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

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.


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 half, probably closer to a third of genetic backgrounds, a given caloric restriction paradigm will not extend lifespan, and in some fraction of those that will shorten lifespan, okay, so that's important to appreciate, especially if we're going to start recommending this to a genetically complicated population, like humans, you know, dogs. Another is this thing around timing. So, you know, there's all this inter interest in intermittent fasting time restricted feeding. So I typically think of intermittent fasting as 24 hours or more. And time restricted feeding is shrinking your window of eating within a 24 hour period. My take of the literature is that it is unconvincing, that there is any longevity benefit from time restricted feeding or intermittent fasting, unless you also calorically restrict. And another way to say that is, all of the benefits that people have claimed in terms of longevity and health span, really, from time restricted feeding and intermittent fasting might be due to the fact that those animals were also calorically restricted.

Nick Jikomes 52:30

So another way of saying that would be that the benefits people are seeing from daily intermittent fasting or time restricted feeding, don't obviously extend beyond the fat extended beyond the caloric restriction component of that these are useful tools people have for restricting calories. Yeah. So that's really what's going

Matt Kaeberlein 52:49

on. So I want to be careful not to immediately extrapolate to people, because I'm talking about the mouse studies, because remember, all of this idea that these are longevity interventions really comes from the animal studies, because we don't know in humans, right? Nobody's done the clinical lifespan study, right? Nobody's going to. So I'm being careful in what I'm saying. Because I want people to understand everything you've heard about these diets as longevity diets comes from the studies in mice and rats. Yeah. And there, it is clear to me at least, that there are, at best, minimal, and by minimal, I mean single digit lifespan effects compared to 60%. Probably not even that, at best, minimal longevity benefits, when you do these experiments in an isocaloric manner where they are not calorically restricted. So the interpretation of that is all of the benefits come from the caloric restriction in laboratory animals. I see. So now what about in people? And yeah, I think I would align with what you said, which is that absolutely, these are really useful tools for many people to reduce their caloric intake or manage their caloric intake is great, do it. But I, there's no evidence that I'm aware of that these aren't longevity interventions. Unless you are calorically restricted. And then I think we get into the this sort of bigger question of, you know, is caloric restriction, a viable longevity strategy and people? And does it actually slow aging and people, I think there's reason to believe that it probably does impact the biology of aging in humans, similar to the impact that it has in rodents. But I also think in people there are all sorts of potential complications that go along with chronic caloric restriction, like the fact that we live in a complex environment. All of the social implications of caloric restriction like this was probably before your time, but when I was a graduate student, there was a very active group called the caloric restriction society of people who are self practicing caloric restriction and you know, they they had an active presence in the field, they would come to meetings they they had a very active discussion group online. And there were a lot of psychological complications that went along with practicing that diet in many of these individuals. And so I think that it's, it's just really hard in people. And, you know, there was a sort of high profile scientist named Roy Walford, I don't know, again, probably before your time, but he's an interesting dude, actually. So he did a lot of the early mouse caloric restrictions, not early, we're talking 80s 90s caloric restriction studies with Rick weinrich. And he wrote a book called the 120 year diet, and he actually was very active in kind of starting this caloric restriction society, you know, and then he died in his I think, late 70s. So, you know, there there are not the, and again, it hasn't been long enough to know for sure, there aren't very many people who can maintain that lifestyle. Right. And the the, the sort of high profile cases didn't end well. Yeah. So I worry that that is, certainly I mean, it's not even a worry, I am rock solid, confident, that is not going to be a strategy that you can use across the population. And I'm not sure that even if you could, that on average, it would be net beneficial for most people.

Nick Jikomes 56:14

I mean, aging is a concern for everyone. It's a it's a problem that's been with us. For all of human history. Nobody, for the most part wants to die, everyone wants to live as long as possible, or at least be as healthy as they can for as long as possible. The science has been progressing, lots of exciting things are happening and have been happening for a number of years, you see a lot of chatter online, from experts and from non experts around Aging and Longevity. And people throw around terms like slowing down aging, or they might say, stopping aging, or they might say reversing aging at a high level, how do you start to parse some of that stuff? Can we actually reverse aging? That's already happened? Can we only slow it down? But we can't stop it?

Matt Kaeberlein 56:58

I mean, I would say there's nothing theoretical that says we can't reverse aging. I think, again, this gets back to this issue of how do you define aging? Right. And this is where I think unfortunately, a lot of people are being very sloppy in their terminology. So most of the people who talk about reversing aging, are talking about reversing one or a few aspects of aging. Right. And so I think we've known for decades, you can improve health, right? That shouldn't shock anybody? Is that reversing aging? I wouldn't say it is some people do. Right? If you have gray hair that used to be black, and you color your gray hair black, did you reverse aging? I mean, you reverse the phenotype of aging. That's really I mean, I'm not saying that that's equivalent to reversing epigenetic age. But at some level it is you've taken a phenotype of aging, which in this case, is epigenetic changes, and you've reversed them. Did you reverse aging? Only if you believe that that's all of aging, right? So that's where I think the sloppy terminology comes in. What I would say is, you know, that when we see interventions that improve health, and improve function across multiple organs and tissues, then you can start to make a case that you have at least partially reversed biological aging. We have no data. And nobody has shown any evidence that they could take an old animal and make it young again, that's what I want to see.

Nick Jikomes 58:28

What would that look like exactly, in principle,

Matt Kaeberlein 58:33

it would look like an old animal that is looks young again. So basically looks young again, I would say, and also has restored the functionality of a young animal. So if you look at sort of obvious things like activity, movement, strength, look at tissue and organ level, you see a heart that's functioning like a young heart, a kidney that's functioning like a young kidney, immune system, functioning like a young immune system, and then you look at the molecular level, and you see all of these things reversed, right? That's a heavy lift. Like I'm not at all trying to say that that's going to be easy. But if you want to, but if you want to claim that you've reversed aging, then this is sort of my personal view, to me, claiming that you have made an animal aged backwards is a pretty big claim to make. And so I would say it's really on the people making those claims. To demonstrate, it's like, it's not my job to prove that you haven't caught somebody days in reverse. It's your job to prove that you have, right. So I think you really need to show that you can you can actually reverse at least the vast majority of changes that we see go along with age, all

Nick Jikomes 59:38

the way down to the molecular level. Absolutely. Absolutely.

Matt Kaeberlein 59:41

And, and I think that's, like I said, theoretically possible. And there's reason to believe that, you know, some of these new technologies like epigenetic reprogramming might get there. But nobody has done it yet. And so I think it's actually counterproductive to go around claiming that we reverse aging, because honestly, I mean, look, I don't know, I can always, like everybody's frame is a little bit different. We all view the world through our own sort of lens based on our past experiences. But I gotta think, to the majority of people out there, when you've got scientists claiming that they've reversed aging, that the, the average person is going to look at that, and it's just gonna be like, that's, that's crazy, right? I mean, maybe not, maybe people actually believe it. But to me, that seems like that seems like science fiction, you know, I think you would want to, I would want to see somebody at least shown a laboratory animal that you can make an old animal Young.

Nick Jikomes 1:00:41

What's an example in the in the literature from the last few years were a scientist has claimed to at least partially reverse aging, but you don't think they've demonstrated that?

Matt Kaeberlein 1:00:50

I mean, there are lots so you can go find like if you if you go look, if you just do a PubMed search for, you know, reverse aging, the plenty, plenty of titles. And let me say also, like, I think we're all guilty. At least many of us in the longevity field are guilty of sloppy use of terminology like I, I've never used, I don't think reverse aging that way. But I used to misuse the word healthspan all the time. So I'm willing to say that this is something that we all could do better at, right. So I'm not, I'm not necessarily wanting to signal in single individuals out, I think this is a pretty widespread problem. There are certainly some high profile people who have kind of abused the terminology. But this is a widespread problem. And it's becoming wider spread, because I think once a few people see individuals doing it, and getting high profile publication, it kind of feeds on itself. In the long run, maybe it's not gonna matter. I mean, maybe what's going to happen is, that phrase reversing aging is going to really come to mean in most people's minds, slowing aging or targeting the biology of aging, they don't really believe that it's reversing aging, they just use it that way. What I what I would say, though, is again, one of the problems I think, with using that phrase reversing aging and trying to make it out like you've done something that's never been done before, is just misleading, because like I said, we've known for decades, if you take a you know, 65 year old person who's overweight and sedentary and you put them on a healthy diet, and you get them to exercise, Functionally, they're going to be better. Yeah, right.

Nick Jikomes 1:02:25

And you're gonna be able to measure a bunch of physiological markers that look younger. That's right.

Matt Kaeberlein 1:02:28

Yeah, so this is not anything beyond what we've been able to do for decades. Yeah. And even like, you look at rapamycin and I certainly wouldn't claim that rapamycin reverses aging, because it doesn't it doesn't reverse aging and all tissues and organs but you can take an old mouse, you start giving it rapamycin, its brain gets better, its heart gets better, its immune system gets better, its ovaries get better. So it's oral cavity, you can reverse periodontal disease. So this is not anything beyond what we've been able to do for decades. And so it's kind of being presented as if it's this you know, shiny new object it because it's being because the words are being used to mean something different than what they actually mean.

Nick Jikomes 1:03:08

Yeah, the language the language is the use of language is itself changing. Yeah, that confuses us. Say more about rapamycin. Let's just give people who don't already understand a brief overview what is rapamycin? And how did it become? How did it become that it was used in the aging world as opposed to its original use? Right?

