Aging, mTOR, Sirtuins, Rapamycin, Metformin, the Truth of Resveratrol & Longevity Supplements, David Sinclair & Anti-Aging Myths | Matt Kaeberlein | #151

About the guest: Matt Kaeberlein, PhD is a Professor of at the University of Washington and CEO of OptiSpan. His research focuses on the biology of aging and longevity.

Episode summary: Nick and Dr. Kaeberlein discuss: the biology of aging; mTOR, FGF1, growth & metabolism; sirtuins, NAD & NMN; longevity drugs like metformin & rapamycin; facts & myths about longevity molecules like resveratrol & taurine; controversies in aging research related to prominent Harvard researcher David Sinclair; epigenetic clocks; healthspan & lifespan; and more.*This content is never meant to serve as medical advice.

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Matt Kaeberlein 4:41

This is OptiSpan offices. And then right next door is or a biomedical so they're a company we spun out of my lab and as the U DUB. They do high throughput, longevity drug discovery using robots and worms. We can go take a look. Okay.

Nick Jikomes 4:57

Yeah, that'd be great. That'd be great. Um, Just want to start off by telling everyone a little bit about who you are, what your scientific background is.

Matt Kaeberlein 5:03

Sure. So, my name is Matt Kaeberlein, I am the CEO of OptiSpan, I guess I would describe optive span as a healthcare technology company. So our mission is really to create tools, technologies, protocols, to enable science based proactive preventative health care for as many people as possible. So we are very much of the belief that the current healthcare system is not as effective as it should be, to put it mildly. And that, really, it's it's centered around what I would call reactive disease care. Typically, we wait until people are sick before we try to do anything about it, then we try to treat their disease, we really want to help enable more proactive preventative health care, by both detecting disease early but more importantly, by empowering people to keep themselves healthy. And so I spent, you know, most of my career until about a year ago in academia, studying the biology of aging, I think that the biology of aging is certainly the most important risk factor for most functional declines, and diseases that people experience. So I think one aspect of this, you know, transition to what I call 21st century medicine with Peter Thiel would call medicine 3.0. I think targeting the biology of aging is an important part of that. But it's only part of it, there's also, you know, a huge component that involves screening for problems before they happen. And taking steps to ensure that we've sort of optimized our physiology as much as possible to maintain health. So I think you need all of those pieces. And that's really what we're all about here. So like I said, my background, really is I'm trained as a research scientist, and my entire career in research was spent trying to understand the mechanisms of biological aging. And why is it that all animals appear to undergo physiological decline as we get older? And what are the mechanisms and what aspects of those mechanisms are shared across the animal kingdom? With the expectation that the mechanisms of aging that are similar across the animal kingdom will be relevant to people? Yeah,

Nick Jikomes 7:28

one of the things that's super interesting is if you take a comparative approach to aging, and you look across many different species, you think about this in evolutionary terms, all animals age, there's important differences between certain species. But something that's very interesting that I've talked with others about is there is this very lawful relationship between how long an animal lives how big that animal is, and its metabolic rate? Yeah, right. So small. This is why we talked about dog years. Yeah, we are dog's age faster than us. Small animals tend to age more quickly, they have shorter lifespans. How do you how do you think about that relationship? Why does that relationship exist? And what does that start to point us to?

Matt Kaeberlein 8:11

Yeah, so great question. It's actually more complicated than that. Because when you look across species, what you said is true. smaller species tend to age more rapidly have have a higher metabolic rate than larger species. When you look within species, it's actually flipped. Smaller individuals tend to age more slowly. And we understand I think the mechanisms of within species variation based on body size pretty well. So we can get into that if you want to, I think we don't really understand the mechanisms for a cross species relationship between body size and longevity. So certainly, that sort of metabolic rate rate of living hypothesis is one hypothesis that's been around for a long time. Essentially, the idea there is that the faster you're burning metabolism, the more rapidly you accumulate damage associated with metabolism more rapidly growing age, that's almost certainly part of the story. I don't think it's the entire story. We know of species that kind of seem to break that correlation a little bit. Yeah. So there's more than that going on. I think. And I think this is really one of the mysteries in the field right now. Because, again, if you look at the within species variation, mi dogs are almost an outlier, where within the same species, you have about a two fold variation in lifespan based on body size. In most species, it's, it's much less than that. But if you look across species, we're talking many orders of magnitude variation from very small animals to very large animals. So that variation and rate of Aging and Longevity across species is, you know, much larger, and we really don't understand the mechanisms and the hope would be if we could understand the mechanisms that might offer opportunities for therapeutic approaches that are much larger effect size than what we have available today. I think one thing And it's worth saying though, is from an evolutionary perspective, even though this isn't satisfying from, for a molecular mechanism perspective, from an evolutionary perspective, it kind of makes sense because larger animals tend to reach sexual maturation later. So you have to evolve. Mechanisms of slower aging in order to be successful from that sort of evolutionary perspective. If you're not going to reach sexual maturation for months, or years, in the case of humans, for example, the other thing that's worth appreciating is larger animals have more cells. So they have to evolve more robust anti cancer mechanisms, because they have so many more opportunities, for example, right, just from a stochastic perspective of cancer causing mutation arrival arising, you have a lot more opportunity for that to happen if you have, you know, 100,000 a million times more cells.

