since the late 1970s and here is the aging pattern of the A-type flies versus the C-type flies This is the logarithmic Logarithm of the mortality rate. So the higher the data go The more likely an organism is to die. These are data from 20 cohorts of thousands of flies each It's about a hundred thousand fly experiment And what you see here, which is the normal aging pattern on this this completely sucks Okay What you see over here In the purplish color, which is the a trader park trash reproduction cycle is boom aging is taking off From about 14 days of age in the fruit fly life cycle in the med school lifestyle aging doesn't even start until After about 30 days of age in those particular flies. They don't get to reproduce until they're at least 26 days of age However all through this period they produce eggs The start of aging is not the start of life the start of aging is not even the start of reproduction and physiologically The start of aging is defined by the decline in the forces of natural selection because aging is nothing other than The decline in age-specific adaptation because natural selection is giving up on us Quantitatively and progressively now a whole other body of research is the fact that aging stops At late ages which is full of radical promise and someday I may come back to this meeting explain about aging stopping And what you might do about that, but I don't have time today What I'm really showing you here is the power of experimental evolution over a small number of generations to completely Retune the aging pattern which sort of makes it look like hey, we should all be well adapted to agriculture instead What I'm now going to summarize is some math We did to investigate what happens in a population when an environment or nutritional regime changes and That is it's a mathematical corollary of the cartoon. I showed you that at early ages populations adapt very fast to a change in Environmental selection regime. It's a completely general mathematical result But at later ages Adaptation responds slower because they're at those ages the force of natural selection is weaker That's why we have aging, but it's also why as you will see you're right sort of That means as natural selection will rapidly improve adaptation to a new environment or new lifestyle at younger ages But at later ages it won't so that was an intuition I had in 2010 we did the math on that from 2010 to about 2012 Not showing you any of that and then Grant started his PhD in 2012 and we thought Let's look at age dependent patterns of adaptation to three different diets Because unbeknownst to us we've done a Neolithic revolution in our lab. I'm gonna just explain that quickly I'm gonna be talking about my a fast reproducing populations at the first part of for most of this talk And now I have to go into the diet history of our flies. You have to pay careful attention to this part so we got our flies from the backyard of behind a barn in an apple orchard in Massachusetts and The northeastern Drosophila melana gastro populations of the United States Have been evolving there since the 1600s living off of chiefly rotten apples Drosophila melana gastro the fruit flies. I use don't feed off fresh fruit. They only feed off rotting fruit And there's some of their maggots coming out of an apple That is their ancestral diet their long ancestral diet, but we brought them into the lab in The 1970s and soon put them on in 1981 a banana-based diet banana and molasses and The flies I'm going to first going to show you have been on that diet for more than a thousand generations in human terms that's like 20 to 30 thousand years of Absolutely rigid adherence to a brand new diet And that's plenty of time to adapt these populations to this new diet starting Around ten years ago. We experimented with an entirely novel diet based on orange Replacing banana. So what we have here are three kinds of diets a long ancestral fly paleo diet a Long-standing but still evolutionarily relatively recent banana diet Think neolithic revolution for our flies and here we have a completely novel diet that we know for sure our flies have never been adapted to Which is orange? And I'm going to take you through data on flies on these three diets Okay, the data. I'm going to show you is all going to be about our best measure of instantaneous function Which is the capacity of a fruit fly to survive Over a one-day period which is this Yeah, that's just like useless This px parameter age-specific survival probability from hx to x plus one Mx in females is the number of eggs. They lay between hx and x plus one Denominated in days the product of those two things px mx, which does actually appear in the equations in my field is A compound measure of your ability to survive and do something useful to a Darwinian which is reproduce So this is like not only the fact that you are 62 years old at a cocktail party But you might meet somebody new and exciting and do something about it That's px times mx. So at every adult age x we have this compound measure of your ability to survive and Reproduce or in human terms perhaps survive and contribute to science or some other field of endeavor So here are the core predictions that come out of the math for three different diets the entirely novel diet is in orange and dotted the evolutionarily recent or Analog agriculture neolithic diet is in blue and the long abandoned diet Fly paleo diet is dashed and red and our prediction is that at early ages the Dietary regime where the flies will do best will be the blue diet the evolutionarily recent one which remember is banana Blue means banana in these data Our entirely novel diet is in orange. It's oranges and our fly paleo diet is in red It's the apple diet and what this is showing is strong early adaptation in the banana diet Of course, no adaptation at all to the the orange diet But at later ages they converge Because the adaptation to banana didn't reach the later ages at later ages the long abandoned Fly paleo apple diet is the best diet according to the theory What do we actually see? Okay That's the question So to make this a little more concrete in a type fast reproducing flies we have Total of six cohorts we study Well six for each diet six on banana six on orange 12,000 individuals were studied a million eggs were counted and here's the predicted result just on the evolutionarily recent diet banana Like organic agricultural diet versus orange think High-fructose corn syrup seed oils all the nasty stuff none of us should be eating twinkies The idea is that at early ages the organic agricultural