The Rich Roll Podcast - David Sinclair On Extending Human Lifespan & The Science Behind Aging

Episode Date: April 23, 2019

Everybody grows old. Everyone dies. But is this scientific fact? Or is it merely a story based on history and our current understanding of biology? What if we instead consider aging as a disease? This begs the question: what is the cure? Welcome to the mind of David Sinclair, PhD, one of the world’s leading scientific authorities on longevity, aging and how to slow its effects. A professor in the Department of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, David obtained his Ph.D. in Molecular Genetics at the University of New South Wales, Sydney in 1995 and worked as a postdoctoral researcher at M.I.T. where, among other things, he co-discovered the cause of aging for yeast. The co-founder of several biotechnology companies, David is also co-founder and co-chief editor of the journal Aging. His work has been featured in a variety of books, documentaries, and media, including 60 Minutes, Nightline and NOVA. He is an inventor on 35 patents, has been lauded as one of the Top 100 Australian Innovators, and made TIME magazine’s list of the 100 most influential people in the world. In addition, David is the author of the forthcoming book, Lifespan: The Revolutionary Science of Why We Age — and Why We Don't Have To* which hits bookstores on Sept. 10 and is currently available for pre-order here*. This is an absolutely fascinating conversation on all things human lifespan, aging and longevity. We begin with the specific scientific mechanisms that contribute to biological degeneration. Then we dive deep into the hard science David and his peers are examining to better understand what contributes to aging and how to prevent it. According to David, the prospect of living to 200+ is not a pipe dream, but a very possible reality. If humans could indeed double lifespan, how would this change how you live? And what does this mean for the future of humanity? This conversation travels deep into the scientific weeds. Perfect for the geeks among us. But it's also grounded in practical takeaways for all of us — because David's work isn't just about extending lifespan. It's about learning how to live as vibrantly and energetically as possible for as long as possible. It’s an honor and a privilege this brilliant man’s pioneering work and wisdom with you today. Plus he's a lovely guy. If you enjoyed my episode with Dr. Valter Longo (RRP #367), a fellow brilliant warrior in the longevity space, then I’m fairly confident you’re going to love this one. So break out that pen and paper, because you're going to want to take notes on this one. I sincerely hope you enjoy the episode. Peace + Plants, Rich

Get your NAD levels up. You can do that with being a little bit hungry. You can also do that by restricting the total amount of protein that you bring on board. So eating a lot of steak would be about the worst thing you could do. Never exposing your body to any changes in temperature, probably another thing. Basically everything that makes your body happy and sedentary and unstressed is bad for you. And the reason is that you're not engaging your survival circuits. But now we can kick those survival genes into action by putting our bodies under a bit of stress hormesis or eating plants with those molecules that signal stress.

We call that xenohormesis. And that is right now, with the exception of some clinical trial proof, that exercise and dieting is really the best thing we can do for our bodies. Exercise is a treatment for the body that actually puts the entire system in a state of defense. And so it's less about getting the blood to flow and more about getting your tissues to act younger. And that's really the huge benefit that you get from exercise. That's David Sinclair, and this is The Rich Roll Podcast.

The Rich Roll Podcast. Here's a couple uncontroversial facts. Everybody grows old and everybody dies. But is this actually set in stone? Does it have to be this way? What if we thought about aging as a disease, as a curable disease? And what would you do and what would the world look like if we could suddenly live to be 200 plus years? My name is Rich Roll.

I'm your host. This is my podcast. And this is but a few of the topics we explore today with one of the world's leading scientific authorities on longevity, aging, and how to slow its effects. David Sinclair is a professor in the Department of Genetics at Harvard Medical School. He's co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging. He obtained his PhD in molecular genetics at the University of New South Wales, Sydney in 1995, and worked as a postdoctoral researcher at MIT where, among other things, he co-discovered the cause of aging for yeast. David is the co-founder of several biotech companies. He's also the co-founder and co-chief editor of the journal Aging. His work has been featured in a variety of books, documentaries,

and media, including 60 Minutes, Nightline, and Nova. He's also an inventor with 35 patents to his name, has been lauded as one of the top 100 Australian innovators, and he made Time Magazine's list of the 100 most influential people in the world. Finally, he is the author of a new upcoming book entitled Lifespan, the Revolutionary Science of Why We Age and Why We Don't Have To, which comes out September 10 and is currently available for pre-order. Check the link in the show notes to check that out. If you enjoyed my episode with Dr. Walter Longo, a fellow brilliant warrior in the longevity space, we mentioned him a few times today. That was episode 367.

Or if you happen to hear David on Joe Rogan's podcast a few months ago, which was great, by the way, then I'm fairly confident that you're gonna love this one. We're brought to you today by recovery.com. I've been in recovery for a long time. It's not hyperbolic to say that I owe everything good in my life to sobriety. And it all began with treatment and experience that I had that quite literally saved my life. And in the many years since, I've in turn helped many suffering addicts and their loved ones find treatment. And with that, I know all too well just how confusing

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I empathize with you. I really do. And they have treatment options for you. Life in recovery is wonderful, and recovery.com is your partner in starting that journey. When you or a loved one need help, go to recovery.com and take the first step towards recovery. To find the best treatment option for you or a loved one, again, go to recovery.com. Okay, David Sinclair. So this is a mind-blowing conversation on everything aging, longevity, the scientific mechanisms that contribute to biological degeneration, and the hard work that David and others are devoting to both better understanding these mechanisms as well as learning how to prevent and even reverse them. I want to say up front, it's not just about living as many years as possible, but more about how to live as vibrantly and as energetically as possible for as long as possible. That's really the goal here. I should also say that this one gets pretty deep in the weeds scientifically, which is, of course, perfect for the geeks among us.

But it's also grounded in practical takeaways for everybody. In addition to being a lovely guy, David is a true pioneer. It is an honor and it is a privilege to share this brilliant man's work and wisdom with you today. So without further ado, I give you Dr. David Sinclair. Good to have you here. Thank you for doing this. Thanks for having me on. I'm excited to talk to you. This is a subject of personal interest, of course, and I think interest of everybody. And the work that you're doing is really not only fascinating, but obviously revolutionary or potentially revolutionary. So

first off, thank you for the work that you're doing. And I look forward to exploring this with you. I think a good place to start would be just hearing a little bit about what got you interested in this field to begin with. Like why longevity? Why aging? Anti-aging? Yeah, sure. I think we're all the same when we're about the age of four or five. We realize that we're not going to be around forever.

And even scarier for a young kid, your parents are going to die and your grandparents are going to die and your pet cat's going to die. So I remember going through that very vividly. My grandmother, who essentially raised me, was a very honest person and she would just tell it as it is. And she said to me as a four-year-old, yeah, yeah, I'm not going to be around. Your parents are going to die. Your cat's going to die and you're going to die.

And I went, that's a bit of a shock to a four-year-old who you know he probably still believes in santa claus at four it was brutal and that may be the turning point in my life uh but what most kids do and it's been well studied is that they bury that thought it's just too sad and it's it's distracting to dwell on that every day of your life. So we actually, we typically forget about it by the age of six or seven. And then it doesn't emerge till we get into our late forties, early fifties. And we think, okay, maybe there is no such thing as immortality, but up until then, most people don't even think about it. I feel like we still don't really think about it. don't even think about it. I feel like we still don't really think about it. We certainly don't talk about it. And death is almost a verboten subject. And our exposure to the reality of

death and aging in its most late and mature forms is something we do our best to whitewash and remove from our field of vision. Yeah, I agree with that. And it really takes a lot of courage to be able to think deeply and ponder your loved one's mortality and your own. And so I also, I don't think about it too much myself, though I probably do think about it more than most. But seriously, I think if all of us right now would consider what they have right now and losing all of that and most likely not seeing most of these people ever again, if any of them. I mean, that's a pretty sad thing, and I don't mean to depress everybody, but that's something really worth appreciating, that we are here right now, most of us are healthy, but that will not last.

Mm-hmm. Yeah, I feel like we uh we all intellectually understand that to be the case but i think there's something innately human about being in denial of that truth in order to kind of get through the day like on some level i have this signal in the back of my mind going yeah i know it's going going to happen, but I might just evade that somehow. I think I'm going to get around that. Yeah. Well, that's what we do. That's why we survive as human beings.

It's a pretty cruel thing to have a species that's conscious of its own mortality. It's not a happy thing. And most animals, actually, as far as we know, all animals except us go through life not knowing that they're going to die and that their family is going to die. But we are burdened with that. But as a coping mechanism, and I believe that it's probably evolutionary wired into our genome, that we don't think about that. Because people who did always worry about dying, their tribes probably died out thousands of years ago. Right. Well, it can be paralyzing too.

And you talk about this in the, you were nice enough to send me that introduction to your new book that's coming out at the end of the year. And you talk about your grandmother and the impact that she's had on you and her sort of lifestyle antidote to this ethos of living your life in accordance with the ticking clock, right? That she wanted to live this joyous, I mean, she sounded like amazing, right? She's

living this joyous childlike existence, you know, until her body could no longer keep up with her spirit. Right. Well, as a young kid, she was still in her 40s. She had my father when she was 14, 15. And so that allowed her to be very young as a grandmother. But she was also mentally young. She was vivacious. She's one after 1956 when Russia cracked down on a revolution, went as far away from Europe as she could, which was Australia. Sydney is where she settled and where I grew up. And there she felt free. She was oppressed for most of her life with rape and pillage going on. And she got to Australia and everyone had enough to eat and they had money and they had sunshine and she just loved life. And so she was one of the first people I hear to wear a

bikini in Australia. And she got taken off Bondi Beach for in the 1950s wearing one of those. It's incredible to hear that knowing what I, you know, knowing what Bondi Beach represents, that she was like the first person to wear a bikini on that beach and got chastised exactly yeah yeah these days you get chastised for wearing a top yeah if you're a woman uh but yeah she went lived in new guinea uh with the natives for a while and hung out there uh by herself my father had to go get her because she was probably drinking a fair amount um she says she tasted human flesh up there with the cannibals. So that's a pretty big thing for a woman to do that in the 1960s. So she was great. She raised me to just love life, to always stay young. And she says, grownups ruin everything. Stay young.