Nick Jikomes 10:53

So so if a whale had the cancer detecting, and cleanup capabilities of a mouse, it wouldn't even make it to sexual maturity. Got it? Yeah. So before we get to the within species pattern, because that's interesting, that it's different from the across species pattern. So across species, smaller animals tend to live less long lives in large animals. There are outliers, as you mentioned. So tortoises famously have long lives. I believe naked mole rats live way longer than you would expect, when we look at those outlier species. Do when we see do we know what the mechanisms at play there? are at play there that make them outliers? And do they converge on anything? Are they all unique? That's

Matt Kaeberlein 11:34

a good question. I would say we don't, we can talk specifically about naked mole rat. Because there are there are a couple of interesting ideas there. Other than the naked mole rat, this hasn't really been studied in detail. And most of the studies that have been done, have been done through and this isn't meant to be critical, the use of the word biased, but through a biased lens, meaning people look at the hallmarks of aging, which gives us a handle for understanding aging. And they ask, if we look in, you know, very long lived clams or other species, can we find evidence that these hallmarks of aging are decelerated or delayed. And so from that context, people have found evidence for things like, you know, improved proteostasis. So, proteins are either able to maintain their conformation better, or in response to some sort of stress that would normally cause proteins and misfold, they're better able to maintain or they can degrade damaged proteins faster. So those things are true. But it's also true that people went looking for that. So you have to be a little bit careful not to draw causal arrows. So I think we'd certainly don't have a very good comprehensive understanding for why these species are able to, apparently age at a much slower rate certainly live much longer than smaller species or in these outlier species, why they don't why they break that correlation. naked mole rats are interesting, and there are a couple of people. So Shelly buffin, Stein, was kind of the first person to really make naked mole rats, a very powerful model in the study of aging. So she actually she's awesome. She used to, like go and collect these animals from Africa and bring them back into the laboratory. And so she's done a lot of work identifying, you know, like I said, some of these mechanisms around proteostasis are anti cancer mechanisms. And then Vera Garber, Nova Rochester is the other person who has identified a couple of interesting potential mechanisms. So one mechanism there, that Vera found has to do with the type of hyaluronic acid that naked mole rats make they make a very long chain, hyaluronic acid, which Vera has proposed, is involved in in mediating some of the potent resistance of naked mole rat cells to cancer. So I don't I don't know that they really understand the mechanism there. But they have been able to provide evidence that at least in culture, this very long chain hyaluronic acid kind of prevents the naked mole rat cells from from becoming cancerous and being able to develop some of the phenotypes of cancer cells. So

Nick Jikomes 14:11

what uh, what exactly is that molecule? Is it the same thing that you see in skincare products? Exactly the

Matt Kaeberlein 14:16

same thing? Yeah. So it's a natural metabolite. And this gets very rapidly to the edge of my understanding of how your chronic acid but it's my understanding that even humans make hyaluronic acid of various lengths, and, but naked mole rats for reasons that I don't think anybody knows make a very, very long chain, how you're on ik acid, which can impair I think I get a little bit outside of my area of expertise. So I think it has to do with the ability of the cancer cells to metastasize. And I don't really understand why but it's, it's got something to do with with the process of going from, you know, it doesn't affect I don't think the oncogenic mutation, but it's the process of going to metastatic cancer that attenuates, whatever the reason that many naked mole rats are very clearly highly resistant to cancer. So, it for a long time, people thought naked mole rats didn't get cancer at all. And then Shali showed that in a few of their very, very old animals in their colony, they were able to detect tumors, but it's at a much, much lower rate. And Vera's model is that it has at least something to do with this hyaluronic acid isoform that they make. And Drew has actually done an interesting experiment where she took the naked mole rat gene for this long chain, how you're on a gas and and put it into laboratory mice. And the effects are kind of modest, but it looks like there's a hint at least of a beneficial effect just for moving that one gene over into my so pretty interesting.

Nick Jikomes 15:44

Interesting. I mean, do you think it might have something to do with them being subterranean? And I'd imagine that environment is different in many ways, including their composition. Yeah.