Matt Kaeberlein 1:03:24

So yeah, so rapamycin super interesting drug it was originally found from an expedition to Easter Island where they were looking for soil samples. And this is my understanding of that. The reason why they were looking for soil samples was because it had been observed that the people of Easter Island which also Rapanui, that's where the drug gets its name rats and mice and the people of Easter Island, even though they went barefoot, didn't get tetanus, at least not at the rates that you would expect. So the expedition went, they're trying to look for microbes in the soil that might have production of molecules that would protect against tetanus. What they found instead was a bacterium in the soil that produced rapamycin. And so it was originally sort of developed. Well, it was it was observed that you could take rapamycin and put it on cells, and it had what's called anti proliferative activity. So it basically slow the cell cycle of dividing cells. And so that got people excited for cancer anti cancer purposes. So some people started developing it for potential anti cancer purposes, became a research tool that was used. That's actually how the protein mTOR was discovered by treating cells with rapamycin and then looking for mutants that were no longer sensitive to rapamycin, but it got developed clinically as use as an immunosuppressant. And so that was how it was first FDA approved was to prevent organ transplant rejection. And so we have a lot of this was, you know, I don't know 2530 years ago now that it was first approved. So we have a lot of data on rapamycin use in people All in the context of organ transplant patients. And so that all happened, you know, that was all happening in the clinical world. And then as I mentioned, it was being used as a research tool to kind of figure out the the biochemistry of mTOR, and how the mTOR complex worked and and then this was around 2003 2000 for four different labs sort of all simultaneously got interested in mTOR as a regulator of longevity in yeast, that was work that I was doing, C. elegans and fruit flies, and none of I don't know about the others. Like, I don't think anybody would was really talking to each other about this. It's like this happens. Sometimes it's science where you just all sort of converge on the same thing independently. And it all happened around the same time. And so in each of those three very evolutionarily divergent species, the four groups kind of independently found that you could genetically turn down mTOR and increase lifespan slow aging. And so for me, when we first found that the mTOR mutant was long lived, I had never heard of rapamycin. And so of course, I went to the literature and, and and found that, you know, mTOR is actually mTOR stands for mechanistic target of rapamycin. So the protein is actually named after the drug, we were genetically knocking it down, and there was this drug that could do the same thing pharmacologically. So it made sense to test whether the drug could also extend lifespan. So we actually did that experiment, first in yeast, published that in 2006. And then, I think that body of work, our work and the others, in worms and flies led to Dave Sharpe proposing rapamycin to the interventions testing program as a molecule they would test so the interventions testing program is in the National Institute on Aging funded program to test drugs in mice for effects on lifespan still happening today. Anybody can propose compound, you have to write up a proposal. And then if it gets selected, it will be tested at three sites independently to see whether it affects lifespan in mice. So Dave Sharpe proposed this as must have been like 2005, right around right around 2005. That they started the experiment. And it extended lifespan in mice. I think when it extended lifespan in mice, then everybody started paying attention before that, you know, those of us who worked in invertebrates were excited about it. But I think, you know, the larger community hadn't really yet caught on. But once we found that it worked in mammals the same way, then it really became, you know, highly interesting and highly studied, the clinical people started noticing, even then I don't know what the clinical people did. It's kind of funny in this field, right? It's a little bit less today. But you know, when I was a graduate student, you had a lot of people who thought that you couldn't learn anything about ALS. But it's funny because I worked in yeast as a graduate student. So the worm and fly people were like, You can't learn anything about aging, studying aging in yeast. And then the mice people, like you can't learn anything about aging, studying aging in worms and flies, then the humans, you know, the people who did clinical stuff be like, you can't learn anything about aging unless you study aging in humans, right? So I think that mindset still persists. But it was more so even back in 2009. I'm not sure they started paying attention. Yeah. But now we know it's funny, because when I first started in this field, there was a lot of debate about whether or not the biology of aging was conserved, right. Yeah. Now we know that's true. Yep. We don't know how much of its conserved but a lot of it is. So certainly the broader field started paying attention when the mouse study was published. The other thing about that mouse study, though, that was really important. And I think also sort of a paradigm shift was for for sort of reasons that are funny, we can go into the story. But for reasons that are funny, they didn't start testing rapamycin until the mice were 20 months old, which is about the mouse equivalent of a 60 year old person. Nobody thought that was going to work. But it worked. That was the first time a drug had been convincingly shown to have longevity benefits starting in middle age. Now, we know that you can do that with other things as well. But at that point, I think for me, certainly, and I think for many people in the field that really changed the way we thought about the plasticity of aging.

Nick Jikomes 1:09:16

So at the time, you would have predicted that giving it earlier in life would have had this effect, but not that late, or

Matt Kaeberlein 1:09:21

it would have a tiny effect late in life. But it was how big was the effect? So in the first study, it was about fit 14% I think, which you know, at the time was was pretty good for longevity interventions. And now that they've gone on and done dose responses, it's been pushed up to about 25 30%. So

Nick Jikomes 1:09:38

rapamycin has this longevity effect. Can you say a little bit more about the physiological effects it has and any negative consequences that it might induce? Yeah,

Matt Kaeberlein 1:09:47

so again, I mean, one way to think about rapamycin from a biochemical perspective, it's extremely clean. Only target we know of is mTOR and in fact, it's a specific complex, so mTOR the protein axon to complex says mTOR complex one and for complex to, rapamycin is very specific for him for complex one at least directly. Okay, but mTOR complex one. So we talked about how this is sort of a key node in this network, right? Regulates everything it seems like in the cell. So what are the downstream mechanisms by which rapamycin is affecting longevity, there are probably a lot of things you could point to the big ones that I would point to are very potent anti inflammatory, it seems to be relatively specific for the types of chronic what people call sterile inflammation that accumulate with age. In other words, the immune system reacting to signals that shouldn't be reacting to. So it's a very potent anti inflammatory it boosts process called autophagy, which is something we'll call it this the cellular recycling center, right? So it's a mechanism by which cells can break down damage or no longer useful macromolecules and reuse their, their building blocks. It has very potent effects on metabolic function. I hesitate to get too far into the details because I'm not sure we really understand exactly how rapamycin is affecting metabolism, it certainly can shift fuel utilization. So you know, glucose versus fats, and it can bypass at least certain types of mitochondrial dysfunction. So we published you know, this was probably back in 2000 got 2012 paper where we showed you could rescue a severe mitochondrial disease in mice with rapamycin. So again, the mechanisms are completely clear, but you can definitely bypass certain types of metabolic dysfunction with rapamycin, at least in a disease state. So it has complicated effects on metabolism, can actually protect mice against diet induced obesity, if you give them enough for rapamycin. It regulates protein synthesis in again, very broad and complicated ways. And there's data from the invertebrates that these effects of mTOR and rapamycin on protein synthesis are at least partially causal for the longevity benefits. So there are at least four pretty big buckets you can point to where those things might be important for rapamycin has effects on longevity. My thinking on this has shifted quite a bit over the last decade, I think in in mice and probably to some extent in humans. Given that we don't still know how efficacy efficacious rapamycin is going to be and humans offer longevity is is, at least much of that's mediated through the anti inflammatory effects, I believe, but not all of it. So like, for example, you can improve heart function in mice. And there's some evidence in dogs and people with rapamycin. That's, I don't know that that's an anti inflammatory mechanism. I think that's probably more effective rapamycin directly in the heart. So it's complicated. So you talked about you want me to go on to talk about side effects? Yeah, let's

Nick Jikomes 1:12:56

talk about side effects. Because that was gonna be my next question is this sounds like, all good. Yeah. What what? Why would someone maybe hesitate? Should should everyone in middle age be thinking why not take recommends? I

Matt Kaeberlein 1:13:06

don't know the answer to that that question. But I can tell you why there's hesitation around it. Right. So again, first of all, I think there should be hesitation, right? Again, this gets back to this risk reward like, do we know enough about the likelihood of reward and the likelihood of risk and what those look like to make a calculated decision? So I think the reasons why people would be concerned largely stemmed from the way rapamycin was developed. So remember, I talked about how it was developed clinically as an organ transplant drug. And that was sort of independent of what we were doing over here in the Research Room. So in that context, rapamycin has been used extensively in organ transplant patients. It's used at high doses, along with strong immunosuppressants. And so in that context, there is a long list of side effects associated with rapamycin. The most common side effect is mouth sores. So in organ transplant patients, these can actually be pretty severe ulcerations of the mouth, which actually cause a lot of people to stop taking the drug and they don't heal.

Nick Jikomes 1:14:09

Is that really a mouth thing? Or is it like an epithelial cells?