Yeah. And she had this mantra, this A.A. Milne poem, right? About maintaining your sort of six year old self throughout your life. That's right. Now we are six. And she would read that to my brother and me. And she would just say, make the most of your life. Stay young. Don't listen to the naysayers. Adults are mostly naysayers.

And leave a mark. Do what's good for humanity. She was a humanist at heart even towards the end of her life a declared humanist and so her goal and my goal is the same which is nothing matters except making the world a better place after you've been here profound especially given that so much of the work that you do is at the cutting edge and it's impossible that that's not going to ruffle feathers and create you know a cadre of naysayers who are trying to take it down a peg well yeah I mean

it hasn't been an easy career even from the outset as Volta long ago and your show rightly said it was rough in the old days, studying aging wasn't even considered a true science. But like most careers, if you try to push the envelope and say things that others have never said before, you will have people who try to pull you down. But it's, you know, I'm pretty stubborn. And I keep my eye on the goal, which is to help humanity. So these daily fights and things don't really get me down so much. Right. So your grandmother has this profound impact on you, and you're a young enterprising university student in New South Wales. And from what I gather, there was sort of one particular

lecture that kind of turned things for you, that got you out here to the United States? Well, there was. Prior to hearing the lecture, I remember sitting playing cards with my friends, and I didn't try that hard in college or in school. Mostly we were playing cards and drinking heavily. But I do remember one moment telling them all, do you realize we're probably the last generation to live, quote unquote, a natural lifespan? And others who are downstream of us, our descendants, are going to live a lot healthier and longer lives than us. And we've been born one generation too early. Do you realize how sad that is? And they just went, yeah, deal the cards, David, shut up. But that stuck with me.

And so when I heard the lecture from Lenny Guarente, who was an MIT professor, still is, he came and he talked about a project that had just started up in his lab over in Boston to study yeast aging, same yeast that's in bread and beer. And I was studying yeast for my PhD. So I knew yeast intimately. They were my friends. I would look at them under the microscope. And what he told me was they age. And I didn't know that. Most people don't know that yeast cells get old, they get fat, they get slow, they get sterile. I didn't know that. Yeah, they're little creatures. They're a lot smaller than we are, but they have the same

struggles through life. They have to find mates, they breed. And so I thought that was a wonderful way to start studying aging. Because if we can't figure it out for yeast, we've got no hope figuring it out for humans. Sure. So that begins this lifelong journey, this exploration into aging and longevity. So before we embark on that, let's define our terms. I mean, what is aging from your perspective? Well, I've come to the conclusion that aging is a condition. I will be bold and say it should be declared a disease. And that often strikes people, most people, as ludicrous. But let's do some thought experiments here.

One being if I was to tell you, Rich, that I just found your real birth certificate, okay, and you say, well, what is it? And I'm telling you, unfortunately, you're 100 years old. Are you going to want to die tomorrow? You're healthy, you're fit. old. Are you going to want to die tomorrow? You're healthy, you're fit. So the point there is nobody who's healthy and vigorous and enjoys their daily life and enjoys their family wants to die. So often I ask people about how long do they want to live? And the typical answer is, I don't want to live beyond 80 and God forbid 100. And that's because they don't think of people who are old

as being anything worth fighting yeah right so that that's one aspect on the aging as a disease if you go to the merck manual of geriatrics which is the bible of this field the definition of of a disease versus aging is very simple it's a cutoff. If something bad happens to your body and you're in a minority in the population, that's a disease, something worth treating. But if it happens to 51%, then hey, that's natural. That's just aging. We should just deal with it. That's what God gave us. And that's ridiculous. If you're off by a fraction of a percent, it's aging. By that argument, diabetes and heart disease are just conditions of life, given how many people are succumbing to these diseases.

Well, heart disease is about 40%. So that's borderline, right? If it was 51%, it might just say, hey, too bad, that's aging. Yeah, well, dis-ease, right? It is a, you know, a disease is a condition in which your body is out of balance in which there is a lack of equilibrium and processes are not you know functioning properly so by that argument it makes perfect sense that you would qualify it as such well we can call it whatever we want you know it's it's our world we can create it ourselves and there's so there's no

law that says aging is not a disease just as there isn't a law that says it is a disease. But what we choose to call it really determines how we go after it, how we classify it. And classifications have a big impact on regulation. And right now there's no country in the world that considers aging a condition that can be treated. So even if a doctor had a pill that could treat aging, that doctor could, but it'd have to be off-label, prescribe a medicine to help you. That's crazy.

That's really crazy. Probably the best thing a doctor could do for you is to give you a medicine that would prevent pretty much all chronic old age diseases. But right now that's not possible because of the regulation. But we don't die of old age. We die of diseases that are precipitated by declining wellbeing, right? I mean, how does that, how do you think about that? All right. Well, so let's take cancer, for example, that if you smoke, it increases your chance of getting lung cancer by about fivefold. And we worry about that. We spend billions of dollars on trying to treat cancer and prevent smoking. Getting to the age of 60 increases your chance of cancer by a thousandfold.

Aging is the root cause of, by far, orders of magnitude of all of these diseases that we eventually get. They're not separate things. Aging is what causes these. How many people do you know that get heart disease and Alzheimer's in their 20s? Very few. The reason is because the body is young enough to fend off these diseases. So my approach to this is that if we can figure out why we get old and how to reprogram the body, the cells in the body to be young again, we won't get those diseases. And even if we have those diseases, the body can heal itself like we were 20 again.

Okay, so then when we age, what is actually happening on a cellular level? All right, so let's go back just 50 years to set the stage of where we are now, because it's pretty exciting times. 50 years ago, well, let's go back to the 1950s. Everyone was excited about radiation, or scared, probably is a better way to put it. And there are a lot of theories that were put out. So Leo Szilard, Peter Medawar came up with these theories about the mutation hypothesis that we lose our genetic information, mutations occur, and they accumulate during our lifetime. And that's what causes aging. And mutations largely occur by radiation that we're exposed to. It's like a breakdown in the structure of the DNA.

Right, right. So you lose the information in the structure of the DNA. Right, right. So you lose the information in the genome. But two things have happened just in my lifetime. First of all, that idea that mutations themselves cause aging has been largely disproved. You can make mice that have loads of mutations. You can knock out their ability to repair these things and they don't get old.

They live a normal, healthy lifespan. That's just one example of a whole litany of examples of why that theory from the 1950s is, in my view, most likely to be not as prominent, if not just downright wrong. The big thing that happened early in my career in the 1990s was the discovery that there are control genes that control our body's health and longevity. And so single genes control health.

So it's not as complicated as we once thought. You can make one mutation and an organism, whether it's a yeast, in the case of my work in vultures, Cynthia Kenyon's done worms. These organisms live a lot longer, ostensibly by mimicking fasting, calorie restriction, and exercise. And that was a big deal. That was a paradigm shift in thinking. There was a lot of debate and argument. We're all over that now. We all agree so essentially it's just so i understand there are specific control genes that you can identify and when you just tweak those it has that downstream impact that you're seeking right so the analogy would be you've got your your body is a car it wears out but what we didn't realize

until the 1990s what that but was that there were body shop repair people who go in and they constantly fix you. It's just that as you get older, they become decrepit themselves and they don't work very hard. And we've now got these genetic and increasingly pharmacological ways and dietary ways of getting them out of bed earlier in the morning and fixing your body. But then the next big change that happened was that we asked the question, well, what are these longevity repair genes actually doing downstream to keep the body healthy? In other words, why does calorie restriction work so well? And we in the aging field have come up with eight or nine, what we call the hallmarks of aging, the underlying causes of aging from telomere loss to

mitochondrial decay to proteins misfolding. But I think there's actually one of those pieces of the pie, one of those eight or nine, that's above all of them, that rules them all. And this is what I think is the basis of what I'm calling the information theory of aging. And how we came across that's a pretty interesting story that goes all the way back to my original days at MIT in the 90s. Well, do tell. Will do. So when I got to MIT, what I wanted to figure out, and don't forget, I was in a dream team of people, so I'm certainly not taking credit for most of this. But one of the things I was personally excited about was trying to figure out why don't yeast cells live forever? Because they're small, they're pretty simple.

And what we and the team for sure deserves credit for finding was that there's a set of genes in yeast cells, and also in our bodies as well, though at the time we didn't know it, that sense the environment. So when a yeast cell is hungry, or it has too much temperature change, you make it hot, you make it really cold, or you subtract out some amino acids, it will live longer. And that is because it's activating a set of genes called the sirtuins. And they're called sirtuins because their first yeast gene was called SIRT2. Now, what's key to this whole information theory is that SIRT2 is an acronym. It stands for Silent Information Regulator Number 2. Number 2 doesn't matter. But the Silent Information Regulator is a really big deal, and we didn't understand it at first. regulator is a really big deal and we didn't understand it at first. So just a little bit about genetics. Silent information is essentially a gene that

switched off and stays off and in yeast that's the genes that control whether a yeast cell is a male or female. So SIRT2, that gene was known already to yeast biologists in the 1980s to silence genes, to keep them off. And what the lab that I was in, Garenti's lab, discovered is that if you mutate these SIR genes, SIR2 and SIR3, SIR4 genes, the yeast cells live longer. We didn't know that a silencing gene would have anything to do with longevity. We thought that we'd find an antioxidant gene or something like that, or a mutation fixer. But out came this silencing, what we now know as an epigenetic regulator. And that was,

that blew everyone away, but it was very confusing. Why would a gene regulator have any impact on longevity? But what I think now is that the major cause of aging is a loss, not of the genetic information, but the epigenetic information of the body. So explain the difference between genetics and epigenetics. Right. So genetics is really easy. It's just the ATCG code in the DNA strand. It's digital information. Instead of being zeros and ones, it's four letters, chemical letters. And that genome is split up into various little sections that we call genes that typically make proteins. And they take care of us. But what we haven't really talked much about in the public is the epigenome,

because in part, because it was much harder to study. We've only just got the tools now to read the whole epigenome. But really put simply, if we could take a journey inside the cell and then delve into the nucleus where all the DNA is, we wouldn't see it just flopping around. The DNA strand is very tightly packaged in other proteins called histones. And those histones can be tightly bundled up with the DNA. Basically, DNA wraps twice around a histone and then moves onto another one like a bead on a string. And those histones come together very tightly to silence genes. So that's what the sirtuins do. They bundle up the genes so that they get switched off. Or the histones might be spread out and they allow the cell to read the gene. And that's how a cell

says, oh, these genes should be on when we're young and that cell should be a neuron and that cell should be a liver. And that's what we call the epigenome. It's the system that controls how the DNA is packaged and says to the cell, these genes should be on and these genes should be off. Essentially, the expression of the gene, whether it is expressed or not expressed, is a function of epigenetics. That's true, but I put it in different terms than other scientists that I know of. Because DNA is digital, the epigenome, if you look at it, is actually analog. And analog information is extremely subject to noise over time. It's the main reason we switched to digital.