Matt Kaeberlein 15:53

i It's a good question. I don't know about the how your onic acid. Presumably, there's some reason why they evolve this very long form. But certainly other aspects of their physiology, like resistance to hypoxia, that, yeah, mole rats are super resistant to hypoxia. So there's all sorts of physiological mechanisms that are that are going to be adapted for that subterranean environment, there's also the social aspect. So you know, naked mole rats have this, this social hierarchy where they have a queen, right? And then a bunch of, I'm not going to get this exactly right. Shelley's explained it to me, and this is again, not my area of expertise, but they have one reproductive female in the colony at a time. And, and that's, again, a very different social structure compared to most mammals, right? In some ways, it kind of more resembles bees, again, for my superficial understanding, which also have some interesting aging properties, right. So. So is there a social evolutionary component to the social structure, species that has influenced their aging phenotype?

Nick Jikomes 16:58

Maybe Maybe they're less stressed, because they don't have to worry about

Matt Kaeberlein 17:01

that? Part of it? Yeah.

Nick Jikomes 17:04

Yeah, I mean, that's actually, who knows, but that there could be something to that. Yeah. I want to ask you a vague question and give people a sense for the different sort of mental models that are out there around aging. So the question is simply what is aging? Or to say, in a slightly different way? What are the different ways that people out there generally think about it, and maybe an anchor point here is, you know, one end of the spectrum could be it's a completely passive process. We're just accumulating damage over time, like our cars. And another side to this could be that it's a very tightly regulated sort of pre programmed thing. Yeah. How do people think about it?

Matt Kaeberlein 17:41

Yeah. So I think I think that's a good framework, because I think there are right there are different lenses. First of all, I think that word aging is somewhat problematic, because people come into it with their own preconceived definitions, right. So just as an example, because I've been doing this for 20 plus years now, when I think of aging, I immediately gravitate towards biological mechanisms, because that's what I've been studying, right? Most people don't think that when you think about aging, so I think it's useful to kind of put those those frameworks around it. So fundamentally, I think what you asked is the question that often comes up, which is, is aging programmed and by programmed that word really means? Is the biological aging process selected through evolution to happen? In other words, is it something where it is a program in our genes that is going to occur? Because it was selected for that reason? And I don't think there's much evidence in humans or most other animals for programmed aging in that context that it was selected for, there are a few cases like salmon that you can point to where there clearly is this defined programmed aging process or program senescence, I guess, I should say. So I don't I don't think there's much evidence for that. I tend to believe that aging is more a byproduct of an absence of selection, where once you have done your job of reproducing and passing your genes on to the next generation, there's really not a lot of reason for natural selection to prevent aging. And and I think, intuitively, that makes sense. And I think that lines up pretty well with most of the data that's out there on the genes that affect longevity, they don't appear to have evolved because they regulate longevity, they appear to have evolved because they regulate growth and reproduction. And I think things like mTOR and these nutrient sensing pathways are a really good example for understanding that so so mTOR is one of the better characterized longevity proteins, or genes. And what mTOR does is fundamentally it senses the environment and helps the cell or organism make the decision whether it should grow and reproduce, or at the moment limits not favorable for growth and reproduction, shut down growth and become stress resistant. Right? It turns out that one of the key features in the environment that are really important in that decision making process is food, right? You have not much food around really bad idea to have babies because you don't have anything to feed them. So Emperor primarily senses nutrients, when there's lots of food around mTOR gets turned up, that accelerates growth and reproduction also accelerates aging, when there's not very much food around mTOR gets shut down, that slows growth and reproduction and promotes a stress resistance state. The delayed aging we see with turning mTOR down is probably a byproduct of that enhanced stress resistance. And people have speculated that that's because, again, from an evolutionary perspective, it makes sense to survive long enough until the environment changes and becomes favorable. And there's food around. Yeah, so I don't I don't think I think that's a really good example, where it's pretty likely that mTOR evolved to regulate growth and reproduction. And it's kind of an accident that it regulates aging, but it's really the growth and reproduction aspect. That's

Nick Jikomes 21:08

yeah, but you know, you've got these little molecular machines like mTOR, and other things, it looks like you've got a sort of a programmed aging program. But as you said, it's really just a byproduct of the fact that they're regulating growth and reproduction and what's being selected as when an animal actually reproduces. Right, exactly.

Matt Kaeberlein 21:26

And I think this is where a lot of the arguments over programmed aging, kind of get off track, because people can be meaning the same thing, but to one person programmed means and this is what I believe it means from the evolutionary literature, that natural selection has acted for that reason. Yeah, it could still be a program. It's just that's not, that's not why that program was put in place. The program is really to control development and reproduction, not aging.