Matt Kaeberlein 1:14:13

The little salty? Yeah. So

Nick Jikomes 1:14:14

anywhere else that they have effects? Um,

Matt Kaeberlein 1:14:16

you know, I don't I don't know how much that has really been looked at. I don't know the answer. I don't I don't think it's very prevalent, but potentially in intestine as well, you might expect to see, you know, at least a loss of an intestinal barrier function. It's a good question. I should go look, I don't remember seeing that in the organ transplant literature, but But it's possible that it's there. But that is that is the most common side effect in organ transplant patients. Obviously from like life threatening perspective, that's not a huge concern, but its quality of life can have a big impact. Interestingly, people taking rapamycin off label who aren't organ transplant patients. That's the only side effect that I've seen that's statistically significant, and those are more likely canker sores, so it's not the severe ulcerations. The other things you would worry about though, and this is the one most people would be worried about is immune suppression. I mean, that's what it's called. It's an immune suppressant. Right? So you would be concerned if you were taking an immune a strong immune suppressant, even if it had a benefit from the biology of aging. Again, it really only takes one severe infection to kill you. Right? Yeah. So you'd be concerned about that we'll come back to the immune suppressive if they're real effects of rapamycin, but that would be the big concern. The other things people I think would be moderately concerned about would be hyperlipidemia. That's not uncommon in some organ transplant patients and glucose dysregulation so there's, there's the sort of pseudo diabetic like phenotype that can develop an organ transplant patients taking rapamycin, none of those things things are really seen in the long lived mice taking rapamycin, except that they don't develop the pseudo diabetic phenotype in the sense that the mice don't have higher fasting glucose levels or higher a one C. Interestingly, if you give mice who've been taking rapamycin for many months, oral glucose tolerance test, they do show a an impaired response on an OGTT. So there's some thought that this that's why I call it a pseudo diabetic phenotype, because there's some they don't have true diabetes. But there's some thought that because of rapamycin has effects on metabolic state, that you've kind of shifted the metabolic state of the mice to a, a place where when you then give them a non physiological bolus of glucose, they don't aren't able to respond the same way that they would if they if they were in a sort of more normal mTOR. State. Again, that's sort of hand wavy, mostly because we don't understand the the biochemistry there. Okay, so those would be the side effects. You'd be worried about. What do we know about side effects in people who are taking rapamycin off label, meaning their physicians have prescribed it for something other than organ transplant, or one of the approved indications? Most some of those people are taking it off label for autoimmune disease. Many of them are taking it off label because they think it's going to help them from a longevity or healthspan perspective. So we published a paper last year where we collected data from 333 people using rapamycin off label. And we compare that to about 150 people who've never used rapamycin. And obviously, there's lots of limitations to that kind of data, lots of caveats, but the things that came out of it that I think were pretty believable and looked pretty solid to me was one of the comparisons we did was we asked people in the last three months have you experienced and then we had a list of like 44 Different things that had been previously associated with rapamycin side effects. And so we compared people who have been using rapamycin for at least that three month period to people who never use rapamycin, the only thing that was statistically significantly higher in the rapamycin users was mouth sores, that actually was very reassuring, because that's exactly what we would expect from the organ transplant literature. So then John on who's one of the co authors on this, he's a DDS, dentist, PhD, has now gone on and looked more closely at that data. And that's where I get the result that these are these are more like canker sores, not these ulcers that persist. So So that seems to be pretty mild but probably real. There were six other things that were statistically different but they were all lower in the rapamycin group. So is that are those benefits are Meissen maybe? I don't know. But I think I'm pretty convinced based on that. And based on a lot of the anecdotal, you know, data that I'm aware of, that the side effects of rapamycin outside of about 15% of people getting canker sores are pretty minimal. Now, again, we don't have a lot of data on people taking rapamycin off label for many, many years. Certainly you could uncover side effects over that timeframe. The one thing that I think, and again, it wasn't statistically significant in our dataset, but there was a slight trend. I do believe that it's likely that rapamycin, even off label use of rapamycin and like, you know, four to 10 Mix per week, probably has a slight increase in risk of bacterial infection. I also think there's an even stronger benefit in terms of viral infection, that risk of viral infection, or at least severity of viral infection goes down with people taking rapamycin. But again, that's pretty speculative. So So I but I do think there is a slight increased risk of bacterial infection.

Nick Jikomes 1:19:34

So in animal models, you can use molecular genetics to turn down mTOR you see longevity boosts you can use something like rapamycin to pharmacologically turn down mTOR you see the similar similar type of effect? What do we know about turning down mTOR in the brain and what that does?

Matt Kaeberlein 1:19:55

Yeah, so again, I think you degree of inhibition is going to be really important here. So there were actually a lot of concerns much like in the muscle community, you will hear people concerned that rapamycin would actually induce sarcopenia, which is muscle loss with age turns out is protective, at least in animal models. But that's because mTOR is required for muscle growth. Same thing is true in brain mTOR is required for learning and memory and memory formation. And people did experiments, you know, 1520 years ago showing that if you hit neurons and mice with enough rapamycin, you can actually impair learning and memory. And

Nick Jikomes 1:20:34

that's what you'd expect, right? Because in the brain, even though cells are largely not dividing, and there's no growth in that sense, when they strengthen their connections and make new synapses, that's got to turn on mTOR and protein synthesis and all that's exactly

Matt Kaeberlein 1:20:46

right. So it's thought to be mostly a protein synthesis mechanism. So if you hit cells with enough rapamycin, you inhibit mTOR enough, you're going to impair synthesis of new proteins, and that's required for lots of stuff, including memory formation, right? So, so there was concern that rapamycin would accelerate dementia or impair learning and memory. There have now been many studies done in aged mice and mouse models of dementia, Alzheimer's disease, Parkinson's disease, and in most cases, you get a protective benefit from rapamycin treatment or genetic inhibition of mTOR. in those contexts, and again, many mechanisms have been proposed, probably the best work in this area was has been done by Veronica Galvin, who was at University of Texas, San Antonio is now at University of Oklahoma, where they've done a lot with these hypomorphic genetic constructs where you can, you know, control, genetically control mTOR expression specifically in the brain, and show that you get changes in cerebral vasculature cerebral blood flow. So, so that's their primary model is that you actually improve cerebral blood flow. There's also pretty good evidence that maybe through autophagy, or through other mechanisms, you can reduce, you know, plaques and tangles in the models that develop plaques, plaques and tangles. So I think that the bulk of data suggests that at least in the context of aging, and at least at the doses of rapamycin that extend lifespan, there is a protective benefit both for brain changes associated with normative aging, and in mouse models of these neurodegenerative diseases. I'm trying to think I'm not aware of any real solid data in people looking at cognitive function in this sort of off label rapamycin users or even an organ transplant patients, I don't think there's any evidence one way or the other in organ transplant patients that I'm aware of. The one thing I will say is that many of the people using rapamycin off label are using it, because they are a bowI for homozygotes, with the hope that it will, you know, reduce their risk of developing dementia because because that's, you know, probably the strongest common genetic risk factor for dementia is being homozygous for A bully for

Nick Jikomes 1:23:05

how common is off label use of rapamycin now? And is it reasonable for people in or approaching middle age to think about

Matt Kaeberlein 1:23:12

that? Yeah. So I don't know what the answer is to how common it is, other than it's way more common now than it was two years ago, or four years ago. There are a growing number of physicians who have become comfortable prescribing rapamycin off label, but I you know, in terms of numbers, I, you know, I've speculated that it's more than 10,000 people in the United States but or maybe it's 100,000. I don't know. There are a lot of people I'm surprised by how many people tell me that they are using rapamycin.

Nick Jikomes 1:23:40

So these are people that just go into the doctor and they say, I want to get on rapamycin because they think it might have all of these benefits

Matt Kaeberlein 1:23:46

usually, yeah, so I mentioned there, there are a fair number of people who have sort of it oftentimes sort of independent of even knowing about the longevity literature happened on rapamycin through autoimmune or chronic immune condition. So there are a series of case reports in the literature with a variety of different types of autoimmune disease, where people have shown pretty dramatic improvements in a subset of patients from rapamycin use. So there's a population of people who have gotten into off label use of rapamycin that way. But yeah, I think the majority are probably coming from the healthspan longevity perspective. And there are even now a couple of, of places I'm not involved with either that are I think, starting to do telehealth rapamycin so makes it easier for people to get it I think for a long time, people who wanted to try rapamycin had a hard time convincing their physicians that that you know, it was safe enough because again, most physicians if they don't know about rapamycin, they're only going to know about it through the organ transplant literature. Yeah, like why would I give you an immune suppressant? Right. So there is I think people are becoming more comfortable but still, by and large, most physicians are not going to be comfortable prescribing it often. They will.

Nick Jikomes 1:25:01

You were involved in some early findings from earlier in your career about these things called sirtuins. What are the sirtuins? And what do they do at a very basic level biologically Yeah.

Matt Kaeberlein 1:25:14

So, sirtuins are a family of what are called NAD dependent protein deacetylases. And so, the primary role of sirtuins there are others that do some other chemical reactions, but just for the sake of simplicity, the primary role of sirtuins are is this deacetylase function where they take acetyl groups off of other proteins. Now, this was so, and I first got interested in in sirtuins before certain the word sirtuin existed because I was studying a protein in yeast called ser two. That's actually where sirtuins come from Sir two ends. So ser two is the founding member of the sirtuin family of proteins. This is an evolutionarily conserved family of proteins yeast have cut I should know this five sirtuins and humans have seven. So but they're in every organism. So the reason why I got interested in ser two is sort of has to do with what we were studying in yeast, we knew that the ribosomal DNA was important for aging in yeast, we knew that co2 was at the ribosomal DNA and also at telomeres, which are important in aging. It was and for other reasons was sort of an obvious thing to test. So I tested whether if we turned up sir to activity, we could extend lifespan it did. That was the first evidence that activating sirtuins could have an effect on longevity that was part of my PhD thesis result. At that point, though, we didn't know what the function was biochemically. Nobody knew sort of this mystery protein that was important for aging. But nobody knew what his biochemical function was. So another person in the lab, Shinichiro Omi, who was a postdoc at the time, was trying to figure out what the biochemical activity of sirtuins was. And he discovered that it had this deacetylase activity. And deacetylases can take acetyl groups off of lots of proteins. But at that time, at least, they were best known for taking acetyl groups off of histones. And that's important because histones sort of pack the DNA and can control which genes get turned on or turned off. And deacetylation is a really important mechanism for turning a gene on or turning a gene off, right, because it controls the proteins that pack the DNA. So Shin found that it was not only a deacetylase, but it was this NAD dependent deacetylase. And that that is the first time that biochemical activity that was sort of a new enzymatic activity showing that it coupled NAD to histone deacetylation. So it was a big deal at that point. And that also because NAD is involved in central metabolism, linked central metabolism to gene expression. So

Nick Jikomes 1:27:49

this was this was a link between how a cell is metabolizing. And which genes it's going to then turn on or off.