And so the epigenome, the problem is that it has to be analog because even in the first life forms that had an epigenome, they need to change their gene expression in response to what we eat, to the time of day, whereas the genome doesn't change essentially. And so this analog system had to exist, but being analog means that it's very hard to copy. It's also very hard to maintain in a pristine state over a period of two weeks for a yeast cell or 80 years for a human. And so I'm fairly convinced given the work we've done over the last 10 years, a lot of it unpublished, that the reason we age is that it's the analog information in the body that's lost over time, not the digital. In the same way that a compact disc has digital information,

and if you scratch it up, you lose the ability to read the right songs at the right time. Right, that's super interesting. How does that square with this definition of epigenetics that's out there that's a little bit more kind of woo-woo ephemeral? This idea that you had a great-grandfather and he suffered a certain trauma

and that is expressed in your psychological behavior in 2019. Isn't that part of the epigenetic conversation? It is. It absolutely is. And so the epigenome, I think, is even more interesting than the genome, which gets all the attention. So the epigenome doesn't just tell your cell how to exist throughout your life and whether it should stay a liver cell or a neuron, but it also, you can pass epigenetic information from one generation to another. So if a yeast cell was stressed during its lifetime, its daughter

will also be. Inherit that stress. Exactly. And that happens to us as well. We've done some experiments in my Sydney lab at the University of New South Wales, where we stress the mother or we make her fat or we make her hungry. And the offspring, in the case of the fat mother, are prone to diabetes because of the epigenetic transferability. That's so fascinating. But the good news is that we've now, because we know this and how to control the epigenome somewhat, we can now treat those offspring and prevent them from getting diabetes.

That's wild. So controlling the epigenome, polishing that compact disc, getting the body to reset the epigenome to being healthy and young is what I'm focusing intensely on right now. And so to extend that metaphor, keeping that compact disc super polished,

making sure the integrity of the analog aspect, the epigenetic aspect of the aging mechanism is running properly involves this SIRT2, right? Like, let's get back to that, because that's where I'm starting to like, I don't quite understand what you're saying. Okay, so SIRT2 is sitting on these genes, bundling them up, and making sure that they stay off.

So let's say you're a nerve cell, a pristine young nerve cell, you're a 15-year-old or 20-year-old young kid. Your sirtuins, particularly three main ones, there are seven of them, three of them are doing this, they say, okay, all of the neuron cells, you don't want to express a liver cell, so let's keep that quiet for the rest of your life. That's what these sirtuins do. But the problem is, we find, is that the sirtuins have other roles besides keeping genes silent. They actually are very

important, particularly number SIRT1 and SIRT6. They are involved in repairing damaged DNA as well. And the worst type of DNA damage that they have to repair, the most fatal for the cell, potentially fatal, is a broken chromosome, what we call a DNA double-strand break. And in yeast, when I was back at MIT, we had a paper in the journal Cell that said that these sirtuins, they move to DNA breaks when they're needed, move away from the genes that they should be silencing. These genes come on temporarily, probably as a stress response. And then they have to prepare the break and then they hopefully go back to where they came from. The problem is we found in yeast, and we are finding this also in mammals, is that they don't always find their way back to where they started. And so over time, find their way back to where they started. And so you, over time, you lose the youthful gene expression thanks to the mislocalization of the sirtuins and other proteins, not just sirtuins,

but they're a bellwether of this, this seedy scratching. So they're sort of like ambulances or, you know, the California highway construction crew who's been dispatched to a certain, you know, pothole or problem, they fix it. But over time they start to, the radios don't work on the way home and they get lost. Is that it? Yeah. I couldn't have put that better myself. Right. And the worst part about it is that it's, it's a positive feedback in the sense that now you've got some, these pothole workers who've lost their way

and you're not fixing the potholes as well and you get more and more potholes which distracts these workers even more and this is why after age 40 particularly after age 50 you get this massive decline in health and we have actually engineered yeast cells and a mouse in a way that we can distract those seroproteins and see them age more rapidly, essentially create some few extra potholes and distract those workers. And we actually do see that aging goes faster. But the good news is, for the mice, anyone who's's worried about our animals we have ways of reversing that now and one of the things that you've discovered in the search to try to create greater functionality here is the impact of something called nad on this process, right? Exactly. So the sirtuins turn out to be enzymes and very special enzymes. Think of them as the crew that's directing the pothole repairs. Or like I said,

the body shop repair people. They literally modify other proteins to do a better job at repairing the body. And by modifying, they remove chemical groups called acetyls. And in doing that, they can actually have a much bigger impact on the body than just one enzyme alone. They control hundreds of other repair enzymes. But they only work, they can only remove that little acetyl piece off other proteins if they have NAD around. Technical terms we call it a co-substrate, but that just basically means if you don't

have NAD, the sirtuin enzymes, they can't silence genes, they can't repair DNA, and by the way, without NAD you're dead in a matter of minutes or less. It's like the key sustenance for sirtuins. Exactly. But NAD is a pretty boring molecule. At least it was until sirtuins were discovered. It's needed for basic biochemical reactions in the body. And you can find it in textbooks.

If you studied biology in college, you would have read about NAD. And before we came along, people had really forgotten about NAD. They said it's a housekeeping molecule. We know everything we need to know about NAD. And before we came along, people had really forgotten about NAD. They said it's a housekeeping molecule. We know everything we need to know about NAD. And then along come the sirtuins and it's, wow, NAD isn't just there to keep us to do chemical reactions. It's sensing how much food we eat, preferably less, how much we exercise, preferably more, and even things like hot and cold. And in the yeast cells, it turns out if you stress those yeast cells a little bit with those treatments, you turn on the ability to make more NAD for the sirtuins to do a better job. And so now you can have the sirtuins keeping those genes silent and also repairing the DNA and finding their way back

home much more easily. So NAD is the best way we know of to keep those sirtuins active and able to cope with that repair and silencing process. And as we age, do we develop a deficiency of NAD? Yeah, we do. That's the sad thing is that when you measure NAD in animals and also in humans, we have about half the levels we once did. Once you reach some almost 50 now, I haven't measured my NAD levels, but I would say it's probably based on the studies,

about half of what it was when I was 20, which is a scary thought. This is a molecule that's needed for life. We now know it's a molecule needed for the sirtuins. We've also found that many diseases are associated, if not caused by low NAD levels. And so I think one of the approaches that we're taking has a lot of promise, which is to give the body extra precursors to NAD to raise those levels back up to youthful levels and let the sirtuins do their work. And this is the NMN. That's NMN. NMN, don't confuse it with M&Ms.

They're not as good for you, probably. Probably not as tasty. Actually, I have tasted NMN, and it's pretty sweet. It's not a bad molecule. So often people wonder, what is NMN? It stands for nicotinamide mononucleotide. Actually, the nucleotide part of it interestingly is related to dna it's one of the early molecules that formed on the planet when we first had life

but anyway nmn is taken up by the cells you can eat it you can give it to mice in their water supply it goes into the body very rapidly and the body turns it into NAD in one step. And that step is what gets activated by stress. So go back to yeast, for example. When we shock the yeast with a lack of glucose, sugar, or give them a bit of heat or take away amino acids, they will make more NAD by converting this intermediate into NAD. And we think that's true for the body as well, for our bodies. When we exercise, if we go hungry, we see more NAD produced. Still over time, you lose it. And this is a product of hormesis, stressing the body to create a favorable downstream result. Exactly. So hormesis is at the crux of why exercise and dieting is good for you,

why calorie restriction makes animals live longer. And we didn't know that until the early 2000s, but all of this came together. And then we figured out for yeast, this entire pathway. And then we've been working on testing whether that hypothesis in, or at least that fact in yeast is true in us as well. And so far, it looks like it's surprisingly similar to what we learned there. So you've developed this NMN, I guess you would call it a supplement. Yeah, supplement product is something that you take. Your skin looks amazing.

There's not a gray hair on your head. You're 50, right? Looking very youthful. A good ambassador of the work that you do. And this is very interesting. So by supplementing this, you are basically taking out an insurance policy that allows your sirtuins to function the way that they're supposed to without this degrading impact over time. Is that an accurate assessment of the idea here? Yes, you've got it. And so I don't know whether these molecules that I take are going to be

helpful. But I do know that they're not hurting me, as you said. And if I'm around, you know, and all my colleagues are old, we'll know something is happening. But what's important, I think, for your listeners to know is I am trying to get these molecules at least tested, if not proven, hopefully, to work in people. And so that requires a lot of time and money and effort. Right. And so there are ongoing clinical trials. One of them's run out of Harvard University at the Brigham and Women's Hospital.

And we're early stage. We've just done the safety studies. But later this year, we should have a readout of what we call efficacy, which would be testing whether what we see in the mice, some of it is recapitulated in older patients as well. And eventually, I want this to be a drug that will treat diseases as well. Right. So yeah, so FDA approved the pharma route, not the supplement route. Right. It's very hard to straddle both. Actually, I think it's impossible to straddle both. And so I've chosen to take the pharma route because I want to be able to

have something that is proven to work, is safe. And I just think that for me is the better path for me. I want to be someone that is not conflicted, is not trying to promote anything. I never sell products or try to endorse anything. And so people can come to me or I can give lectures freely and people can know that I have no hidden agenda. But you have your hands in all kinds of companies out there. You're a very enterprising entrepreneurial scientist.