Nick Jikomes 21:50

Yeah. Yep. That makes sense. When we think about, you know, like things like mTOR, and the connection with things like diet, so So again, in evolutionary context, really, ultimately, what selection is always going to be selecting for in some sense, is reproductive viability, getting you to a place where you can reproduce. Obviously, if you're a longer live species, or it takes you longer to mature, you have to have add on mechanisms that prevent you from dying before you get to that point. So that's where you would talk about things like anti cancer mechanisms in a larger body to address exactly. If you get to the point where you reproduce. At that point, selection can relax. And so what you're saying is that that's why we see this connection where you have some like mTOR, controlling growth, reproduction. And a byproduct of that is necessarily that's going to affect longevity in some way. But it's really, it's really there in order to cause the animal to grow when conditions are appropriate. Right for survival and reproduction. Yeah, exactly.

Matt Kaeberlein 22:50

And I mean, to tie this stuff to actually one thing to say on that is, you know, Michael rose did some some very sort of important classic experiments. A few decades ago now, in fruit flies, where he was actually able to show that in these organisms where you can undergo many, many generations, you can actually select for increased lifespan by selecting for animals that reproduce later. In other words, you can population a larger population of animals, and you only allow those individuals that reproduce later to pass their genes on to the next generation. You can over many, many generations actually select for a longer lifespan, kind of for what the reasons you were saying is that you, if you're only allowing those individuals to pass their genes on, you have to have kind of evolved mutations are mechanisms to allow for that later reproduction to make it that far. So I think that's a proof in principle of at least part of this idea that it is possible to evolve those kinds of longevity mechanisms, obviously. I mean, he wasn't able to do those experiments to the point where you could get fruit flies living as long as mice. But who knows if and if you could carry those out long enough, maybe you could actually start to see something similar to the magnitude of longevity effects we've seen, we can see if we look across nature. The other piece here that's interesting, though, is this will take a certain full circle back to the body size. Discussion, this within species body size, relationship to longevity seems to be primarily controlled by these growth, signaling pathways like mTOR, insulin IGF one growth hormone, those are the factors that are determining the within species longevity and anti correlation with body size.

Nick Jikomes 24:34

Can we dig into that a little bit more so within species, larger bodied individuals, they have more growth, that's why they're bigger. So things like mTOR and these other pathways are presumably kicked up and those individuals that is leading them to live shorter lives on average, yeah,

Matt Kaeberlein 24:50

at least. So that is very clear, when the signaling is determined during development, right. So in other words, it I kind of said that backwards. The body size is determined by the amount of signaling through primarily growth hormone, IGF one and mTOR. During development. If growth is if those signals are high during development, you get large individuals, if it's low, you get small individuals. And you get large individuals are going to be aging faster and shorter lived. And so there were sort of classic experiments done by Cynthia Kenyon in the 1990s, in Worms, where she showed that if you made mutations in the insulin IGF one pathway in C. elegans, you could double lifespan. So this is the sort of classic DAF two mutations. And then there was also work from Andy barky, and others in mice, showing that if you had mouse mutants where they were deficient in growth hormone, or IGF one signaling, through development, they would live 60 70% longer. And then you've got dogs where we have this body size relationship where big dogs age faster than small dogs, the largest determinant of single genetic determine of body size in dogs, is this IGF one growth hormone pathway. So it all lines up that in the laboratory animals, you can target in a targeted way make these mutations cause bigger animals to become smaller, and they live longer. And then in dogs, we've got this sort of natural population, pseudo natural, I guess, humans sort of evolved them. But it wasn't with the goal of evolving longevity, you've got these natural populations, where you have this big variation in lifespan based on body size. And it turns out, the determinant of that is IGF one and growth hormone. So it all makes sense.

Nick Jikomes 26:40

So these larger bodied individuals, they don't live as long. And they've got higher levels of these growth pathways, building them during development. That's why they're bigger. What do they actually die of that gives them a shorter lifespan to the cancer more?