Matt Kaeberlein 1:27:56

Yeah. And longevity because we have this other longevity piece over here. Yeah, so it was really interesting and exciting and sort of catalyzed this whole area of research around sirtuins. Now, I think from the longevity side, kind of like I was talking about with tour earlier. You know, people thought it was kind of cool that this worked in yeast, but it was yeast like, what does that mean? Then a postdoc in the lab, Heidi Tenenbaum at the time showed that if you overexpress, the worm version of ser two, you also extend lifespan in C. elegans. And then Steve Hall fans lab showed that if you ever expressed the fly version of cert two, you extend lifespan and flies. So that again led to this evolutionarily conserved function for sirtuins as longevity factors, or at least that model became popularized. So then now, you know, lots and lots of people started studying sirtuins, they tried to find longevity benefits for all the seven sirtuins in humans and, and throughout this whole, you know, this was, it was 1999, when we published our first cert to yeast paper. So in the 25 years since then, God. Lots of people have tried really, really, really, really hard to find important roles for sirtuins in aging, the mouse, sorry, the worm and fly stuff has been a little bit controversial. It's not completely clear to me that sirtuins are potent regulators of longevity, even in worms and flies, certainly not clear in mammals. And so it's sort of led to this. It's an interesting phenomenon where all of this momentum got built up and all of this. You know, it was people's careers depended on this model being right, that, you know, a lot of effort went into proving the hypothesis that sirtuins were this really important longevity regulators. And it just really hasn't panned out. I'm not saying that they aren't involved there in that network. I just don't think that they're particularly good nodes for tweaking the network in a way that increases longevity. And so really the only evidence in mammals right now that At sirtuins might have a relatively robust effect on longevity comes from a specific sirtuin called 36. And even that really hasn't been replicated outside of a single lab. So I'm not saying it's wrong, I'm just saying, I've been in this field long enough. And I've seen a lot of shiny objects that I don't get too excited until I see, you know, multiple labs replicate the same finding, and you want to see it genetically, and you want to see it pharmacologically. And you want to understand the mechanism. So I'm still kind of on the fence about sirtuins as a viable target for, you know, longevity, or healthspan. And

Nick Jikomes 1:30:35

so are you basically saying that a lot of the hype around sirtuins come from some of those early findings that you and others were involved in? But a lot of that stuff just hasn't been replicated and panned out in the way we thought it would?

Matt Kaeberlein 1:30:47

Yeah, I mean, the yeast, the yeast stuff has been replicated so that I'm rock and I did that work, obviously, I'm biased. Other people have replicated, right. So I'm confident about that result, at least in the strain backgrounds, we were working. And again, there's, you know, this is something a lot of people don't understand, oftentimes, in these laboratory studies, you know, you work in a specific genetic background. Yeah, yeah. And oftentimes, the findings in that genetic background are not tested in a variety of other genetic backgrounds. And sometimes you get different results in different genetic backgrounds. In fact, I would say that's more common. That's more the rule than the exception.

Nick Jikomes 1:31:22

I mean, you mentioned earlier, you know, caloric restriction, exactly. Different genetic backgrounds and get the opposite effect. Yeah.

Matt Kaeberlein 1:31:26

So So, but I'm confident that the yeast stuff is rock solid. And I think the fly in worm stuff, I'm not saying it's wrong, but I think the effects are relatively small and probably context dependent. So there's aspects of the environment or the experimental setup, that influence like maybe the temperature, for example, that influence whether you see a lifespan benefit. And when you're talking about a small effect, that's also sensitive to environment that leads to challenges in replicability. And so that's why I have, you know, really tried hard in my career, to study things that are robust and that work every time because I think when you get in this gray area, really trying to study small effects, it just gets really hard and you're very prone to getting misled and going down a path that ultimately is not productive. Well,

Nick Jikomes 1:32:13

I want to have a general discussion about supplementation and things like that. One of the but I will also want to tie it into the sirtuin stuff and what's known and unknown about the biology under the hood. You know, there's a lot of hype around AI Bucha called Mmm, that's a popular supplement amid mononucleotide. How does that tie into this? What's hype and what's real

Matt Kaeberlein 1:32:31

so so the way it ties in is I mentioned sirtuins or NAD dependent deacetylases. So nicotinamide mononucleotide, nicotinamide riboside Are the two sort of shiny object NAD precursors, right that, that can, in theory, boost NAD levels, niacin can do the same thing that's just not very exciting, because we've known about it for decades. So these are all things that are in the same metabolic biosynthesis pathway for NAD. In other words, if you take enough of them, and you are deficient for an ad, you're boosted converted into NAD, at least theoretically.

Nick Jikomes 1:33:06

And then it goes down with age. In general, that is

Matt Kaeberlein 1:33:09

the model that has been put out there. So again, this is where I mean, unfortunately, this is just the reality of I don't think this is unique to the longevity field. I see it most in the longevity field where, you know, there are individuals who publish high profile papers, who have a very vested interest in a particular model. And then they publish high profile reviews, where they talk about these things as if they are established fact. But

Nick Jikomes 1:33:37

they're basically talking about their own work. Yes. Which is one piece of the greater literature

Matt Kaeberlein 1:33:41

and often, you know, even though it's published, I still think of it, like I said, is kind of preliminary until multiple people have seen the same thing.

Nick Jikomes 1:33:48

Yeah. I mean, just for those who are listening, you know, when oftentimes when you read a review paper, the reviews are sort of meant to be someone that has been in a field and they are summarizing the full body of literature about something. But sometimes that gets historically

Matt Kaeberlein 1:34:02

that's what, that's what reviews were supposed to be. And again, you know, maybe I'm being a little bit, maybe I'm getting a little jaded or something, but I feel like over time that mod use, those are less and less you see those kinds of reviews. Yeah, what you see now more prospective reviews is the person's perspective, which is fine. Yeah, if it's labeled as a perspective, but it's labeled as a comprehensive review of my own work, which is often what

Nick Jikomes 1:34:26

these things become. And like, you know, as a grad student, or even just someone injured in science, you often go to review thinking, Yeah, this is like the objective view of this whole body of work rather than someone's perspective. Yeah,

Matt Kaeberlein 1:34:37

exactly. So I think this idea that NAD levels generally declined with age is overstated. So I think what's clear is that at least in certain tissues, in mice, in AD sometimes declines. In people there's very little evidence to support this. And in fact, there was a participant looked up Oh, yeah, there was a pretty decent comprehensive review written I was probably late 2022. And I don't remember the exact phrasing. But the the phrasing basically was that this is overstated that it might be the case that NAD generally declines with age, but there's really very little evidence to support that. So I think we don't know. But yes, the conceptually, if NAD levels broadly declined with age, then boosting NAD levels might have benefits in that context. So that's one piece, but then there's also this sirtuin piece, and that's how the NAD precursors first started being studied. So this now we're gonna go back, you know, to when I was a graduate student or slightly after that. So after, after I had shown that if you overexpress cert two, you could extend lifespan, there was a lot of interest in understanding that. It's a sort of a different story. But sirtuins got linked to caloric restriction, again, that model has, I think, largely been disproven. But there for a while was this model that caloric restriction was increasing lifespan by activating sirtuins. And that was mediated through this NAD mechanism. So caloric restriction increases NAD activates sirtuins. So then people started studying these NAD precursors as a way to activate sirtuins believing at that time that activating sirtuins would increase lifespan and improve healthspan. It turns out, NAD is involved in a lot of other things in the cell that don't involve certain, like Central metabolism, a lot of a damage repair and a bunch of other stuff. So I think the idea that if the NAD precursors have any benefits that those benefits are mediated by sirtuins is pretty speculative. And then there's still this piece of do NAD precursors, generally speaking, have benefits? I don't know the answer to that. My speculation is there are going to be a subset of people who have certain types of metabolic dysfunction where NAD homeostasis is perturbed. And in those people, yeah, NAD precursors probably will have a benefit. And there's some evidence in mitochondrial disease models for that. Broadly speaking for aging, I'm not convinced.

Nick Jikomes 1:37:02

Could be true, but it also might have a negligible effect.

Matt Kaeberlein 1:37:05

Yeah. And there's other work that suggested that, you know, these NAD precursors, which are, you know, pretty expensive relative to, you know, niacin. All get broken down in the gut to the to the same precursors anyways, by the gut microbiome. So

Nick Jikomes 1:37:20

why would someone buy an animal supplement rather than niacin? Well,

Matt Kaeberlein 1:37:23

I mean, I think that there is there are the, the side effects of niacin, right, like flushing, right, that some people experienced that can be unpleasant. So that might be one reason. Also, because that's what the influencers are telling them to do.

Nick Jikomes 1:37:38

It so with respect to NAD, though, nice, and we'll do the same thing? Yes. Okay. I want to ask you about resveratrol. I think you can imagine why. Let's just start very simple. What is it? And how did it first come to be associated with the aging? Yep.

Matt Kaeberlein 1:37:53

So I mean, resveratrol, Resveratrol is a drug this, but it is, it is a small molecule that's been around for, you know, many, many decades, right. And people have studied it. It's a natural product, poly phenol, it's found in, you know, grapes and other plants. You know, the thought is that some of these poly phenols are produced as stress response and the plants or mechanisms to, you know, fend off other animals that might eat the plants. But in any case, these things are produced. There's a whole family of polyphenols, obviously, that people are excited about. Resveratrol, first became of interest in the longevity field, from a study that was published out of David Sinclair's lab in 2003, where what they were doing, I mean, it's pretty smart idea what they were doing was looking for small molecule activators of sirtuins. And they looked at the yeast, sir, to

Nick Jikomes 1:38:50

thinking thinking in the way that you described earlier, if we can find a way to an answer to it will have this longevity. But absolutely,

Matt Kaeberlein 1:38:56

if you believe that sir, sirtuin activation is a general longevity intervention, then we did that genetically in yeast, if you found a small molecule that did it, you should be able to get the longevity benefit. And so they created this what's called in vitro assays. So in the test tube, for screening large numbers of small molecules to find things that could activate ser two and 31, the human version of cert two in a test tube, and they found resveratrol and quercetin, and I don't know, five or six other things with the similar sort of poly phenol structure. And so then they published that they could activate cert to in the test tube with these molecules, and that they could activate ser two in yeast cells with these molecules using a couple of different readouts of ser to activity. So remember, I mentioned that serve to as an NAD dependent histone deacetylase When you activate ser two, what you do is you turn down gene Express Russia at the places in the genome, where certitude has this activity. So they have markers at these places in the genome that they could see were being turned off and turned down. So they published that resveratrol increased silencing turned down gene expression through a sir to dependent mechanism. And then it extended lifespan in yeast. So that was the original paper. And then again, it was in yeast, it got published in Nature, but I don't know how many people really paid a lot of attention to it. But then they went in a couple of years later published that you could put resveratrol in the chow of mice that a high fat diet, and prevent the diet induced obesity and increase the survival of those mice. And that led to, you know, the whole and because resveratrol is in grapes, it's high in red wine. People got very excited, you can just consume drink red wine and live longer, right. And again, it's a great story. I wish it was true. So that's how it got introduced into the field.