diet will be clearly superior But at much later ages they should converge Because we're not fully adapted to the banana diet at every age and here are the results So what you see here is that all through these early adult ages the flies do better on the banana diet than they do on the orange diet But at later ages in fact the data converge And at later ages You can eat your twinkies just as well as you can eat your whole wheat cereal Okay, you're not adapted to either one at later ages All right Then the question is what will happen with the long abandoned fly paleo apple diet Versus our banana diet, which has been our standard diet for a thousand generations Here the amount of data is even greater. We have 36,000 individuals more than four million eggs counted This is our prediction that at early ages the banana will do as well or slightly better on the The fly will do better on the banana or as well on the banana as the apple But at later ages where we're saying adaptation hasn't penetrated yet The flies will do better on the apple diet and again We're measuring our instantaneous health measure px times mx and here's the result Result is basically at early ages. It doesn't really matter that much whether you eat the banana or The apple diet if you're a fly But at later ages it starts to matter more and more now. Let me just explain Why this is a very conservative test? It's a very conservative test because we're doing a completely half-assed emulation of the fly paleo diet Because you know, we are synthetically creating a rotten apple medium out of cultured yeast and organic crater Joe's apple sauce The actual flies would have had a more complex diet They would have been eating partly off rotten other fruit and vegetable stuff in their environment and they would have had a very different lifestyle The banana diet is the exact emulation of what they've had for a thousand generations So so this is their real version of the organic agricultural diet So what I'm saying here is this is a total lame-ass fly paleo emulation Yet you still get the clear superiority on this lame-ass emulation So, yeah, maybe you're just eating grass-fed beef and grass-fed lamb and Wild caught salmon and you're not eating the wide spectrum of animal-derived foods that we Consumed through a million years or more primarily in Africa But even a lame-ass emulation of a paleo diet Still shows a significant benefit later in life now one critique of this experiment Which we've already seen in manuscript reviews is well, this is because of some weird feature of the biochemistry of apples To which we say bull because we have a critical experiment that shows it's not just the apple It's actually the relationship between the force of natural selection Because if you change when the forces of natural selection crash that is to say when we expect aging to stop You also change the timing of When natural selection is strong and therefore the timing of when you'd need to make a switch from organic agricultural foods to paleo foods So all the data I showed you to this point was on the a type flies early reproducers We also have diet Transition data from our C type flies which are late reproducers which are frankly not analogous to what human populations do Because we love to reproduce early and often But it tests the principle that it's not just the f-ing apple It's actually the interaction between what the forces of natural selection are doing relative to a new environment So there are the C type flies we're switching to different system and this different system We're switching from the result at the top the a type flies where You predict only an early advantage or good performance from the fly version of the agricultural diet in the C type flies where natural selection is stretching out over many more Ages deeper into the adult lifespan the theory predicts that you'll have a prolonged period of superiority on the banana Which is what these flies evolved in and the transition to the fly paleo diet Will not be beneficial until much later You get that because I know this is complicated. I'm switching from the top Prediction to the bottom prediction Because I'm using not the a flies which are in the top, but the C flies which are in the bottom Okay, and this has all been done with like real math This is the cartoon version of it and here are the results If you are sustained on the banana medium and you reproduce much later but only on banana medium you sustain a Functional improvement on the banana medium if humans had not reproduced until The age of 40 45 or 50 all through the last 10,000 years While we're living on agricultural foods Everybody in this room would do fantastically well on an organic agricultural diet Only very very late. Do you see the switch over to a slight benefit on the apple? But it's still you know your choice clearly on the last your biggest benefits that are earlier ages on the banana So what does this all mean what this all means is? If you revert to your long abandoned ancestral diet at later ages, you'll get a health benefit So our prediction is that 10 year old children will not derive much of a paleo benefit Okay, but there aren't a lot of 10 year olds here so What we're what this research implies is? Organic agricultural diet into your 30s great You'll probably have a transition zone where it doesn't make a lot of difference when you're my age I'm in my 60s. You should be on a paleo type diet Even if it's only a half-assed emulation based on stuff you can buy a trader Joe's or Whole Foods And yes, that is indeed what I do. Thank you very much We have about 10 minutes of questions. I think the PXMX prediction curve was very non-monotonic Whereas your Resulting data work. Well, it was all over the place, but you drew the line in the middle Which was straight so it's counter-intuitive to me that it would be non-monotonic. Why is it? Like that The actual math is is more like the data though. Those are just lame figures that are cartoons that we drew to Try to communicate the actual math derived figures are More like the data the data look the way they do because those lines are actually fit by maximum likelihood procedures on Your final conclusion that you could switch diets in later age and get the benefit That's actually not shown in the experiments that you did where you kept The flies on the diet throughout their entire life. You do a switching at some point in their age So how do you know there couldn't be some? Early-on effect that's cumulative that you can't get rid of later Wouldn't you have to do the experiment where you