Matt Kaeberlein 26:52

Yes, I think that's a good question. I don't know if we really know the answer to that. It may also be somewhat species dependent. So you know, mice get a lot more cancers than even dogs do dogs get more cancers than people do? I think cancer is kind of the low hanging fruit there. But I don't, I'm hesitant to say it's all of the story. I'm in fact, I'm, I'm pretty confident it probably isn't the one, I think, interesting tweak on this idea. So if you look at dogs, this is where I think the best data exists. If you look in dogs, big dogs seem to age more rapidly than small dogs do in pretty much every tissue in Oregon that this has been looked at in terms of pathology and kidney and you know, you look across the organs, they get more cancers, they get more arthritis. The one place where that seems to be different is the brain. So big dogs do not seem to have a higher incidence of dementia, just matched to chronological age, if anything, they might be a little bit protected, which is also kind of interesting, because there's, there's data and it's not super clean. But there is data in mice that high levels of signaling through IGF one and insulin signaling in the brain may actually be protective against dementia. So it may be a case where this these growth pathways are actually doing something different in the brain in terms of brain aging, or at least dementia versus aging in the rest of the body. The other thing that's that's worth mentioning here is there was a study done by Valter Longo, which is very cool, where they went and studied this population of people who have a growth hormone mutation. The they're called lone dwarfs. And they looked at people who were kind of genetically matched in the same village, I don't remember what country this was in somewhere in Central or South America. And they looked at longevity and cause of death in these people. So you have humans who have low levels of growth hormone their small. It turns out, there's no difference in longevity, compared to the big people in the same population, but cause of death is completely different. So the loan people were, if not completely, almost completely protected against cancer and heart disease, and I think diabetes as well. But they had much higher rates of death due to alcoholism and accidents. That's what it said in the paper. So I don't know exactly what that means. But I suspect part of that is, in humans, it's a little bit more complicated than saying dogs are certainly a laboratory mice. There's the social component. Yeah, height. And this is if you look in the literature on this, it's kind of interesting, because, you know, many, many decades ago, there was this sort of myth that taller people were healthier and lived longer. And I think that was in part because of the social benefit, right? That accrues to being taller. But now that we've been able to look in larger populations and different populations around the world, that actually doesn't seem to hold up. And in fact, there's a little bit of a cost in longevity to being taller, but the actual cost is probably bigger than that. But it's sort of offset by this social benefit that accrues to being

Nick Jikomes 29:57

yes, there's a biological cost because if you're bigger You've got more of these growth pathways that were turned up during development. And that's giving you the cost, right? But you get the social benefit of being taller in almost every culture I can think of, generally, if you're taller, all things being equal, you're gonna be, you're gonna have more social status, right? So one way that I guess, to think about the population we're just talking about is maybe alcoholism and accidental deaths were higher and the smaller individuals because they had lower social status, on average, they were more stressed. They weren't coping with that something's

Matt Kaeberlein 30:27

my guess. Yeah, I don't I mean, again, it's a gas. Yeah, pretty plausible.

Nick Jikomes 30:31

Interesting. So you mentioned that I think you were being careful with your words, you were saying mTOR IGF one, these growth pathways when they're turned up during development? Yeah, that's when you create a bigger body. And that comes with a longevity cost? What if they're turned up? After you become an adult? That's obviously something people do on purpose sometimes? Yeah,

Matt Kaeberlein 30:52

I don't think we know the answer to that. So again, my speculation is that the most of the effect is determined during development. But a small amount of the effect is determined post developmentally and, and the data to support that. I mean, certainly with rapamycin, we know you can start giving rapamycin to old mice and you still get a pretty significant longevity. But then rapamycin blocks mTOR That's right, it turns down mTOR Yeah. And there's one study from I know, NIR Barzilai was part of this study, there were other people. Sorry, guys, there were other people in that study as well just remember where they gave, I think it was an anti IGF one antibody to age mice and saw a pretty small but statistically significant effect on lifespan. So I think you can get some benefits by turning down these pathways in middle age, but it's not of the same magnitude that you get from doing that during development and creating a small body sized individual. I'm trying to think if I know of any studies where people have intentionally turned up these pathways in laboratory animals, in adults in adults, yeah, post developmentally. I'm not thinking of any. I know, it's probably you're referring to humans. We do this all the time. Right. Yeah. So there's, it's interesting, because you know, for many years, like I remember when I was a graduate student, the the anti aging, Doc's giving growth hormone were all the rage, right? And those of us in in doing these, this work in the laboratory were like, but that's the opposite of what we do in mice. So I, my take on that in humans is, I don't think I haven't seen anything that makes me convinced that growth hormone therapy in older people has a major longevity cost to it, there might be a minor cost. Also, I haven't seen anything that makes me believe there's a longevity benefit to it. So my intuition is is probably not moving the needle much either way.