Nick Jikomes 1:40:55

Okay, so So just to summarize, so far, before we dissect this further, there was this idea that turning up, sir, to had a longevity benefit. The idea because people did that through experimental models using genetics, if you could find a small molecule that does that. And that does, in fact, provide longevity benefit in humans. That's sort of like the Holy Grail. Now people can consume the small molecule, and they will get this longevity benefit. That's what we're aiming for it. So the original yeast result with resveratrol, resveratrol, do you have confidence that it holds true?

Matt Kaeberlein 1:41:28

I have confidence that does not hold true. So I mean, to put this in context, the reason why I have confidence is because we tried and tried and tried and tried to reproduce it. But the reason why we tried to reproduce that had nothing to do with resveratrol. So this was work that I was doing as a postdoc along with Brian Kennedy at the time, where I alluded to the idea that there was this hypothesis at the time that caloric restriction was acting through sir to write that caloric restriction activated sir to and that's how it was extending lifespan. So Brian and I had actually come up with genetic evidence that caloric restriction and Ser two were acting in different pathways, we could show that you did not need sir to to get lifespan extension from caloric restriction and we combine them to get additive effects. So it was mapping to two pathways. And we thought we David had published this really cool resveratrol result where we had now a drug that we could pharmacologically mimic the genetic overexpression of ser two. So we I mean, you probably get this. I don't know if everybody watching this understands that when you're doing experiments, you like to do the same experiment multiple different ways, and make sure you get the same answer, right. So we thought we could do it genetically. But we also have this drug, we could do it pharmacologically and test our model using a drug and see if we get the same answer. So we tried resveratrol, and we couldn't get it to work. And we try it again. And we couldn't go to work. And we try it again. And we couldn't get to work. And we called David and said we can't get it to work. What did you guys do? And so he he kept giving us different lists of things to try. We tried them all, I we must have done this experiment 30 times. I mean, it was a massive amount of my time. But I mean, I'm not joking, like literally these lifespan experiments, I must have done it 30 times, I bet if I go look at our database, we've got 6070 experiments by now anyways, we never got it to extend lifespan. And then we and then at some point we gave up, we were like, Okay, we've tried everything. We don't actually think this is extending lifespan. But they showed that you could put it on yeast cells and activate sir, too. So what what's going on here? So maybe maybe there's something about our cells, let's put it on the cells and see if we're activating certain we couldn't get it to activates or two in the cells. So then we thought maybe it has something to do with this test tube assay. And so then we started talking to a group at the Fred Hutchinson Cancer Research Center, Tony Bedell, you

Nick Jikomes 1:43:48

were trying to replicate the result in your own little experimental setting. And now I think you're about to tell me you went to try and read, you're now going to look at the specific experiment they did and look for a difference. And we

Matt Kaeberlein 1:43:58

did the same experiment they did in yeast. Okay, couldn't replicate that. Okay. It was the exact same experience exact same experiment, we actually Well, at first, we were in a different strain background, and then we got the same strain background. So we Yes, we did as close as we possibly could. We even suggested like, I would go to Harvard and do it there. Or they could send somebody here and do it here. David didn't want to do that for whatever reason. So we tried as hard as we could to get it to work and tried to replicate their conditions as much as we possibly could. And here's the thing, they reported a huge effect. They reported like a 70% effect on lifespan. That is that's massive. That's huge in this experimental system, right. So I mean, I really feel like we did as much as

Nick Jikomes 1:44:38

we possibly could, you should have at least seen some effect even if it wasn't 70%. I

Matt Kaeberlein 1:44:41

think we did everything we legitimately could to replicate that. I feel pretty good about that. So so we started thinking though, maybe it has something to do with this test tube assay, because we could get the test tube assay to work okay, you could actually get the same kit that they use the same substrate. By that point the company had actually commercialize the kits. So it was a research tool that was available. We could see resveratrol activate sir to in the test tube, just not in the cells. And so then we went and we were talking with Tony Bedell off at the hutch and and another group at the time. And they both had sort of independently come to the conclusion that that specific substrate used in this in vitro tube was different structurally than a typical protein. It had a fluorescent groove. So that so this is maybe worth spending 30 seconds on, what what did what what David's collaborators had done was create a peptide that looked like a histone, remember sirtuins or NAD dependent histone deacetylases. So it looked like a histone. But then they put a fluorescent group on the end of it, which is not biological.

Nick Jikomes 1:45:47

So it wasn't the native histone, it was a modified version of that. And it was a short

Matt Kaeberlein 1:45:50

peptide. So it wasn't the whole histone it was just a short short piece of it with this fluorescent group. And what that fluorescent group allowed them to do was do the high throughput assay, because you could see light, right? So you can see how fast this deacetylation reaction was happening. So it's very smart, very smart setup in the test tube. It turns out, though, that that fluorescent group allowed resveratrol structurally to change the conformation and I don't know, I don't even know if we know like as a as a community, whether it changes the conformation of the substrate, the peptide or the sirtuin, but it changes the conformation in a way that allowed the sirtuins to have better access to the acetyl group and deacetylated.

Nick Jikomes 1:46:30

So resveratrol was activating things in that context. It was an experimental artifact.

Matt Kaeberlein 1:46:34

So basically, we were very generous in the title of our paper, which was substrate specific activation of sirtuins by resveratrol, so it activated specifically for this substrate, might there be proteins in cells that have that same structural feature or something like it, maybe we couldn't rule that out? What we could, I feel rule out is that resveratrol did not extend lifespan in yeast and does not appear to activate co2 in yeast. So I feel confident about that. And I feel confident saying that I'm not going to blast the rest of the resveratrol literature. But I'm pretty sure that that yeast result is not real.

Nick Jikomes 1:47:08

So when people think about resveratrol, and they have this association with the longevity stuff, the idea is you consume resveratrol, it's going to have longevity benefit that taking that in a couple parts. So first of all, is it if you consume something like a food or red wine or whatever with resveratrol in it or a supplement, you're specifically ingesting resveratrol, how much of that is actually going to get in your body absorbed,

Matt Kaeberlein 1:47:36

I haven't really followed that closely. My impression is that the consensus seems to be that resveratrol has very low bioavailability. And so it would take a lot to get enough resveratrol in circulation to achieve the same doses that have been associated with health benefits in mice. I also think it's worth saying though, that nobody should take resveratrol thinking it's a longevity drug. Resveratrol is the most debunked longevity drug out there. There was a meta analysis done, I think in 2023, where they tried to look at essentially all of the published life lifespan studies with resveratrol in any organism, yeast, worms, flies, mice, the median result was zero. And that includes worm experiments. So resveratrol does extend lifespan and C. elegans. The median result, including the worm experiments was zero from take the worm experiments out is less than zero. Okay, so and that's, I don't know how many were in there more than two dozen, probably even a lot more than that. So this has been tested a lot. And it's

Nick Jikomes 1:48:49

pretty certainly there's no evidence that resveratrol has a longevity benefit in vertebrates at all. In fact, I would

Matt Kaeberlein 1:48:54

say even stronger than that there's evidence that resveratrol does not have longevity, I think when you do this sort of meta analysis, where you're getting up to very large numbers, so this is one of the challenges, right? It's when somebody publishes that something has an effect, it's really hard to disprove that. Because there's all sorts of differences of conditions, blah, blah, blah. And I'm gonna believe that when I say blah, blah, blah, I'm not trying to be dismissive. It is true that conditions matter, right. But I feel like when you start getting up into the dozens of people trying to replicate these experiments, and the net result is zero. That's pretty convincing that the real result is probably zero. Tory, let me let me just make an additional comment on that, though, because this is where people get all bent out of shape. I'm not saying that resveratrol doesn't have any health benefits. There are lots of studies out there in disease models in mice, maybe in diet induced obesity in mice, where there are there's evidence that resveratrol can have effects in that context. So that's important and should be studied further. I'm not convinced though, because of the bioavailability issues, that that you can convincingly get those levels in P

Nick Jikomes 1:50:00

Before I move on, I do have a question. So you mentioned the initial result with resveratrol from David Sinclair's lab, we just went through all of all of the stuff there around the inability that others had of replicating that result. The mouse experiment they did for diet induced obesity in overweight mice. Why was that the experiment that was done naively, I would think that you just take sort of regular lab mice and see if there's a longevity benefit in a regular mouse, you would think

Matt Kaeberlein 1:50:25

so. Yeah. Okay. So I mean, I, I suspect that they did both. And they published the one that works. Got it? And that's in fact, common, in fact, yeah, it's not uncommon and in fact, the interventions testing programs so we talked about rapamycin extended lifespan and the interventions testing program. Resveratrol did not extend lifespan in interventions testing program. So I think and other people have reported this as well, Resveratrol probably does not increase lifespan in mice that are normally aging. It might in mice fed this you know, weird height. It wasn't even a normal high fat diet. It was this weird coconut oil diet. Okay, interesting. It was. I mean, I've heard rich Miller talk about it. He's, he's got very, he's, he's hilarious. He has a very strong wit. But he talks about the diet. I don't remember the words he uses, but it actually causes the mind they I think they develop so much fat around their organs, they end up suffocating. Oh, wow. And I don't know how resveratrol protects you.

Nick Jikomes 1:51:24

Okay, so it's not even the normal high fat diet. It's some weird diet. Right. Interesting. Okay. I want to move on. So another molecule that people get really excited about with respect to longevity is taurine. Yeah, you can buy it by the kilogram. It's cheap and easy to consume. Apparently, across species, you observe a decrease in taurine.

Matt Kaeberlein 1:51:49

So yeah, I mean, I think so. And I was a co author on that that taurine paper that was published in Science, I had very little to do with it. We did some of the worm in yeast experiments, but but I was a co author just for full disclosure.