Well, I do, but there's nothing you can buy from me. So there's nothing I'm going to gain really immediately. But I do entrepreneurial activities, not because I'm interested in the short-term gain. I want to leave a legacy. And so I've had my eye on that goal since I was in my 20s. And that goal is to leave a mark. And I'm not just satisfied with publishing papers in these journals. I want to have a medicine, if not hopefully a few of them,

that will save hundreds, if not hundreds of thousands of lives. Thinking forward towards that creates a lot of interesting thought experiments around what would actually happen should your mission come to fruition, right? So is your mission to end aging as we know it like what is the specific goal that you're striving towards here uh well i'm not trying to end aging uh i'm i don't believe that there's going to be immortality but i do believe that the way we've been going about

medicine for the last couple of hundred years can be improved the way we've been going about medicine for the last couple of hundred years can be improved. The way we've been going about it has been take one disease at a time and study it and ignore aging and hopefully make a medicine to treat that. And so we've been very successful as a species making medicines that prevent and treat heart disease, for example. But what's that got us? We get an extra couple of years of life and that's all because other diseases are still coming along right behind. But we end up spending those years with other chronic diseases, and we're actually spending

longer times of our lives in a sick state than we used to. And that's really, to me, it's something you wouldn't even wish on your worst enemies is to extend life, but not extend health. Right. If you were to identify the sort of ultimate age that we could perpetuate, I mean, what is that? Is that 35? Is it 25? Is it 46? Is there a chronological period of time where you think the human mechanism is functioning at its peak and that's where we we could we should just sort of lock it in yeah well i don't know i'm 50 and i feel like i'm still 20 so i'm not seeing any decay so any any age between 20 and 40 50 is fine with me i mean clearly the athletes athletes lose their ability to perform at that level, but

I'm a mental athlete and my brain is far better than it was even a year ago. So I definitely don't want to go back in time, put it that way. But what's interesting about athletes is we're finding that because we know a lot more, they know a lot more about how to keep their body young, part, you know, part of what they eat, how they live. We're seeing these athletes, also actors, take Tom Cruise, are looking a lot and acting a lot younger physically as well than what we had just 20, 30 years ago,

previous generations. Yeah, are you working with Tom Cruise behind the scenes? Not Tom Cruise, no. No, but somebody else. Somebody else you don't want to say. Well, there are plenty of people I get to meet. It's a fun job, I put it that way. Right, right, right.

Well, all these billionaires who are injecting themselves with young people's blood, there's certainly a lot of interest in youth and longevity amongst the well-heeled. So I'm sure you've got a Rolodex of fascinating people that are trying to get your time. It's true. And I help as much as I can. And often I'm asked, well, David, you're working on these medicines and how come only super rich people get access to you? First of all, that's not true. I reply to every email that I can.

But also, it's similar to the Wright brothers, the phase that we're in now with aging, in that we know that we can build a glider. It's flying. We've seen that. We know how to do this. It's just a question of strapping on an engine and taking off and flying around. And we're building that.

But that takes entrepreneurs. It takes investment. And certainly the early 1900s required millions of dollars of investment. And who were the first people that were flying? It was probably wealthy people, people who knew others. And it's not so much elitism, it's just that's how all technology rolls out. And so I see this as going as rapidly as possible and my mission to roll this out to everybody on the planet. And not just wealthy nations.

I've pledged to make the drugs that I'm making available to everybody on the planet as soon as possible. Well, it is true that people are looking, you know, more youthful in their later years. And we're seeing athletes who are performing at a very high level at ages that people would have thought was impossible, you know, 15 years ago. And that's super interesting. And I would imagine that's a function of a multitude of factors, including, you know, people have to, these athletes have to make, there has to be a way for them to make a living so that they can continue to do this. But one of the things that was super interesting about the

studies that you've done on mice with NAD and NMN was the increased blood flow that was uh created that led these mice to have like this something like a 60 to 80 boost in their ability to like be on a treadmill and and and produce uh you know an athletic output i mean that i read that i was like wow like what's the athletic implications of that is this doping or is this like cool like what's happening here well it it's certainly cool science um whether or not it's it should be considered doping or not i'm not really sure because we're talking about boosting a natural molecule that's in your body anyway. It's increasing blood flow, right? It's like it's improving your vascular delivery system. It is. So let me explain how that works.

What we discovered was that the sirtuins, let's go back to those guys again, in the lining of your blood vessels, they're not very active as you get older. And one of the main reasons that you don't respond well to exercise, you know, if you're 70 or 80, maybe even younger, and you exercise, you still aren't a super athlete because they're, what we think is the major reason, one of the main reasons is that the lining of your blood vessels, the SIRT2 and SIRT1 is the main gene, doesn't have enough NAD around. And what was remarkable was that we could treat mice with this NMN molecule, just give it to them in their water supply,

raise the NAD levels back up to young levels in the blood vessels. And now we had old mice that, first of all, they acted as though physically they'd been training, but they hadn't been. But also if we gave them N and men on top of exercise, they became super athletes beyond what exercise alone could get them. That's wild. And it's super cool as well because one of the major causes of disability and frailty as we get older, even into our 60s and 70s, why do we feel tired when we're older?

It's because we don't have enough of this blood flow. And very few people have ever thought to figure out why that is. And so that's why we jumped on that. And so imagine, it's great for young people as well. I think it could keep people in tip-top shape, especially people who cannot exercise as much as they want, like myself, who types for a living. But more importantly, far more important than people like me, is those people who are already frail, people who are in bed or who cannot really walk very far, we give them potentially these NAD boosters, as we call them. Let's call it the MIB626, which is the drug form of what we're developing.

Give it to them for a few weeks. And they hopefully, what I hope is we'll see is they have the energy, they have the new blood flow, they can start to walk again. And that's a virtuous cycle, a positive feedback in a good way so that they get out of bed, they walk, they get more exercise and get back into mobility because it's the lack of mobility that ends up killing people. Yeah, yeah, yeah. And what are the implications on atherosclerosis? Like, can it reverse arterial damage and create, you know, greater plasticity? Like, how does that work? We haven't tested NMN on that, but others have.

And we find that this SIRT1, SIRT2, is extremely important for protecting the cardiovascular system from plaque as well as keeping it youthful. And so there was a study by Doug Seals at the University of Colorado, just to mention a much an independent study, they gave NMN to old mice and similar to the way we saw new blood vessels growing, they saw that the existing blood vessels had much better plasticity and resilience as well. And so the hope is if we can get these molecules to be super potent and targeted to the right part of the body, we'll have all of those effects on people. And does this also have implications for mitochondrial decline? Because isn't that another key aspect of aging?

Well, it does. And just to preface that, often what I'm saying sounds too good to be true. Because pretty much every time people ask me that, yeah, it does that. It cures this, it cures that. Well, first of all, we're still in mice. We don't know if it works in humans, but we're going to figure that out in the next year or so. But yeah, you asked me about mitochondria. We've published, these are all cell and science papers.

So these are top studies. These aren't just off the rack kind of stuff. So a lot of work has gone into them. What we showed in mitochondria was that raising the levels of NAD in cells fixed what was a really curious defect that happens as the mice got older. So what was that? What we found is that the organelles, the different parts of the cell that have different genomes, so we have the nuclear genome, our chromosomes, but we also have mitochondrial DNA inside those mitochondria.

We found that those two genomes were not communicating as the mice got older. And so we called it genome asynchrony. And it's essentially, if you want to put it into some sort of an analogy, a metaphor, it's as though when you're young and you're a young couple, the people get along. They're in this small apartment. They communicate well. But by the end of it, they're in this small apartment, they communicate well, but by the end of it, they can't stand each other, they're not communicating. We see that with the mitochondria. Staring at their phones at dinner, not talking to each other. Yeah. I mean,

imagine how bad that is for our bodies. And so we figured out why that occurs and traced it all the way back to the lack of NAD. So by replacing or replenishing the NAD, the mitochondria started communicating the nucleus. The mitochondria said to the nucleus, hey, give us some protein like you used to when we were young. And that completely restored the function of those mitochondria in the muscle. And so we called that reversal of aspects of aging. In fact, those muscles that we looked at in those mice, those mice were two years old. And within just, I think it was two weeks of treatment, they were just like a young mouse. Wow. Implications are insane for something like this. I mean, that's amazing. Are there any negative consequences of this? I just feel like there's often a hubris in humans with this sort of thing

and our reductionist scientific method to zero in on one thing and we see this positive implication and we are blind to all these other aspects of what goes on because it's a holistic machine. There's a lot going on. There's a lot of dominoes that are stacked up against each other here. That's right. And part of the problem, I think, with medicine and why pharmaceutical industries had trouble making drugs with outside effects is that they are, first of all, that they're using synthetic molecules that the body has never seen, in part to have patent protection and supercharged molecules but also the problem is that they're intervening in aspects of the body that normally don't change and it'd be like revving up a mini cooper's engine

but not making sure that they have the right gearbox and tires to deal with it. And so the approaches we take, we try to change those parts of the body that changes naturally when we exercise or when we diet. And that's why philosophically, I'm less concerned about side effects because we're really just replacing what we've lost with age, similar to the NAD levels. But are there side effects? Well, we haven't seen any. We've just been giving NMN to mice for the last year or so. We haven't finished the study. And thank you to all of the people online who crowdsourced, funded that study. But we're already seeing a lifespan extension in those mice. And so that's exciting. And every time you see a

lifespan extension in the mice, it's hard to argue that we're hurting them. Now, maybe there's something going on, but maybe they're depressed or something. But other than that, they are otherwise perfectly healthy. Now, again, these are mice. We haven't treated humans. So that's why we're doing these safety studies. I don't stay up at night worrying about the side effects given what I've seen over the last year in many years in many labs across the world. There have been thousands of animals treated with these molecules. Nothing that rings alarm bells. But if you wanted to push me, right, Rich says, David, you got to come up with one thing

that you could see might be negative. It would be blood vessel growth. If you have a tumor already that needs a good blood supply and we grow more blood vessels, that would not be good. And so that's actually why we've done a couple of studies in mouse cancer models and given them NMN. And the good news for the listeners is that we've not seen any deterioration or acceleration of those cancers. And in one case, we saw that the tumors grew much more slowly than without the NMN. But that doesn't really mean that it's perfectly safe. So that's, it's one of the reasons why I'm doing these clinical trials is that, first of all, I want to be the first person to know if it's unsafe. My family definitely wants to know that. But I want to be able to sleep soundly knowing that I'm

not doing any harm to anybody. Yeah. Me being a non-scientist, I've been operating under this idea that, you know, part of aging is a result of free radical damage and that we should be eating a lot of antioxidants to combat this free radical damage. And when you were talking to Joe, you were sort of dispelling some aspect of that conventional wisdom. So can you explain that a little bit? Yeah, so free radicals are part of the story, but really it looks like just a minor part of it. So free radicals will cause DNA damage.