Nick Jikomes 32:50

So we don't know. But if it affects us there, it's not big enough that we've noticed yet. Yeah,

Matt Kaeberlein 32:54

exactly. Exactly. Right. I think testosterone is kind of interesting, because that's also, you know, going to promote growth, at least in in certain tissues. Right. And I don't again, I haven't seen convincing data one way or the other. I think, certainly, from a quality of life perspective, I've seen, you know, certainly lots of anecdotal stories of people who saw a pretty significant decrease in testosterone in their 50s 60s. When I'm talking men, primarily women, hormone replacement therapy, to me, and like, maybe I'm gonna get myself in trouble. But to me, the data is pretty clear that that net beneficial for more people than it's harmful in what

Nick Jikomes 33:34

does that look like in women? What is the hormone replacement that they actually use? Yeah,

Matt Kaeberlein 33:39

I mean, estrogen is the primary component of hormone replacement therapy. I think there are a whole variety and typically, for postmenopausal Exactly, that's exactly the context. Yeah. And I don't know how much of this you followed, but there was a pretty famous study that kind of came to the conclusion that hormone replacement therapy in women increased risk of cancer. And so that's why for many years, doctors, many doctors stopped prescribing hormone replacement therapy for for men, postmenopausal Peri menopausal women. That I think the, you know, the pendulum has swung back the other direction. And again, you know, I think that there's very, very strong evidence that for many women, hormone replacement therapy has a lot of quality of life benefits and also, you know, helps maintain bone density helps maintain lean mass, both of which are important going into, you know, postmenopausal aging in in women. So I think the, the, in the cancer risk, seems to have been, I don't want to say it's an artifact of the study, but it has to do with the type of hormone replacement therapy, the women they were studying were taking and the way that the data was analyzed. So I think it was largely exaggerated is the consensus I I

Nick Jikomes 35:00

see, yeah, I mentioned there's a lot of things have to be balanced here. So if you, for example, if you had, say, a slight increase in certain cancers with hormone replacement therapy, but at the same time, you're less frail and less apt to fall over, and you're less likely to die by other means. You have to think about all these,

Matt Kaeberlein 35:18

I think that's exactly spot on. And I think, you know, just sort of removing ourselves from that specific case, I think that sort of overall risk reward analysis often isn't done in our current sort of, you know, medical structure, it's like, there's very much this risk aversion that if there's any risk,

Nick Jikomes 35:38

if the one marker is above the one level for the one negative, and we just don't do anything,

Matt Kaeberlein 35:42

instead of saying, even if there's a little bit of an uptick in risk for, for, you know, certain types of cancer, the additional benefits from body composition, you know, may outweigh that. And so that off that analysis often isn't, isn't done, for sure. So anyway, so that was a little bit of a tangent. But all of this is to say that, again, I haven't seen anything to make me convinced that hormone replacement therapy, these these growth, promoting hormone replacements, you know, for hormones that decline with age and many people, that that has a significant risk of accelerating aging. And I think for many people, it's pretty clear that it has pretty substantial benefits for quality of life. This may also be a place where mice and to some extent, dogs, because of just the way so I think the biology of aging fundamentally, is very highly conserved. But the phenotypic manifestation of that is going to be different in different species. And I think in humans, unlike in mice, for sure. And in dogs are probably somewhere in the middle, the phenotypic manifestations in in elderly people who make it into their 70s 80s. And 90s, you know, is loss of lean mass, yep, risk of fractures, frailty, that has to do right with with maintaining muscle function and maintaining bone, structural integrity and joints. So these growth promoting pathways while they might accelerate, you know, other phenotypic manifestations of aging, are protective for those things that in humans are proportionally probably more important than they are in mice. Yeah. So these studies in mice may not reflect exactly what is going to impact quality of life and people exactly

Nick Jikomes 37:21

like lab lab, mice don't have to worry about falling down the stairs for right. And

Matt Kaeberlein 37:25

they do get fractures, like there have been people who've done, you know, micro CT analysis of skeletal structure in aged mice at time of death. You can see spinal fractures and things like that. But we don't quantify that in the laboratory, because the mice are still moving around in their cage, right. So you have to go look for it. And it doesn't probably limit lifespan the way it does in in a lot of people. I think I think this is another place where you know, there's this. I don't know, if it's a controversy there. There are people who are very vocal on both sides of the dietary protein discussion, right? Yeah. And I think that may be another example where yes, in mice protein restriction, at least sometimes can extend lifespan very robustly. But again, mice are not really experiencing loss of bone density or loss of muscle mass to the point where it limits their lifespan, I'd be very hesitant to tell, you know, a 50 year old 60 year old person that they want to go on a very low protein diet. Right, right, because of the risk you might run from, from inducing sarcopenia or inducing, you know, loss of bone density.