Nick Jikomes 1:51:59

Can you summarize that basic result? And then yeah,

Matt Kaeberlein 1:52:01

this is work. Vijay Yadav. He's the lead author really mean that was a lot of work they put into this study. So the summary is that at least in Worms, flies in mice, you can get increased lifespan by supplementing with taurine. And in primates, there's some evidence for healthspan benefit. So even had some primate studies in there. And you can at least find evidence and all of those organisms that taurine levels decrease with age, I want to be a little bit careful not to suggest that that's going to be and even if people there's some evidence that taurine levels decrease with age. But I want to be a little bit careful to not suggest that that's going to be true in every population, every genetic background. And, and I I don't know if it's been published yet, but I have seen data in people from other populations that did not see a decrease in taurine. So I'm not sure how universal it is that taurine levels decline with age in people or even in dogs. There's some evidence that it does, but I don't know how how generalizable that's going to be.

Nick Jikomes 1:53:07

So I mean, do you believe that basic result, though, that when they the results are on supplementation, you give exogenous taurine to different animals, and it extends lifespan?

Matt Kaeberlein 1:53:15

I do. I do believe it, I think, again, you know, I've seen enough mouse experiments that work in one genetic background and not in another that I still, you know, it's a really solid paper. I mean, it's a lot more work that's in than is in most papers, but it's still the first report. And so even though I'm a co author, I want to see it replicated, optimally replicated in other genetic backgrounds. So hopefully, the interventions testing program will test it, I think, if I saw, and this is again, probably worth mentioning, because ITP has come up a couple of times, the interventions testing program uses a mouse strain background called un pet three, which is actually a four way Cross for different strain backgrounds. So it's genetically heterogeneous, each individual is different from every other individual. The taurine work, I believe, was all in C 57. Black six, so that's a standard inbred mouse. Yeah,

Nick Jikomes 1:54:09

and that's maybe important to mention for listeners is when we when we do experiments in animals, they're often in inbred strains that are very homogenous genetically,

Matt Kaeberlein 1:54:16

right. Yeah, no, that's exactly right. And so it's and I mean, many people will argue that the ITP genetic background is superior for the reason that it is genetically heterogeneous. I think that's valid. I don't know that I've seen enough to convince me that black six isn't as good of a background but from a genetic perspective, genetically heterogeneous is going to be closer to people for sure.

Nick Jikomes 1:54:40

Metformin, what is that drug and how does that fit into the longevity issues? Yeah,

Matt Kaeberlein 1:54:45

so Metformin is the most widely prescribed anti diabetic drug in the world. Its mechanism its mechanism of action is complicated. It has many targets, but I think the one that is most commonly thought to meet In the anti diabetic effects is an activator of a protein called a MP kinase, which I alluded to earlier. Also in this longevity network, a MP kinase interacts with Tor Ampy kinases was sent central metabolic sensor. So most people think of it as an energy sensor. So when there's lots of ATP, the energy currency of the cell, right, that tends to lead to decreased MP kinase signaling, when there's not enough MP, ATP, MP kinase gets activated and that boosts metabolism. So there's, I think, a body of literature showing that activation of MP kinase genetically, at least in invertebrates can increase lifespan. And Metformin became of interest, I think, primarily because there were some early mouse studies by a guy named Anissa MOV, where they were using a short lived cancer prone strain of mice. So you know, C 57, Black six will have a mean of the controls should live to about 850 to 900 days in a good experiment. In fact, this is a cautionary tale. If you see somebody do a lifespan experiment and see 57 Black six on the controls or 600 days runaway, like do not even read that paper, because it's not interpretable in my view, they should be about 150 900 days. And this amount was using a strain. I don't remember exactly what it was, but it was less than 600. So short lived, cancer prone strain. And there they showed that Metformin could increase lifespan. And so people became excited by the idea that this anti diabetes drug that was very safe, very widely used and people activated MP kinase might be a good longevity drug. And so then people started looking in the human literature and noticed that diabetics taking Metformin were at lower risk for a bunch of different age related diseases, then diabetics, not taking Metformin. And so that was kind of consistent. But of course, that could just be because you're improving their diabetes. And I think what really got people excited was a study several years ago now reporting that in one particular population, if you look at all cause mortality, diabetics, taking Metformin had much lower all cause mortality than diabetics, not taking Metformin, but even a little bit lower all cause mortality than non diabetics, not taking Metformin. That's really exciting. If real, it turns out that hasn't been replicated since then, been people have tried. So I actually don't think that result is real. But this has led to a lot of enthusiasm around the idea that Metformin is this cheap, relatively safe, widely used drug that in people could be tested for benefits for age related diseases and longevity. So now let's go back to the mice for a minute. It turns out that people have studied Metformin now in longer lived strains and the interventions testing program clearly showed no effect from Metformin on lifespan in the genetically heterogeneous mice. There was one study from Rafa de Cabos lab in 77, Black six mice that I think was I think the title here was very unfortunate, because the title said something about, you know, Metformin improves lifespan and healthspan. In mice. When you look at the data, they tested two doses of metformin. At the low dose, Metformin increased lifespan by I want to say 4%, a tiny, tiny lifespan effect. I don't know if I believe it. But at the other dose, it shortened lifespan by 10%. higher dose. Yeah. So the conclusion that Metformin increases lifespan seems a bit selective to me when it actually shortened lifespan by a lot more at the other dose. But regardless, I think the data I think most people have settled on the consensus that Metformin probably doesn't increase lifespan, at least in longer live mouse strains, or if it does, it's a very, very small effect. So the question is, you know, given that, how excited should we be about Metformin as a potential longevity drug in people? My feeling is that again, Metformin does affect MP kinase MP kinase is in this network. Again, I'm not convinced that Metformin is a great tool, though, for perturbing this network in a way that is consistent with slower biological aging or increased longevity. We'll have to see because because people I think are going forward with the I don't know if you've heard of the term trial targeting aging with metformin, large clinical trial, and people mean, I hope it works, but would not be my first choice. If I was trying to pick the best options and be like 10 or 12 on the list, given what we know from the animal studies and what we know from the human epidemiology. The only thing I think that's probably worth mentioning is I also think that people tend to much like I personally believe people tend to over estimate the side effects from rapamycin I think people tend to underestimate the side effects associated with metformin. I think Metformin is a safe drug in the context of diabetics, right because you get a lot more benefit from fixing your diabetes than the potential side effects you get from Metformin but the concerns with metformin there and there are a few outside of the sort of gastrointestinal stuff that some people experience, the things I'd be concerned about are lower testosterone. I don't know what fraction of men that happens in, but it happens in a significant fraction of men, and the accumulating sort of evidence that Metformin might offset the molecular beneficial effects of exercise. And again, I'm not saying that's rock solid, because that data is still pretty early. But there's been more than one study now in both animal models and in people suggesting that at least some of the metabolic changes that are thought to be beneficial in the context of exercises are attenuated by Metformin. So I'd be a little bit concerned about that. I think if you're a diabetic and your doc prescribed Metformin, take your Metformin if you're not a diabetic, personally, I wouldn't take Metformin off label for potential longevity benefits,

Nick Jikomes 2:00:51

you know, based not only on how I know, sorry, science actually works in practice, based also on how hot the aging field is, right? Everyone, everyone literally in the world wants to figure out how to age more gracefully. No one really wants to die. For the most part, we want to be as healthy for as long as possible, obviously. So obviously, this is going to be a hot field. There's a lot of venture capital pumping into companies that are working on anti aging stuff, there is a lot of grant money that goes to researchers to study this stuff, because it's it's of such wide interest. Do you worry that the field is being contaminated? And that there's a lot of sloppy science being done?

Matt Kaeberlein 2:01:34

So let me comment on that in a minute. I want to I want to comment, though, on this idea that there's a lot of money being pumped in the into the field because there's actually not compared to in the, in the research side, compared to cancer, heart disease, you know, if you look just at Nia or NIH, one half of 1% of the NIH budget goes to biology of aging, it's a tiny fraction, especially given that biology of aging is the greatest risk factor for almost every major cause of death and disability.

Nick Jikomes 2:02:06

And can you give us a comparison point there, like how much goes a cancer or something like that. So about 350

Matt Kaeberlein 2:02:09

million goes to biology of aging, about 6 billion goes to cancer, let's just NIH, not DOD, where it's probably even skewing things worse. So. So biology of aging is really relatively underfunded, given the potential benefits for health, right, from keeping people healthy, instead of keeping people sick, which is most of what we do with the disease focus mechanism. Cancer is a little bit different, because you can't cure people's cancers, you really can't cure most other diseases. So in any case, I just want to I don't want to, while more money has come into the field from other sources, you hear about the billionaires wanting to live forever, all of that evolution foundation is they say they're going to put a billion dollars a year into the field, which would be great, it would triple the total NIH funding for the field. But compared to cancer, that's still a fraction, right. So it's it's relatively small, because here, it's not as much as you might think. Right. Okay, certainly not given the importance, I would say, are the potential benefits. Okay, so having said that, am I worried about the field being contaminated? You know, I have kind of two feelings about this, I've been in the field long enough that I can tell you the field was contaminated the whole time. So I think the line has shifted, much like it has in the rest of society about, you know, what is the fringe and what is, you know, commonplace? I think, unfortunately, in my view, unfortunately, you know, some of the rhetoric some of the behavior that I don't feel comfortable with has become normalized. I don't know how much of that is our field, because the fields growing, because there's a lot of attention. And how much of that is just because society has kind of become that way we look at our politics. Right, you know, so. So yeah, I'm concerned that some of the poor use of language will turn off serious people. I'm concerned that, you know, some of the marketing of products that don't work is going to give the field a black eye. That has happened in the past, where, you know, I think it's clear the field has been set back by things like that in the past. So yeah, I'm concerned about it. I don't know that there's anything that can be done about it. And I, you know, I don't think anybody in the field scientists on the science side, wants to, like play policeman and call all that stuff out. I mean, I've started done that in egregious cases. But that's no fun. Like, I don't want to be the guy that is always you know, you shouldn't talk like, you know what I mean? Right. So I don't know what to do about it.