We know that. And it'll cause those DNA breaks that scratch the CD. So I'm not saying that they're not completely, that they're irrelevant. But I'm also... Cell oxidation. not completely, that they're irrelevant. But I'm also- Cell oxidation. Cell oxidation, you don't want it. But let's go back to that car analogy. I think we've, in terms of the free radical idea, it's as though we've said, hey, you

know what? The windscreen wiper blades are old. Let's replace those. Let's fix those windscreen wipers. Not realizing that that's the least of our problems. We've got other things that we could do to keep our bodies healthy. And so there's a lot of studies in the world now where people have tried to use antioxidants and failed to extend lifespan in animals. There are some success stories. But you can also think of other reasons why those

molecules, those quote-unquote antioxidants, have actually worked. And one reason that I think is plausible is that those antioxidants that typically come from the plant world are engaging the body's sirtuins and other survival longevity mechanisms. So that they're not only mopping up free radicals, but they're engaging our survival systems as well. And resveratrol would be one of those. Right. So that's what got me started thinking about this. But if you look into the science of this and the literature, pretty much every molecule that we take in from plants

that has medicinal properties, let's say ECGC from tea, what else? So aspirin is also a good example. These molecules have so many different effects on different parts of the cell, different pathways, and so they might activate AMPK while they're inhibiting mTOR, while they're activating sirtuins. That cannot be a coincidence, that these plant molecules have all the right impact on these longevity pathways.

It's as though we've, I would say the only explanation, no, take it back. The main explanation I think is that we've evolved to sense the plant's stress conditions so that we hunker down when we're going to run out of food. There is one other explanation that is that these molecules in plants, we make something quite similar, but we just don't know what they are yet. So there might be a human resveratrol that we haven't found yet. Right, right. And so basically the resveratrol, which is an antioxidant, is also a plant's stress response to some external event, right? In order to defend itself and make itself stronger. And by taking that in, we're having a similar impact on our own cell structure. That's exactly right. And so we found pockets in proteins that sense how much resveratrol is in the

body. SIRT1, the SIRT2 that I've been talking about, has a pocket that resveratrol sticks in and it activates it. We know that at great detail down at the atomic level. But these other molecules also happen to bind at the right place on these proteins. So it's exactly what you said, which is that when the plant is stressed, it's making its own molecules like resveratrol to survive. Plants have sirtuins. Sirtuins are found even in bacteria. And I don't think the plants are trying to make us healthy, but we use them as a way to make ourselves healthy. And we've learned over the last few thousand years, or maybe longer, that if you eat these types of foods at this time of year, and you bottle it, and keep it dark, and put some alcohol in there, it'll preserve

those molecules, and you'll get some health benefits as well and you might get tipsy as well. But we've had to do that empirically rather than knowing exactly how it's been working. Right. And it's problematic as well because it's not as binary as we would imagine. There are all those beta-carotene studies. Like if you take a super dose with this, it will combat all these things and make you healthier in all these different ways. But whether it was a bioavailability issue or, you know, it's like when we extract these healthy aspects of a plant and take them in a singular dose, it doesn't quite have the impact that it does when it's in the complex matrix of the plant food itself. 100%.

You've hit on something that I think about a lot, which is, so we've been just taking the plain resveratrol molecule, but when you drink it in red wine or you take it in its natural form, all of these molecules are coming with a cocktail that's probably finely tuned. Our bodies are finely tuned to. And also what we find is these combination of molecules are actually synergistic. So for example, if you take quercetin, quercetin, some people call it, at the same time with resveratrol, they will both last longer in the body.

And by separating these out, which we like to do as reductionist scientists, we're losing some of that. And also the other problem is that if you're just using a plain chemical like resveratrol or quercetin, these are fairly insoluble. So most of it doesn't even get absorbed. It's only when it's in its natural state, when it's combined with sugars and in many cases fats, that's important to help the uptake. And that's why often when people ask me how much resveratrol would you need to take to have an impact, I have to be careful

because, sure, if you take it in its pure form, you need hundreds of glasses of red wine. But if you drink a few glasses of red wine for a decade, not that I'm advocating that, but there are some signs that that combination of molecules with the alcohol that helps the absorption could be way better, way better delivery vehicle than just eating a spoonful of this powder, which is like brick dust.

Right, right, right. Other than red wine, what are good sources of that? Of resveratrol? Very little is in the food supply, unfortunately. It's a little bit in nuts and of course grapes, but it's very hard to get the quantities besides in red wine. And buying it in powder form, I mean, how much of that is just paying for expensive urine versus real impact? Well, so I don't really know that, but I do know that if you take it with fatty foods, so I take it with yogurt or something that at least will help absorb it,

that it's very helpful. Fat aids with the absorption. Oh, yeah. So we saw levels in mice and humans that were 5 to 10-fold higher with some fat included. And actually we had much better results in the mouse studies when we gave them resveratrol in a fatty diet. And what is it about resveratrol that makes it superior to say something like turmeric,

which is also a powerful antioxidant? Are they qualitatively different or can you switch these things out for each other? I don't know the answer to that um i've actually spent less time studying resveratrol the last decade because i'm more interested in some of these other things and the nad well and now we're beyond that as well with that's certainly exciting it's heading in past the clinic hopefully um trying to figure out what the scratches are on the cd is is is a major focus of my lab right now. So I think that what the future looks like is that we hopefully will be able to take some of these longevity stimulators.

NMN is just one of them, of course. There's senolytics, which destroy the zombie cells. We've got metformin, which seems to be beneficial. metformin, which seems to be beneficial. So I don't want to basically annoy all my colleagues who have spent decades showing that their pathways are important too. But these are mostly preventative. What really we want to do is get you out to 90, 100, 110 healthy, but eventually things will wear out. Things will still decay, even with these treatments. They're not that good, even with a healthy lifestyle. So the new work in my lab is,

what do you do when you need a new kidney, a new liver, or you lose your eyesight? Can we tell those organs to be young again and literally make it young again? The difference between prevention and reversal, basically. Right. You know, it's interesting, Rich, that I think I was one of the first people, crazy people, to use the word age reversal in this field. It was a no-no. Shame on you. It was not well-received, I imagine. It was about five years ago. Now it's fairly common. It's

funny. It takes a while. But you used to be able to say delaying aspects of aging, that was the limit. But it's clear from work that we've published and work that we haven't yet published, that reversing aging is really easily doable. We do it all the time in my lab. I mean, similar to, you know, once you know how something works, the answer is pretty simple. Best analogy is, you know, Joseph Lister said, hey, let's wash our hands before we cut off a person's leg or deliver a baby and save millions of lives, probably right now a billion lives. For goodness sakes, we solved this with soap. Same with aging. Once you know how simple the process is is it's not that hard to fix well we all are familiar with

this concept of of biological age versus you know um what's the other one like experiential age like you know how we look and feel isn't necessarily wed to that our date of birth. So on some level, we have a fluid understanding or conceptualization of aging. Some people look older and comport themselves like an older person than somebody else who's exactly that same age. So clearly there's something happening here that goes beyond just pure genetic blueprint that we can influence through diet, lifestyle, and some of these other factors that you're exploring now. Yeah. So less than half. By some estimates, only 25% is determined by your genetic makeup, and the rest is how you live and your epigenome control, which is great. It means we have much more control over our lives than we thought we did. And we see that now,

that the impact of diet is just incredible. What is the biggest thing that we have control over? What are the most important things? Sure, well, if there was one thing that I could say, if there's one thing you could do, it would be eat less. That's the main thing. And I know you've had plenty of people. Right, we've had Walter Longo,

who's discussed this at length with his intermittent fasting and his fasting mimicking diet and all of that. And I know this is something that you practice and are on board with as well. So what is going on with either calorie restriction or the way that we time our intake of food that has implications on aging or its reversal? Yeah, so calorie restriction is the most robust way to prevent cancer, heart disease,

pretty much all diseases. It's been known for since 1916 and then a very classic study in the 1930s by McKay and colleagues. So we all agree that calorie restriction or intermittent fasting these days works. The question is how. And what we've found is that some of the pathways that we study in the aging field, sirtuins are a major part. mTOR is the other, which Voltaire has talked about on the show. These are pathways that respond particularly to how much we're eating. And if we eat a lot of food, they stop defending our body or telling proteins to defend us. And if we eat less, what happens is they get kicked into action and they do a whole range of things that protect us from disease and even can reverse aspects of aging. And so just to focus for a little bit on the sirtuins, because we're on that theme, So just to focus for a little bit on the sirtuins, because we're on that theme, when you are hungry, your NAD levels go up.

And so now your sirtuins are quite active and repairing the body, and they can make sure that the body doesn't lose its epigenomic stability. In other words, keep those scratches from accumulating over time. And the longer you do fasting over your lifetime, the slower those scratches will accumulate. And so exercise as well raises NAD levels. And your listeners might be wondering, why would exercise and diet turn on these pathways in the first place? Well, what we think is going on is that in early life, in the primordial ponds, there were,

so picture early Earth. There's Earth's covenant ocean. There's these islands and there's little pools. And we think that's where life formed. This is the cutting edge science right now. In those pools are little strands of RNA that have come together from chemicals from meteorites. First cells are forming. Those first cells need to be able to control those genes on and off. So when do you want genes on and off? Well, responding to stress. So if there's a cosmic ray coming and hitting and smashing that genome of that little organism, it needs to have a system to defend itself, to hunger down, survive, and then repopulate that pond when all the other organisms have otherwise died off.

So there's extremely ancient genes that we have inherited from those forebears of ours. But now we can kick those survival genes into action by putting our bodies under a bit of stress, hormesis, or eating plants with those molecules that signal stress. We call that xenohormesis, xenomeaning between species. And that is right now, with the exception of some clinical trial proof, that exercise and dieting is really the best thing we can do for our bodies. Wow. When it comes to fasting, is there any indication like i'm trying to get a sense of can you do it too much are people who are doing these 30-day water fasts are they getting any additional

benefit beyond somebody who's doing vaulter's fasting mimicking diet which actually involves eating you know meals throughout the day or do we still have a lot to learn here well yeah we always have a lot to learn but we know a heck of a lot and more than we did a few years ago what we've found in mice as a field is that and just a study that came out about a month ago from rafael de cabo's lab at nih found that it's it's not so much what you eat, but when you eat. That's so important for those animals and probably for us as well. That doesn't mean that we can just eat whatever we want and go hungry. I think it's a combination of the two things.