Nick Jikomes 38:33

Yeah, I mean, that's another area where it's important to remember that we get a lot of benefit from doing highly controlled experiments in artificial conditions with laboratory animals. But also, we're not looking at naturalistic conditions. If you have mice on a low protein diet, they live longer. They're also not running away from predators and things like this might require them to use their muscles. Yeah, yeah,

Matt Kaeberlein 38:55

I think that's exactly right. So I think just just being aware of the strengths and limitations of the different models that we use is super important. And of course, the laboratory is a very well controlled, it's not completely sterile, but certainly compared to the real world, it's a relatively sterile environment, they're not being exposed to all the pathogens that, you know, humans are walking around in on a daily basis. And so all of those things kind of changed the dynamic. And so what works really well in a controlled laboratory environment, you know, may not have the same effect in the real world. And this is something I, I think about and try to point out a lot, which is that you might be able to take an intervention, right that that increases. Let's say we had a drug that increases lifespan by 100%. The laboratory doubles lifespan of a mouse. It might double lifespan and a person, but if it also makes the person you know, highly susceptible to something that's going to kill them. You only need one event to kill you to offset offset. Yeah. 100% increase in lifespan, right. And in the real world, there's lots of things that could potentially kill you. So you just have to kind of be aware that what we do in the laboratory isn't necessary, even if the biology is conserved isn't necessarily going to work the same way in the real world. Yeah.

Nick Jikomes 40:10

So you've done a lot of work on the molecular biology of aging. I want to talk about some of that, I want to talk a little bit more first about diet. So you mentioned protein. In general, consuming more protein means more mTOR signaling, right. So what are important things we have to keep in mind here with respect to protein composition? So can you start talking about how certain amino acids specifically affect mTOR compared to other amino acids, and what we should start thinking about when instead of just thinking about protein, generally

Matt Kaeberlein 40:40

I can. And I will, I'm hesitant to really, really emphasize that too much, because I'm not sure it really matters in the context of the human diet. So like Leucine is typically talked about as the primary amino acid that mTOR senses through proteins called Sustrans. And that's pretty well worked out. So we we pretty much understand how mTOR is going to going to be most strongly activated by leucine as a specific amino acid, other branched chain amino acids as well. So But having said that, mTOR is also activated less potently by other types of caloric intake. And so again, one way to think about it is mTOR axon a network of proteins that includes a MP kinase, which is a sensor of energy status within the cell, it includes insulin, and IGF one signaling, which are going to be affected by carbohydrates and fats. So well, from a biochemical perspective. mTOR is most potently activated by protein, and leucine in particular, from the network perspective, the entire network is influenced by other types of nutrients and other things in the environment, oxygen level, things like that. So, so I think it's a little bit it's, it's useful to understand from a biochemical perspective, it's maybe distracting from the more important message if people are really worried about trying to restrict, you know, branched chain amino acids in their diet,

Nick Jikomes 42:16

or maybe restrict your branched chain amino acids. But if you're over eating other nutrients, and you're doing other things that stimulate mTOR, it's not really gonna matter.

Matt Kaeberlein 42:23

Yeah. And the other thing I would say is mTOR is not on off right and you want like, even with rapamycin, when when when we give rapamycin to mice, first of all, we're not giving them enough that we are really Nick, you know, hammering mTOR down, and it has different effects on mTOR signaling in different tissues, I think optimally, right? You might and this is speculation, but you might speculate that if we could do this optimally, we might want to turn mTOR down, you know, transiently in the immune system. And you know, more potently in I don't know, I'm just gonna throw out kidney and liver, but not turn it down at all in muscle, right? Yeah, we don't have tools to do that. So we're sort of, you know, stuck using crude things like rapamycin. But even there, the tissue distribution is going to be different. The kinetics of mTOR, inhibition and activation are going to be different. So the way I sort of think about this is protein in your diet is probably all things being equal are going to have a larger impact on mTOR signaling, but but overall caloric consumption from a health perspective is probably going to have a larger impact on health. In other words, I believe and I think there's some data to support this, that a high protein diet in the context of a healthy diet at optimal caloric intake is very different than a high protein diet in the context of a shitty diet, you're eating way too much, right? Yes. And I think most of the data that we have that suggests that high protein is associated with higher all cause mortality and higher cancer is in the context of populations, where most of the people were eating too much and eating a low quality diet. So what I haven't seen yet is a really rock solid, good study of people eating a really high quality diet. And comparing high protein to low protein. I've seen a couple of studies that tried to do this. I don't think any of them are to the point where I would want to say definitively that the the detrimental, the sorry, let me say this, again, the increased risk of cancer, for example, coming from high protein is completely gone, in people eating a very high quality diet, but that's what the studies I've seen suggest. So, but I do believe that these are going to be very different. And the other thing I would say is I think that all things being equal. It also seems pretty clear that a high protein diet makes it easier for people to maintain or build lean mass than a low protein diet. I'm not saying you can't build lean mass on a low protein diet some people have but All things being equal across the general population, I think a higher protein diet, most people are going to be more successful with maintaining or building lean mass. Obviously, you need to actually do some exercise to contribute to that. But I think the data is pretty clear on that. Like, I don't think anybody would really argue with that statement.