actually switched them and we have that experiment and it supports the same result? We we've done a variety of different experiments involving diet switching for decades Basically in a fly the switching period is about three days and there's no real historical or longitudinal effect and My personal experience from making people switch starting with myself About ten years ago Is that it takes about three years to fully make the transition roughly you can translate a fly day to a human year? So but after about three years Leaving aside, of course Like morphological damage You can't repair that but in terms of physiological functioning the transition and flies is about three days and From what I've seen an anecdotal number of cases and Brett's supposed to do this for real Because this is like an introduction to his doctoral research Three years in order of magnitude answer there Does your model provide any clues for how to extend lifespan even beyond the apple diet? By other techniques. Yeah, so we have we have a paper on that as well we have a paper that combines diet with supplementation and With some very interesting results that either grant or I will present in the next year or two probably at this meeting Hi My question relates to the degree of change in the diet Well, the degree of change affects the time that it takes to adapt So you have apples and you have bananas Okay, the apples are rotten. So I don't know what you know in terms of Acronutrients all three of these regimes Synthetically emulate rot Okay, all three of these regimes are supplied with yeast cultures which is Pretty optimal for flying nutrition Okay, but the change in the Neolithic was more from Protein fat best right to a carbohydrate. Yeah, so I agree. Maybe the adaptation would have taken longer Yeah, but at early ages when the force of natural selection is strong probably not a problem I Don't think many experimental evolutionists would disagree with what I just said, but your point is well-taken Last year or the year before we had a presentation I'm a graduate student who did 40 years worth of Fruit fly generation Changing their diet alright and Then I think that was Grant Rutledge. I think that was my co-author on this talk. Is it? Yeah All right, here's here's what he added. Yeah, is that at the end? They gave them the choice of which diet they wanted to Use and they all went back to the original diet. You mean the apple. Yes. Yeah Yeah, so so even though 40 or 40 years with the generations had never seen right so so Your question brings up a very important point Which is that what we did with the flies is far more stringent than the agricultural revolution? Because humans throughout the whole agricultural period even if they're supposed to be farmers and eat the damn bread and everything else Always cheat if they can get their hands on animal Foods they go for a big big time, right? Likewise fresh fruit and other things that we've eaten for millions of years. So yeah humans like the flies really want It's so that's so many thousands and thousands tens of thousands of generations of adaptation to their paleo Analog diet, that's what they want. That's what they like. We also had another presentation of a Professor, I think he's UCLA Who studied that at age 40 in order to live longer you have to convert to paleo. That was his cutoff Yeah, I will say that the formal prediction would depend on your ancestry The more recent your I mean the extreme case is of course Australasian Aboriginal populations Which have no adaptation to agriculture and for them There is no age where that's a good choice They're always better off and the work of Stefan Lindbergh is I think shown that pretty dramatically But the standard view of evolutionary biologists before 1980 would have been that that's true of all of us because there hasn't been enough time Since 1980 evolutionary biologists have switched on That particular point and our view is that at early ages If you do something for a few thousand years, you'll be pretty well adapted to it At early ages Thank you Yeah, maybe yeah, you could speak a word Can you can you say a word about the the basic theory of aging that you hold as a vis-a-vis the mainstream gerontology community That aging is not like akin to a rusting process and then how this and What you call the Hamiltonian lifestyle? Interventions can give rise to that forced out process about which you you hope that we can crush aging the same way we've crushed Infectious disease. Well, that's a lot for me to address or can you just talk about the theory of aging so the first first point is first point first So we've actually analyzed the genomics and transcriptomics of the A and C type populations and they differ at hundreds of sites Across the genome affecting hundreds of downstream physiological pathways. There are not Seven effing deadly whatever's behind aging There are hundreds of features of the metabolism that have to be retuned to live substantially or radically longer So the whole reductionist paradigm of you know, you take this supplement and the supplement and the supplement or we inject you with Turned on telomerase Real data don't show that data where you can actually put all those hypotheses to the test aging is underlain by Almost as much complexity as adaptation itself and of course all the functional genes in your genome underlay underlie adaptation a subset of which Degrade in their value to you as a function of age not because of somatic mutation But because of evolutionary detuning because the force of natural selection is so weak It's like Rhett Butler at the end of Gone with the Wind where he doesn't give a damn about Scarlett O'Hara anymore and you're Scarlett O'Hara Okay, now the second point is I Have been publishing articles on how to postpone or indeed eliminate human aging since 1984 And I have a website on this called 55theseas.org or calm You can find it by going Michael Rose aging and you see something with the numerals 55. You've got to that website More recently we also published an article called four steps to the control of aging I Think by the end of this century we will have aging as under control as we have infectious disease We should say by the end of this century. I believe that people will be routinely living for hundreds of years and Of course, I'm all about the details of how you get there I'm not Glamorous prophet like Arbita Gray and just an evolutionary geneticist who does math and large-scale experiments But but go to the articles or websites if you Google Michael Rose aging You'll see lots of stuff on that