And that's what I do with my own body as best I can. But primarily, you need to be hungry a little bit, preferably every day, but at least a couple of days a week, I think. That hunger creates that stress response that gets the sirtuins doing what you want them to do. It does. The body shop repair people actually get your NAD levels up. And you can do that with being a little bit hungry. You can also do that by restricting the total amount of protein that you bring on board.

So eating a lot of steak would be about the worst thing you could do. Never exposing your body to any changes in temperature is probably another thing. Basically, everything that makes your body happy and sedentary and unstressed is bad for you. And the reason is that you're not engaging your survival circuits, as I call them. And how does that square with studies that are coming out about sauna therapy or cold water therapy? I mean, these are other stressors, right, that I'm sure are having cellular implications. Well, they are, but we don't know a lot.

cellular implications? Well, they are, but we don't know a lot. I'm unaware of any rigorous studies of cold therapy or even saunas, but we do know from anecdotal and historical records that even the Romans knew or thought they knew that heat and cold was good for you. And a lot of northern countries swear by it. At least once a week you want to go into that sauna and then jump into a cold pool. Now, I don't know if that works. I don't think anybody really knows if it works. But what I can tell you is that it does fit with the hormesis idea that we studied yeast years ago. And what I found was that

when you raise the temperature of a yeast cell, it will turn on the sirtuin pathway. It'll make more NAD, give it a bit of what we call a heat shock. We do know that if we cool our bodies down, we shiver a little bit, it will build brown fat, which has a lot of health giving properties as well,

boost those mitochondria, which is always a good thing. So that fits with the science. So that's why, besides the fact that it feels really good and invigorating, I think it's also going to turn out to be healthy as well. Yeah, I think there are some studies that are happening around sauna on vascular health and things like that. I'm not steeped in it, but I know there's certain things that are happening. Yeah, there are some studies. I'm not steeped in it, but I know there's certain things that are happening. Yeah, there are some studies.

I agree with you. There's one, I think it was a few thousand Finnish businessmen who regularly take saunas, and they had protection against heart disease, apparently. It's early days. But, Rich, you asked me earlier, and I haven't addressed yet, what's too much? And I definitely think you can do too much of anything.

And we call, you know, in hormesis, there's this U-shaped curve, inverted U, so that you just have to find the optimal. And that's really tricky, not only because it's hard to know if you're overdoing it. We don't know what those parameters are. We barely know what the biomarkers are if you were to measure them in your blood. But also because it's different for everybody, that your optimum might be different from my optimum. And it's certainly different for men and women and people of different ages. So Volta Longo mentioned that you might want to restrict your protein when you're young,

but when you're older, that will come back to bite you. So there's a lot of variables here, and it's extremely difficult for us to to test one human group let alone all of the different variables well the way i do it is i just overdo everything let the chips fall as they may right so that makes not a good plan yeah right this is the the zuckerberg way it's a fail fast sure but you know i really think that that overdoing it on on your physical body so running over doing it with running for example uh playing some very uh high impact sports we just know already that those are people who tend to have to have their joints replaced in their 50s my joints are pretty good right now but you, you know, back's a little creaky, you know,

ankles are a little stiff when I wake up in the morning, you know, it's like going out and crushing it and putting in giant miles all the time. I mean, you know, this is not a recipe for, you know, maximum longevity. I'm aware of that. But I also, it makes me feel great. Like I, you know, there's countervailing, counterbalancing, you know, aspects to all of all of this well do you measure your biomarkers do you know what it's doing um probably not as precisely as as you would i've had blood work done and um my blood work is fine in fact i'm getting it done again quite soon uh but it's been good uh i tend to get adrenal fatigue that's like the main thing that i have to worry about because I'm just a work hard, play hard person in general. Yeah. Well, if you overdo it, you can also be

susceptible to infections, getting colds pretty badly. I never get sick. I don't have that problem. That's a great sign. One thing that's in common with all of the people that live a long time into their hundreds is that they say when i was younger throughout most of my life i never got sick all right well i got that going for me but i will tell you this my my grandfather um died of a heart attack at age 54 i'm 52 and i've been plant-based for 15 years and an athlete and all of this sort of thing but it started it started to really occupy a lot of mental space because i very much share his genetic blueprint and you know we look alike we we've made similar decisions in our lives we've lived our lives very similarly and it it definitely has me you know a little more freaked out than maybe it should because of that genetic predisposition to heart disease that runs in my

family and despite things i've done to countervail you know to to live my life in contradiction to that um i know it's it's sort of looming there and so what should i be doing well do you know what genome you have i should have that tested i have you haven't tested your genome so we have to hook you up with one of my good friends at stanford you're at stanford's i know that so it's apropos that you go see my good friend carlos postamante uh he's the the dean of uh yeah he's the guy out there he's the guy he's done some pretty important genomes historical uh so kennewick man that kind of thing. He will help you interpret your genome. You can have it done at some of the commercial places if you want.

That's what most people do. It's pretty informative. I found it's not just for fun. I found that I carry some pretty bad genes and I'm modifying my life based on those. And actually to bring it home, my wife has predisposition based on her genome for ulcerative colitis. And she actually ended up quitting her job and doing what she always wanted to do because she figured that she was going to have a shorter health span than most people. And she's modified her life and her diet. And so far, so good. I won't say how old she is. That wouldn't be polite. But at the same age that she is now, her mother was suffering from ulcerative colitis and now has no bowel. And it's not very great for her. So I think that the genome is important to know. I know some people say they just don't want to know.

There's definitely part of me that, because that sets in motion a series of decisions that you make about your life based upon something that may or may not come to pass. So I definitely have concerns about that. Well, let me tell you a story about myself. I had my genome done. I did it at 23 and me, and then I had it done, full genome. And I found out that I carry a susceptibility gene to emphysema, COPD, and that my lungs are not very good at clearing out toxins from smoking. Now, I've never smoked. I'm a militant against smoking, in part because my mother died from smoking. And guess which parent I inherited that gene mutation from? From your mother. It was my poor mother. If my mother had the information that she had after her lung was removed and eventually died from, she probably would have

quit smoking earlier rather than waiting until she had one lung. So you can really be empowered by this information. And I try to avoid dust. I try to avoid secondhand smoke for that reason. Going back to something you said earlier, you said it's important to keep your amino acid, your protein intake low. So explain why that's important. Well, it comes down to an enzyme complex called mTOR. And it's called target of rapamycin. So rapamycin is a... It all started back on Easter Island. We had Sehgal, which is...

He was a scientist who went to Easter Island, or Rapa Nui, which is why it's called rapamycin. And he found bacteria that had this peculiar molecule called rapamycin. And his lab was at Columbia University, and eventually he ran out of money and he was told just throw away all your stuff in your freezers. And he decided not to, and thank goodness he didn't because his freezer was the organism that gave rise to this rapamycin molecule, which is now used to treat a whole variety of ailments, mostly immune disorders, but possibly even aging.

And the reason that we're excited about rapamycin, or at least molecules like rapamycin, to treat aging is that if you disable mTOR or you give rapamycin, which is essentially the same effect, what you do is you trick the body into thinking that it's got a deficiency in amino acids. So mTOR has been around very long time, similar to sirtuins, but its job is to sense how much meat or amino acids or protein is coming into the cell and the body. So if you eat a lot of meat, what you're doing is you're telling the mTOR system, times are great, lots of protein, don't worry, go reproduce, grow, build new tissue, but at the expense of hunkering down and repairing things. And so if you're always

eating meat and always eating a lot and a lot of protein, your mTOR system won't bother to defend you because it'll always be on. And the on for mTOR is actually the anti-longevity. It's the growth and reproduction path versus the hunker down survive mode. Right. So longevity dictates that you want to be doing what's necessary to signal your body to enter into that reparative mode. Right. And that's at odds with when you're younger, you want performance gains. If you're an athlete, you want to build, you know, big muscles and all of these things that that's all fine, but you can't have both. all fine but you can't have both it's very hard I would I would say and and people who are who grow fast are have to be extra cautious because their bodies especially when they're young are spending more of their energy on growing than hunkering down and this is a fact, but it's probably depressing to some people that at least in dogs, and it looks also like in humans, that if you've got a highly active growth system, a lot of growth hormone, it will work against you later in life.

But again, a lot of it's in the control of our environment. If you're a tall person, I'm not, but if you're super tall, I think it's even more important to make sure that what you eat and how you fast and how you exercise is optimal if you want to live the maximum potential lifespan. I have a lot of friends who get testosterone therapy and can get HGH and all of these sort of things. And the idea is it's boosting their virility

and their energy levels and all of that. But I can't help but wonder what the implications are on their long-term wellness and well-being and longevity. Like there's an evolutionary rationale why these things decline over age, right? wellness and well-being and longevity like there's a there's a evolutionary rationale why these things decline over age right uh well you could say the same about nad that it declines and it's not good to boost it so i think that that that's dangerous to use that argument that just because something goes down it it's meant to uh-huh but there have been millions of dollars poured into clinical studies with testosterone

with no benefit to health span, and I believe lifespan as well. And so in our field, we actually regard those studies as somewhat of a failure to deliver. And so I think that the evidence is there that it will give you, testosterone probably gives you great benefits if you're exercising, you can build up more muscle, you're more, quote-unquote, virile. But in the long run, it doesn't help you and probably hurts you. Because it's signaling your body that it doesn't need to produce it on its own? Or because it's stimulating growth in areas that you don't want growth? That would be my explanation.