Nick Jikomes 45:18

You mentioned, you know, I want to ask you more about the tissue specificity of some of these pathways and aging in general. So you mentioned, for example, in dogs, right, the older dogs, the bigger body dogs are aging faster. But you mentioned this interesting exception to that, which is their brains don't seem to fit that pattern. In general, you know, I would imagine that on average, our tissues are all aging at roughly the same rate, how true is that? Are there any tissues that are organ systems in the body that age slower than others,

Matt Kaeberlein 45:46

I think this is just starting to be figured out. So people are just starting to develop tools that at a molecular level, can start to quantify rates of aging in different organs and in tissues. And really, it's just within the last six months that we've started to see some of these papers come out. So from a functional perspective, you know, for a long time, we've been able to measure different aspects of organ and tissue functions and cognitive assessments for brain vision test for eyes, you know, you can do that for heart, you can do it for kidney. And I think the observation there is that it's a very individual thing, right? That, that in some people, they can maintain cognitive function very well, but their hearts go early, right. And we've haven't really had an understanding of that. So I think now these tools are starting to come online, where you can at least measure some aspects of molecular molecular markers of aging, from blood, but get signals from different tissues and organs. So these would include things like, you know, epigenetic signatures, that you can detect in blood, but that can be that are coming from cells from different different organs and tissues. So so so I think we'll learn a lot more in the next few years, there was a really interesting study just came out from Tony Weiss Corys Lab at Stanford, where they used a blood based test. I think it was proteomics, so they're looking at proteins in this case, where they're able to match signatures of organ and tissue aging, and I don't remember the numbers off the top my head, but the take home message is that, that in most people, you can detect, or many people, you can detect signatures of early organ aging, but again, it's very specific. And some people it's the brain and some people, it's hard. And some people it's the kidney, the cool thing there if these tests pan out, is for an individual, you could go get a blood test, you know, and maybe you find that your most of your organs look great, but your kidney shows signs of accelerated aging, is it really aging? That's a different question. But it's probably a sign of higher risk of kidney pathology compared to liver brain part. And so you can then do some diagnostics to to assess that more functionally, and then maybe do some personalized interventions to slow that down or maybe even reverse it that I think is the real power of these tools. When we can look at Oregon species specific aging, we can start to personalize therapies to to to be preventative and proactive and, and catch these things before it reaches end stage disease.

Nick Jikomes 48:29

On the subject of diet, so I know that one of the most more robust results out there in terms of increasing longevity is caloric restriction. What do we really know there? And what are maybe some of the things that people are being misled on what exactly is the caloric restriction that leads to longevity benefit doesn't matter what the exact macronutrient profile is?

Matt Kaeberlein 48:52

I think that's still TBD. So first of all, have to say everything that we know about caloric restriction in longevity, almost everything comes from laboratory studies in mice and rats. I mean, that's been done in other simpler animals. But let's just focus on mice and rats. The little bit we know in people suggests that caloric restriction certainly will lead to weight loss. And that will often improve some of the biomarkers that we have long associated with health like blood pressure, and you know, things like that lipid profiles. And there are some early indications that these molecular markers of biological age like the epigenetic markers, are sometimes reduced by caloric restriction in people is caloric restriction of potent longevity intervention and people no idea. And again, we can talk more about that there are lots of reasons to think it may not be at least across the population. So in laboratory rodents, what we know with certainty is that it is possible to achieve up to about 60% increase in average lifespan so big effect From about 60% caloric restriction below what's called ad libitum. In other words, letting the mice eat as much as they want to or the rats. unclear whether the macronutrient ratio matters. There have been, and this has been this has been work that's been done since really the 1930s. So there's a large body of literature that is a little bit contradictory, I would say, again, it is at least the case that you can achieve these effects on lifespan more or less independent of which macronutrients you restrict. So people have done specific macro carbs, carbs, protein, fat, all three, two of the three, and in every case that I'm aware of people have been able to extend lifespan. So I don't think we really know. It is the case that if you restrict sort of across the board, you get the most consistent benefits. Okay, so what are the things people have been misled about? One caloric restriction always works? Seems like about a third of genetic backgrounds, caloric restriction does not extend lifespan at a given level of restriction. And in many cases, it actually shortens lifespan. Oh, interesting. So there's a strong genotype dependent component here, that should shock nobody. Everything is gene by environment, right. But unfortunately, this sort of sometimes gets represented as if caloric restriction always works. And, you know, there's there are many cases where it doesn't and like I said, somewhere between a third and maybe even as high as a