Nick Jikomes 2:04:41

Yeah. Well, so in terms of a lot of the major results that are out there are the ideas that are being promoted. What are some of the big ideas that have gotten a lot of attention that you think people should be especially skeptical about for now? Yeah,

Matt Kaeberlein 2:04:55

well, I would say supplements in general. So anybody who claims that they have a long job MIDI or anti aging supplement you have to be skeptical of doesn't mean there's no data to support it. But there's certainly no evidence in people for any of these things being longevity drugs. So I think there you have to then look at the animal studies, and you kind of have to, again, try to do the best risk reward analysis, you can. I would also put under the risk category, how much does it cost? That for some people, that doesn't matter, but for a lot of people, if you're spending a couple 100 bucks on supplements, you could spend a couple 100 bucks on a gym membership and get some, you know, much more likely to benefit your health or good quality food. So I think that should weigh in. So I think supplements in general, just be very skeptical of I personally, you know, would say stay away from resveratrol. I'm not a big fan of NAD precursors, we already talked about why? So that's one area. I would I would I would point to I think other than the supplements, the other area that I think a lot of people are maybe misled by are these biological aging tests that are going direct to consumer? Yeah, I was gonna ask you about those. Yeah. So I mean, I feel like the science there is real, right? In the sense that, you know, one flavor, the most common flavor of biological aging tests are these epigenetic tests. So they're measuring changes in methylation. With age of DNA, that's the epigenetic marks they're measuring. And people have shown in mice and people and dogs, there are characteristic changes in methylation with age that correlate with chronological age. And you can find people who are off of that correlation, linear equation, and they're people who are biologically older or younger, right? Calendar epigenetically, older or younger? Yeah. And they are, and then those people with some degree of correlation are more or less likely to die, right, in the next five years, or 10 years. So there's some relationship between these epigenetic signatures and mortality risk, and maybe health risk for different diseases. And that works in a research setting. I think there's two questions about the commercially available epigenetic tests. One is, how do we know these companies are actually doing it right? Like, what's the error? What's the precision? Of if you took the same sample? Did it three times? Would you get the same result? Like we don't, we have no information on that. So we kinda have to trust these companies are doing it right. I don't know about you, I don't trust any of these companies. So I know some of the people at these companies, some of them are good people, some of them aren't, some of them are, but I don't trust that they're doing it right until I see the data. So I don't know whether these tests are actually working the way that we think they're

Nick Jikomes 2:07:31

working, even if they're doing it, right. Like if you if you run the experiment, if you do the measurement twice, there's gonna be some intrinsic error level, we have no idea what that's right. So

Matt Kaeberlein 2:07:39

that's one piece, then the other piece is, we don't actually know what these tests are telling us in terms of biological age, health risks. So all of that is based on correlative studies from long term longitudinal data in people. So maybe this is worth talking through exactly how these these relationships have been made. So in these long term longitudinal studies, people have collected, let's say, blood samples from individuals over a couple of decades. And what scientists have done is look at the blood samples from 10 years ago, and five years ago, and and now and measure these epigenetic signatures. And you can do this with other types of data, you know, proteins, you can do it with metabolites. So these epigenetics, you can build clocks off of just about any sufficiently dimensional data set. So they built these epigenetic clocks off of, say, people their blood samples from 20 years ago, they correlate it with the chronological age of the person at that time. Okay. And then they can do different correlations and say, Well, let's look at the people who died in the next 10 years. So who's still alive? And can we build epigenetic patterns that are reflecting mortality risk, and of course, you can do if your data is sufficiently high dimensional, you can create a subset of features that are going to be strongly associated with whatever you want to associate. Right. And so I think you can make a case that in that population, there is an association between these epigenetic patterns and five year mortality risk, or 10 year mortality risk, or kidney disease, whatever, whatever feature, you have enough people over this 20 years they've developed, that you've got the statistical power to build these clocks. So does that prove that if you now get a blood test, that that same pattern is going to predict your risk of dying

Nick Jikomes 2:09:28

in the next 10 years? Not only might I be in a different population of people defined, however, we want to define that. But also, we're in a very different context. I think that's exactly that's exactly important. People are less healthy by many measures today than they were to think about

Matt Kaeberlein 2:09:40

what the world was like 20 years ago, or 30 years ago, even just the diabetes or not, well, diabetes, but obesity risk, right. Yeah. So the environment is quite different. And so it's possible that these tests are telling you about biological age as a whatever that true measure of biological age is. It's possible these tests are telling you about that. I don't think they are. It's possible. They're telling you about your sort of overall health status. I think that's plausible. It's possible. It's telling you about what your overall health status would be 20 years ago, that's also possible. Right?

Nick Jikomes 2:10:13

So it's almost like they're doing a comparison of you to that population from then. Yeah,

Matt Kaeberlein 2:10:17

that's exactly what it is. So I think that's why it's worth being a little bit. A little bit skeptical. Even if you believe that the companies are doing everything right, the test is 100% precise. It's not clear to me that the result is actionable, and that you should change what you're doing based only on that test, I would put a lot more faith in functional measurements of strength, body composition, you know, blood metabolites, that we know, because of decades of clinical research are predictive of health risk than I would put in an epigenetic test, especially if the epigenetic test is giving you a different answer from

Nick Jikomes 2:10:52

those things. Yeah, yeah, that makes a lot of sense, in terms of things like blood markers. So there's also a lot of products out there now that allow people to do get, you know, take blood samples at home. So they have to go into the doctor to get it to get you know, dozens of markers, in some cases, in terms of like the basic blood markers that you would get for like a routine checkup? What are the what are the ones that stick out the most to you as being important to look at from a longevity perspective?

Matt Kaeberlein 2:11:16

So I think there's two ways I'll answer that one is, I mean, I think the the blood markers you get in most people will get from their typical primary care sort of system. I mean, the ones that are probably going to be most important for most people are going to be around metabolic and lipids. So glucose homeostasis, and lipids because of heart disease, right, glucose for diabetes. But having said that, I think that the basic blood work that most people get is woefully inadequate for what we should be doing. Right. So like, just there's some very, very simple low hanging fruit here that everybody should get a frickin vitamin D, B, 12. And omega three tests like this. It pisses me off. It pisses me off, because it's funny, because because, you know, we've been collecting we have, we have a large number of individuals who've been going through our optive span cohort. And the first time I sat down with the data for, like, 100 people, I'm looking at it, and it jumps out at me that like 75% of people are deficient in D, B, 12. Or Omega three, and a lot of people are deficient in all three, a

Nick Jikomes 2:12:20


Matt Kaeberlein 2:12:20

I'm not joking. 75%. I mean, sure. We live in Seattle, but still, yeah. So I go to a doctor friend of mine, who's who's who I will not say his name to protect the guilty, but I go to him, and I'm like, I just looked at our data. I can't believe it. 75% of people are deficient in one of these things. Like, I know, what the fuck you mean, you know, you're a doctor fix it? Yeah. I

Nick Jikomes 2:12:43

mean, yeah, we're, we're in Seattle, I mean, that many people are Omega three deficient. I mean, we probably eat more salmon than other.

Matt Kaeberlein 2:12:49

Omega three is also a little bit tricky, because what you define is deficient isn't as clear as it is with D and B. 12. Right. So the Omega, I'm pretty convinced by the the Omega three literature that in the United States, the vast majority of people are certainly under optimal, right? I don't know where you draw the line for deficient there. It's a little bit hard, but certainly under optimal. And I have come to believe that, you know, shooting for an Omega index of eight or higher is probably where you want to be that's actually hard. I'm still not defined that index is EPA. EPA plus DHA. Yeah, right? There are a variety of ways you can measure but that's the most common one. And there's a there's a blood test. I think quest, I think it's Quest has Omega check, which will give you both quest and LabCorp have their versions, maybe it's LabCorp. That doesn't make a check, but both of them will give you EPA and DHA, one of them will actually calculate omega index that's easy to calculate. But you know, the epidemiology to me is pretty clear that there's at least a strong correlation for all for those three. I mean, those aren't the only three. Those are the ones though, that I think people are deficient in and don't realize it. And in part because those things, a lot of the vitamins and minerals that you can measure in blood will change really quickly. Right? Yeah. Could be because you took the supplement that morning. Yeah, right, those things take a while to move the needle. So you actually get a pretty good measure of where people are at over the long term. But the thing that pisses me off is it's so easy to fix. And we don't most people don't ever get measured and I didn't get my vitamin D test until I was 51. Like I probably was deficient for decades and didn't even know it right. So that's one thing that I think everybody should just get that test it's it's it's such low hanging fruit we mean from a public health perspective, we should just offer that as part of the standard standard. Give people the frickin supplements for free and quality control it so everybody knows they're getting good quality. Right? This is something like I get that people have different opinions on what government should do that the payback from just making sure that so many people are not deficient in these things is so outweighs the cost of doing that. This is like a no brainer. This is a public health thing. That's easy. This is not low hanging fruit. This is fruit that's on the ground, fucking rotting wood. should do something about it. So anyways, that's my, that's my tirade on on nutritional deficiencies. But that's something I think I think hormones are another big one yeah, that most people don't ever get measured. Or if they do, they only get their hormones measured when they start having symptoms. Yeah, this is a little bit different in men and women, because in women, we expect women to go through menopause around a certain age. And so we kind of know what to look for. And we kind of know what to expect. I think a lot of men have hormonal changes that are impacting their quality of life, but they don't know it, because you never get a hormone test or more gradual crept up on them. Right. And, you know, hormones are important for sexual function, of course, also important for metabolism, body composition, bone density, both women and men. And so that's, again, something that I think a lot of people could benefit from knowing where they're at. And, again, I personally feel that hormone replacement therapy is right for a lot of people. And I talked about body composition, that's the other thing I would point to everybody should get a frickin DEXA in their 40s. And at least once every few years, what is DEXA Oh, DEXA dual X ray absorptiometry. So it's a low it's X ray, but it's very low dose radiation, it's probably about the same as a flight from Seattle to California. So nothing to worry about if you do it once a year, or every few years. So DEXA will give you body fat composition, both total amount and positional lean mass composition, both total amount of positional and bone density, both total and positional. And so those things can be used, obviously, bone density for fracture risk, if you're on the path to osteoporosis, osteopenia, osteoporosis, you catch it early, you can do things to slow down the decline or even improve it resistance training, for example, if you don't want to take drugs. The other thing out of DEXA that I think most people don't appreciate, I mean, lean mass is obviously important. The other thing I think most people don't appreciate is not all fat is created equal. Right? So there's the subcutaneous fat, which, you know, if there's a good fat, that's the good fat, and then there's the visceral adipose, which is the fat around your organs underneath the abdominal wall. That's what people call the bad fat. That's the highly inflammatory fat that probably disproportionately contributes to metabolic disease. Yep. And so again, you can actually be relatively lean, but have high visceral adipose and be at high risk for metabolic disease. You may not even know it yet. Right? So that's another one that I kind of feel like everybody should get. Then the last thing I'll mention that I personally have found very educational. And I know a lot of people who have, if it's done right, is continuous glucose monitoring. So these are these devices that traditionally been used for diabetics now becoming more popular, I think, in fact, FDA just approved and over the counter,

Nick Jikomes 2:17:39

I used one once I'm not diabetic, but I just wanted to see. And right away I learned things that were unexpected to me. I thought at this time in my life two or three years ago, I was eating quote unquote, healthy breakfast cereal that spiked my glucose, like nothing else in my diet yet.