I don't know for sure. But I think just telling the body grow, build muscle all the time is basically sending the wrong message for a long lifespan. Right. What about exercise? What's happening when we exercise and how is that impacting aging, longevity? Well, first of all, let me tell you what exercise isn't it's not just making your blood flow around your pipes and cleaning them out that's what i was led to believe in the 1970s what's actually going on majorly is two things one is it's activating these longevity

pathways in your bloodstream and i've mentioned earlier that the sirtuins are a major part of that but it it's also having highly anti-inflammatory effects and it's able to change the way our bodies actually respond to it the environment exercise is a treatment for the body that actually puts the entire system in a state of defense. And so it's less about getting the blood to flow and more about getting your tissues to act younger. And that's really the huge benefit that you get from exercise. So why can't we diet and exercise ourselves into immortality? That's a good question. Because I think that these defense pathways are not perfect. They don't know how to fully reverse the scratches,

polish off the scratches on the CD. Sure, they can slow them down, but as we lose our epigenetic information, our ability to read the right genes at the right time, that's beyond the expectations of the sirtuins and mTOR. We need something more potent to really reset the body's clock. Now, the body's clock, we actually understand a lot more about that now. We can read that clock in our blood and in our tissues and it's at the level of the genome and the changes to the genome. We've been working on ways to actually reset, literally reset that clock. And that would be the way to not just live an extra five or ten years

in a healthy way, but potentially take a 90, 100-year-old and make them feel decades younger pretty quickly. Wow. So what are the big questions that you're wrestling with right now that you're trying to get answered? And what would be the studies that you would like to see conducted, the research in your perfect world, that would help you make the breakthroughs that you're attempting to make in this? Well, the hot area now,

as the NAD boosters move into drug development, so that's on its way. What's coming down the line that isn't well known is called cellular reprogramming. This is truly resetting that epigenome. What it is, it's essentially telling the cell, can you go and find the information that once existed when you were young and ignore all the other information that's accumulated over time. We call this epigenetic noise in my lab. It's a term that we've had to coin because we've run out of vocabulary. So epigenetic noise, as I mentioned, is caused by mostly DNA breaks and

other things that occur to us. But how do you say to the cell, your DNA should be wrapped up in those histone proteins this way and just ignore all those other changes that have occurred? So we think we've found a way, at least early days. I don't know if you and your listeners are familiar with the pluripotent stem cell technology where you can take a skin cell and turn it into a stem cell. Now explain that. Yeah. So there's a famous scientist called Shinya Yamanaka, and he won the Nobel prize in 19, oh, sorry, 2012. And what he found

was that by turning on four genes in cells, and they can be hair cells, skin cells, liver cells. You can take an adult cell and make it super young again so that it now is what we call a pluripotent stem cell. We call them IPS for short. Those can be made into any other cell type, such as an egg or a liver cell. Whoa. So you could literally take any human any human cell, pull a,

pull a strand of hair, extract a cell, activate those four genes and end up with this stem cell. Well, not only can you, we all do it now. It's commonplace. Every graduate student, it typically works on this stuff. So it's commonplace. But the trick is, how do you use that technology for human health? And we're just learning how to do that now. But what's crazy is I could take your skin cell and I could make a sperm out of it. I could make an egg out of it and I could make a new you that way. It's crazy stuff. That's crazy. But it's doable. But getting back to aging, what does that mean? Well, what we decided to do with some other colleagues who are also in this field, there's about four of us, turn on those Yamanaka factors, as we call them, those reset genes, not in

a cell in the dish, but in an animal and maybe one day a human. Because maybe we could use them to partially reset the age of a cell. We don't want to go all the way back to beginnings we don't want to turn us into all into a stem cell that would be the end of us would be a giant teratoma or a giant cancer tumor but if we could just do a little bit just pulse the body so that it goes back to its earlier age that that would be the big bang in biology. That's just straight up out of a science fiction movie. Well, that's what a lot of us thought. Your face just lit up like a Christmas tree, though.

Like, this is definitely what gets you excited. Well, it does. And it did sound like science fiction. And that's why it took me a couple of years to convince my students to work on it, because they thought it was crazy and it would be impossible but then there was a study that came out from the sulk institute down in san diego from juan carlos belmonte's lab and he did that crazy experiment before we had a chance to do it he gets full credit what he did was he made a mouse that he could turn on these four yamanaka genes in the

animal once it was an adult and ask what happens and what happened was after two days the mice died okay that's not going to win you a nobel prize that's that's not that's not a good start that's a bad day for the mouse especially but what he figured out was that if he switched the system off on that second day the mice were fine well they recovered but they ended up being much healthier and he did this in a what we call a progeroid mouse model but that just means a mouse that ages rapidly it's the same essential mouse that you can find those young patients who age prematurely right the poor kids that get old when they're 13. There's a mouse that is a model for that disease. So the Belmonte lab, they turn on these genes every two days out of a week,

and then, no, it's every two days, and then they wait another two days, and they turn them on again. Those mice live 30% to 40% longer. Wow. So it's sort of like they're getting pulsed with it. Right. So the argument, if you want to criticize the work and a lot of people have, is that they're just making mouse, the mice sick and it's a form of hormesis. But I didn't think that was true because we've been working on this reset button for ages and we thought that was probably the the secret and one of the things we

did was we we had tried a whole bunch of genes for resetting and they didn't work but now we saw that those yaminaka factors could be important and so what we did was we first of all we wanted to figure out why are they toxic what why is it hurting the the animals and so we left off one of the genes that was really toxic it It's called MYC. And MYC is already known to be a cancer-causing gene. So that didn't take a genius. But when we put in three out of those four genes, it turns out that the mice are perfectly fine.

They don't get sick. We've now put it into mice and they're perfectly fine. But what we're seeing is evidence of regeneration and age reversal in those old mice. And because you're seeing it in mice, what does that mean in terms of human health? Granted, it's not a one-to-one ratio. Because you see a 30% to 40% increase in lifespan in a mouse doesn't mean that's going to work in humans like what are the similarities and differences when we move you know up the food chain to more complex organisms yeah right so the it's fair to say that we've cured cancer in mice a thousand times over

it's a lot easier to do things in mice for some reason extending lifespan in mice may be much easier because they only live a few years, whereas we live 80 on average. But these fundamental mechanisms that I'm describing today are found in everything from a yeast cell to a plant, many animals, mice, of course, and us. So these aren't just some esoteric pathway. These are fundamental mechanisms of living things. pteryg pathway, these are fundamental mechanisms of living things. So my philosophy is that as long as we don't do any harm, there's a very good chance that what we can do in a yeast cell, a worm and a mouse will also work in a human because a yeast to a mouse is 99.9% of the way there. It's just that little bit of extra difference. But if you ask a yeast cell,

we're basically a giant mouse. Wow. So in your lifetime, our lifetime, I guess we should say, I don't know what lifetime means given the work that you're doing. Lifetime doesn't mean what it would normally mean, I suppose. given your aspirations, where do you think you will see all of this in, you know, 40 to 50 years from now, like during our typical lifespan? Yeah, what's a typical lifespan? It's hard to see where the world's going by looking backwards. In 1902, would we have predicted that we'd be flying jumbo jets and flying to the moon? I don't think going to the moon. We're pretty terrible at predicting. We're really bad. Right. So Arthur C. Clarke said it's a very dangerous profession that he was into predicting the future, but I'm

happy to do it. You know, it's nothing, no harm in trying to see what the future looks like. And I have a front row seat. So, you know, I'm partially qualified to make these guesses. So what I see for the future is, first of all, that there are two futures. One is if no aging research is successful, what does the world look like? And that's a world that's still pretty good, but it's not great. Pretty good in the sense that the trajectory is that a child born today in the US will expect to live to 104. Remember that this child is going to see the 22nd century, what great things will be available for them, who knows. But even if,

so even if we don't do anything, we're going to have longer lifespans. By the way, in Japan, it's 107. So this is, it's not crazy to say that people will be living into their hundreds. Even given the exploding obesity epidemic and the increasing rates of heart disease and type two diabetes and all of these, you know, chronic lifestyle ailments that are being driven by, you know, our habits and our diets. Yeah, that's a real problem. In fact, by 2050, half the world will be obese. Can you believe it? So that's a real problem. In fact, by 2050, half the world will be obese. Can you believe it? So that's actually one of the developments that I'm working on, developing drugs.

One of the companies that I'm helping is working on an anti-obesity drug that I'm hopeful will be of a large impact. I've got a drug for that. What's that? Move your body and change your diet dude yeah right i know i don't mean to be insensitive there's there to the to the to this epidemic but i think there's a lot of people that just struggle with adopting healthy lifestyle habits correct but even with the obesity epidemic which which is slowing our progress, that line extrapolates to 104.

Now, these are just numbers, right? These are extrapolations. But I think if we're successful with the mTOR inhibitors, rapamycin analogs, with metformin, if it's able to be widely distributed, not yet, but hopefully one day if it's safe enough, and what I'm working on and other things, that we could expect to live decades longer. So in the future, in 50 years from now, the technologies could be remarkable. So think of this. I'm pretty optimistic, but the rate of change in technology still makes my head spin.

This reprogramming stuff, we've only been getting results since May of last year. And we're making advances in leaps and bounds. We've now reversed the loss of eyesight in old mice and other eye defects. And that's just the eye. If this reprogramming really works and it's safe, then all bets are off. Then we could turn back the clock by decades. It's looking like. Now, it's really early, and I don't want to get everyone upset that I'm over-speculating. The caveat is that it's early. But if you'd asked me three years ago, what's the biggest breakthrough, I would have said caloric restriction memetics and exercise memetics. But this true resetting of the clock

is something very different. It's a lot more powerful and potentially dangerous, but there is that glimmer that we've finally figured out why we age and how to turn it back. And that resetting the clock really resets. It's not just lifespan, it's healthspan, right? It's not just living to 104, it's being vital in those later years. Like most people really don't want to be 98 years old and completely feeble and dependent upon people around them just to go to the bathroom and get dressed. Right. Well, most people, myself included, look at what life's like of a late 90-year-old. And I think, God forbid, I don't want to be that age.

And it's fair enough. But what we have to remember is that we're going to extend the healthy period of life so that when you're in your 70s, 80s, 90s, you don't have to worry so much about getting cancer and heart disease and dementia, which is a huge growing problem. And we hope to compress the last period of life when you are sick, the period of morbidity, as we call it. And that's true in the animal studies that there's this what's called the Gompertz-Makum mortality curve that we draw as scientists. And it's a curve that shows that for most of the time people are alive

and healthy, and then you get this exponential drop off of people. And that's true for worms and yeast as well. And that happens really quickly. But there's this tail. Now what we're trying to do is push that curve out as far as we can so that hopefully everybody one day gets to live to 100 or whatever we choose, 130. And then that period is maybe a week of being sick and then you die quickly. Or actually you have the choice to terminate your own life when you're done with it. It's super interesting. I mean, we've seen over the years as science has progressed, increases in lifespan.