Matt Kaeberlein 2:17:55

Yeah, and I want to and again, this is why I say using it right, I think I think the CGM is can be very useful even for people who don't don't really have a structure to the program, I think it was when it's done in a little bit more structured way with education around what it means. It's actually extremely sticky. What I mean by that is its behavior modifying in a way that no other single tool I've seen is people will, like you said, you realize this particular thing that I thought was healthy, actually may not be and you stop eating it. Yeah. And it stays with you, you're not going to unlearn what you learned. The one thing I do think it's important to be careful about though is there is this sort of myth that has been put out there by some of these direct to consumer companies that every glucose spike is bad. And that's a myth, like a glucose Spike is a normal physiological response to certain types of food. Yep. So you should I think the problem is sometimes people get scared into thinking that if it ever spikes yeah, that's, that's terrible. Yeah. And it's not and and, and so I think that can be counterproductive. But in any case, I think CGM is are really useful tools for helping people understand how their body functions and you learn the sort of individual variations because the same the same diet right right may have different effects on glucose homeostasis in different people. The other reason why I think CGM is so powerful is we found in our program that I don't know what the percentages are, but a significant number of people had undiagnosed pre diabetes and diabetes, you find it right away if you're doing a CGM.

Nick Jikomes 2:19:26

Yep. As opposed to not doing that in which case you're only gonna find out months or years later when you have full

Matt Kaeberlein 2:19:32

blown died. Yeah, and I would say you know, HB a one C is probably the that and fasting glucose are the two markers that you will get from a standard primary care blood panel that will cause a doctor to suggest that you might have diabetes, they're pretty good, but they're not perfect. And especially fasting glucose is is really very individual. There are some people who will have low fasting glucose and terrible glucose homeostasis and Some people who will have a fasting glucose, you know, in the low one hundreds, which would be considered pre diabetes. But because if you were a CGM, you'll see these people have what's called a strong Dawn effect. So just right before they wake up, their glucose may come from 80s, up to about 105 110. And we'll stay there for a few hours, and then we'll come back down. So they've got perfectly good glucose homeostasis. But if you take a fasting glucose test, you're going to look like you have pre diabetes.

Nick Jikomes 2:20:24

So what are you guys doing up to span? Yeah, so

Matt Kaeberlein 2:20:26

we, I would, I would frame up the span as a healthcare technology company, primarily, our goal is to build tools, technologies, protocols, that will enable this type of proactive preventative health care for as many people as possible. That's like the big mission, we have some ideas on how we get there. So our initial approach is to do this in the clinical setting. And in a, I don't really like the phrase corporate wellness, but corporate healthspan setting. So create programs that we can scale and export to other providers that do this as well as possible given constraints on economics, right? So in the high end concierge medical world, there really are no constraints, you can do everything. So then the question there is, what is optimal, right? What is the what are the most effective tools that we can bring to bear if really, money is no object? And then within something like a corporate wellness program, or corporate healthspan program, what can we do at a price point that employers or maybe down the road insurers are willing to pay for, that gets you 80% 90% of the way there. So those are the things we're trying to figure out. So we have a clinical program up and running. We call it our Trailblazer program, I am thrilled with what we built, I think the experience from a clinical perspective, is on par with the best of the best in the high end concierge medicine world. I don't actually like the phrase longevity medicine, because there are a lot of people who have co opted that who don't know anything about longevity, then there are a lot of people who have co opted it who are doing offshore, kind of, you know, outside the lines, stuff. So it's got some connotations that I don't like, we're trying to do it right as science and evidence based as possible. And then our corporate wellness program is pretty solid. So we do an expanded bloodwork panel that includes many of the things that that I mentioned, for all of the employees within our corporate client right now we have one corporate client, and our clinical program has about 30 people in it right now. We're shooting for 100. You know, by the next 12 months, we'll probably exceed that. But but all of that those programs are to build the tools, the toolkit, right? So that's what we're working on. Now. We've got the we know what we want to measure. We know how to measure it. We're measuring it, we're acting on it, how do we build the toolkit that allows us to automate that as much as possible?

Nick Jikomes 2:22:57

Do you? Well, let me ask you this. So there's a lot of experts and self proclaimed experts out there, giving people a lot of information, much of it is of questionable quality, who are like one or two people out there? scientists, researchers who have written books or have podcasts or whatever that you would recommend people listen to.

Matt Kaeberlein 2:23:20

Yeah. So the two people I would point to who have have written books are Andrew Steele. I think his book is really well written and also reflects the science in a very solid way, like rigorous way, and Peter Attia. And I mean, I know Peter Peters, it's funny, because he's a little bit controversial in some circles, and I don't understand why Because oftentimes, the controversy is because people sort of misrepresent, in my opinion, at least what he says like, in any case, Peter is a friend of mine, so maybe I'm biased in that way. But I also think he's very thoughtful about the science. And he really does try to take a rational risk reward approach. He's very serious. And so I if I had to pick like one person who I would take advice from, it'd be Peter. And again, we don't agree on everything, but I respect his approach. Having said that, outside of that, you know, I honestly tend not to spend a lot of time paying attention to most of the other people out there. Not because there aren't other good people out there, but but because I don't have the bandwidth to do it. And I also feel like I think the rule of thumb I would take is Be wary of people who speak with certainty on you know, broad topics. Yep. And I mean, I think this is what gets Peter in trouble a little bit of times with you know, some of the some of the criticism he takes is he speaks with certainty sometimes when I don't think he really believes that he has certainty, but most of the time he's pretty balanced and, and says when it's a, you know, a plausible or this is what I think but you know, The people who speak with certainty in, in this space, I think, are usually uninformed. So their certainty actually comes from a lack of understanding of the complexity of this, you know, system that we call the human body. Yeah, right. I think most people who learn enough realize that it's so complex that we really need to be humble about what we understand. And what we don't understand. So I tend to is when somebody says, everybody should do x outside of a few things, I tend to shut them off at that point. I'm like, you know, if you're gonna get that wrong, you're probably gonna get a lot of other stuff wrong.

Nick Jikomes 2:25:35

Well, Matt, this was a fascinating, thank you for inviting me here. I live in Seattle. Make it out topspin HQ today. Yeah, yeah. And I would look forward to looking around a little bit and see what you guys are up to. But is there are there any final thoughts you want to leave people with or anything you want to reiterate that we went over today?

Matt Kaeberlein 2:25:51

I think the one thought that I would just reiterate is, and I sort of alluded to this with the NIH funding. You know, I think most people don't immediately appreciate that. If you look at most of the major causes of loss of quality of life, death disability in the United States and other developed countries, look at the top 10 killers, nine of them have age as their greatest risk factor. And I would say biological age is their greatest risk factor. So again, our entire approach to health for the last 200 years, has been for at least in Western countries has been focused around disease, right? We think of diseases in isolation, we usually wait until people are sick, we try to cure their disease. And that's that sort of approach from the medical side has filtered all the way back to basic research. Most basic research is done on individual diseases, most drug development is done to cure diseases, most medical practices done to treat disease symptoms, right? I think we need a paradigm shift. And this is where Peter A TIA and I align very strongly, we need a paradigm shift in all of those not just in healthcare, but all the way through that spectrum, from basic research on up to focus on what can we do to keep people healthy instead of keeping people sick. And I think there's a lot that we can do outside of the biology of aging, right? Some of these things like fixing common vitamin deficiencies, or, you know, catching things early. But I think the biology of aging needs to play an important role and will play a more important role as we understand that biology better and are better able to intervene in it. So as part of that, I think raising awareness of this idea that, you know, what we have the situation we find ourselves in today, in terms of health care, largely stems from that reactive disease approach. And that's been pretty effective, like a lot of people's cancers have been cured. But it's also created a lot of problems, we've got a lot of people who are living 4030 20 years with chronic disease, that's really expensive. That is not the best way to keep people alive. And so we really, I think, unless we're going to have a catastrophic failure of our healthcare system, need to do this, make this paradigm shift happen. And so the more people who recognize that, hopefully, the faster we can kind of change the system in a way that is that is going to be more focused on health and less focused on disease. And I do want to mention that I think this needs to happen, in addition to, you know, basic research, pharmaceutical, medical professionals at the policy level as well, I think we need to have policymakers in the United States, understand this perspective, and start to take action on changing the system from a policy level. And fortunately, we're starting to see that. So it turns out, there's actually just last year, something called the longevity science caucus in the US House of Representatives. It's still pretty small, but it's a start. And so if we can start to have our elected representatives, pay attention and take action on this, we can start to create incentive structures from the top down, maybe that will help with this shift. So just want to put that out there. And I think the more people who kind of understand that, that perception that that viewpoint, the better.

Nick Jikomes 2:29:16

Alright, Matt, thank you for your time. This was great. And I look forward to talking to you again future. Thanks. My pleasure.

Mind & Matter
Mind & Matter
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