You know, we used to die at then 50 and 60 but as you mentioned you know in the introduction of your book we haven't seen the ceiling change that much you know the oldest recorded person is something like 122 and it's very unusual for anyone to live past 110 that was true way back in the day and it's still still true today. Even though we're living later, we're not busting through that glass ceiling on what's possible. Well, exactly. Until now, until the work that you're doing. Well, I think that's the point, Richard. You're right about that, is that if you look at the history of humanity, it's not a guide to the future. Again, the same way that in 1902 you would have

said humans are not supposed to fly, same thing. We've got now technology that will, we think, change the way humans can live. And the people who once lived over 100, if they spend their whole life with the right diet and the right genes, plus the technologies that are being developed around the world, who says they couldn't go way past that point? How far past? Well, I think anyone who says they know is lying. You're not going to let me pin you down on a number. Well, I'm trying not to because it upsets my colleagues when I put a number down.

But I think the sky's the limit. I think that we have to remember that for every year you're alive, you get another couple of months of life, and that'll continue, I think, and probably be even better. And it gets pretty interesting when you get an extra 11 months for every year you're alive. Because the science is advancing so rapidly? Right, right.

And so we've been very good at extending lifespan by having vaccinations and washing hands and all of that stuff. Now the frontier that's left is to actually modify the body and give it protection from aging itself. And that's where the biggest gains are going to come from in the future. Well, everything is changing so quickly across the board with technology and science right now that it's almost incumbent upon people who are at the vanguard or the cutting edge of what they do to really also be, in some respects, a philosopher. How much time do you spend thinking about the long-term implications of the work that you do should it come to its fruition, right? Like, let's put our thought experiment hats on and envision what the world would look like if suddenly living to 200 was normal. Like, what does that mean for how we populate the planet and cohabitate in a sustainable fashion?

Is that even possible? Right. Well, there are plenty of people who claim they know what the future looks like. They don't. But I'm trying to at least model it, teaming up with economists and philosophers and bioethicists. I feel it's my responsibility if I'm gonna be part of changing the world I need to get the world ready for when this is coming and it's not a question of if it's a when because even if I step out of this studio today and I'm hit by a boss this is still gonna happen okay so how fast

it happens it's hard to know but I think in the next few years there will be one drug that gets on the market that's proven to impact aging or at least aspects of it. And it'll just grow. There'll be a lot more. So in the future, there will be. Sorry to interrupt, but like regardless of whether we philosophize about it and how much time and energy we invest in trying to think about whether this is a good idea or not, it is happening, irrespective. Right. Because that's the way we function.

Well, that's why you're right, that a good scientist should be a philosopher, should be a humanist as well. And many of us are, because we've seen what's coming. And Walter is a good example, Walter Lunger. Okay, so what do I do? So I've been going around talking with politicians and with economists, with policymakers, with bioethicists, trying to, first of all, wake the world up, because most of the world is still asleep that this is coming.

But once people get woken up, and I find finally, over the last few years, there is increasing awareness that this is going to happen, then the question is, what are we going to do with the world? What does it look like? And if it's going to go to hell, excuse my language, can we prevent that? And I really do see our set of fork in the road that if we don't do anything now, this will happen. And if we do something, we'll live in a much better world. And I'm trying to push the world, push the needle. So we head off into that brave, great new world. And some of the things that we have to be very careful with, first of all, there's population growth. There's the environment.

There's what do people do if they're taking social security? Does it wreck the economy? Do their lives become meaningless? Are they just a burden on society? Crazy stuff like what happens when you have politicians that have been around for 200 years and they're still making policy or people on the Supreme Court. A lot of things will change.

Oh, my God, yeah. Yeah? And women, what about them? So can we extend their period of fertility so that, A, they can have the career they always wanted to, and B, will they be around to take care of their great-grandkids and see what happens to them? I mean, right now we live in a world where close to half of all women take time off during the critical period of their careers.

And could that change? And not only that, if you have kids when you're old, especially men who are capable of doing that, there's this response that how can you have kids when you're 40 or 50? You won't even be alive when they're in high school. That should change as well. We can stretch out lifespan and healthspan in a way that allows us to have much more say in what we do early in life, stay younger for longer mentally and career-wise,

take longer to find what we love to do. And even when we're done with a career, we'll be able in this new world to have second, third careers, have a second chance, third chance at the career people always wanted. Not to be contrarian, but at the same time, like I'm just envisioning myself like, okay, I'm going to live to be 200 and be around for a long time. Maybe in my forties, I have a couple of kids take a break, you know, something happens. Then 20 years later, I decided like, I want to have kids again. They're all going to live to be 300 years old because the science will improve.

And we begin populating the planet with people who are going to be around a lot longer, who may be having more children than they would otherwise. Yes, they're productive longer. They're contributing to society for a much longer period of time. But I have a hard time seeing my way around just what I think is the biggest issue initially, which is population control. How are we going to keep the planet from going past the 10 billion mark into the $15 billion mark. How are you game-theoring around that?

Right. Well, who says $15 billion is a problem? That's a debate as well. Well, there's all these other problems that we would have to solve in order to make the planet habitable for that many people. Right. And I believe that they are solvable. Now, I'm not hoping for overpopulation by any means. And in fact, if you do the numbers, the rate of population growth isn't that great if people live longer. Surprisingly low.

And as the world gets wealthier, particularly developing nations, they will have fewer kids. That's proven out. Let's look at the world if we don't do anything about longevity and we continue to treat one disease at a time. We are already heading for a healthcare crisis. Social security is going bankrupt. We've got healthcare occupying 20% and increasing GDP. Of this nation around the world, we're being basically dragged down economically by healthcare costs. The proportion of people getting older is growing dramatically. Right now,

for the first time, just this year, we've got more people over 65 than under five. So there's a gray tsunami coming. It's already here, really, that we have to deal with. So what's the best way to deal with that? Well, you can't just go around hoping that older people will die off. In fact, You can't just go around hoping that older people will die off. In fact, that's a huge waste of resources. These are mostly productive, wise people. So the solution, I think, is to make them and keep them productive members of society. Like my father, who's gone back and started a second career and helps raise the kids.

They're not a big burden on society if they're productive and they're living alone or not needing any help at home. And that's a huge cost saving. It's $50 trillion. Yeah, they're not a drain on society. They're not requiring all these healthcare costs and governmental assistance. And they're actually being productive and contributing. And so Dana Goodman, who is at the RAND Corporation, he calculated that of all of the medical treatments that are being developed from angiogenesis inhibitors, so this is for heart disease and

pacemakers, cancer treatments, diabetes, the one that gives you by far the biggest bang for the economy and for your life is an anti-aging, as he called it, anti-aging treatment. And to give you an idea of the difference, a pacemaker advance will extend a human life at the cost of, I think it was a million bucks to the US economy. To do it for a calorie restriction mimetic or anti-aging molecule, it was, I think, $7,000. It was a There's a million. So this is a cheap way to prevent this loss of the economic activity. That's money, remember, if it's $50 trillion in the long run that it's calculated to be saved by doing this, that is money that can then be used for helping the environment, helping save species, help figuring out things like energy. Let me give you a really good example of why I'm really optimistic about the future. We humans can solve anything if we just put our minds to it. And that's been proven out. I mean, these days I've got a supercomputer

in my pocket, for goodness sakes. In Australia, there was a coal-fired power plant down in South Australia. And there was a big jetty, a wharf, where they would just bring in coal day in, day out, burning coal, global warming contributor. Turns out it became too expensive to run that coal-fired power plant, so they shut it down, putting thousands of people out of work in this little community. So a brilliant bunch of venture

capitalists said, we've got human capital, we've got this wharf, we've got a lot of sunshine, it's on the barren South Australian coast, what are we going to do with that? And they figured out, let's use the sun's energy to pump millions of gallons of water out of the ocean, purify it, put it in greenhouses. And these days there's 30,000 tons of tomatoes being shipped out from that wharf in South Australia. And those people that lost their jobs, most of them got a job at the farm. I love that story. I wish we could replicate that across the board in so many industries that are quickly becoming antiquated and environmentally hazardous. And there's so many problems that I'm concerned about that I feel like despite our industrious nature and our best intentions, we just fumble over ourselves and are unable to

solve. And that tempers the optimism that I have, that I share with you when I see that, when I see problems that are right in front of us that we need to solve and we're seemingly incapable of doing it. I don't know, whether because there's no political will or the incentives are not properly aligned to make it happen. I agree with you. When I was young, I was pretty negative. I didn't even think humans belonged on the planet. We should all just kill ourselves.

We didn't deserve to be here. Wow. I mean, that's dark. But as I get older, I become much more optimistic because I've seen what's possible when you bring armies of smart, dedicated people together. And that's what I see my job. It's one thing I've found that I'm okay at is finding a goal and then bringing people together to solve what seems to be impossible. And you're surrounded by tons of super smart people. What about the psychological implications

on a young person who's presented with this new reality of living to be 200 or 300 years old? You know, talk about a change in the incentive landscape. Like that person suddenly is no longer in a hurry to figure things out. Like how does that impact an individual in terms of how they make decisions about how they're going to make their way in the world when suddenly time really isn't, it isn't the ticking clock, right. That your grandmother spoke about. Yeah, wouldn't that be great? I think that it's a shame.

Or does it just create a bunch of lazy people? That can be a drain on society. People will be people, right? Those of us who get up every day with a mission will continue to do that no matter what age they are and probably vice versa. But it does give you a different perspective so the way we live our lives now we expect to live to 80 and if we're healthy beyond that but what that means is that when we're teens we have to grow up we're in our 20s we have to find a profession in our 30s we have to get good at that. In our 40s, we make the most of it. In our 50s, we're looking at what is our legacy.

Wouldn't it be great if we could be 60 or 70 and say, I finally figured it out. I figured it out. And what is my legacy going to be? And just start again or use all that wisdom to do something brand new. And we are entering a world like that. When we were kids, being 60 was old, 70 was, oh, forget it. And a lot of people that I knew in their 70s

wouldn't even know how to type on a computer. And I find that people now that are in their 70s and 80s, they're playing tennis and typing on Twitter. So we're living in a different world. And just like today, 80 is 50 essentially. In the future, 90, 100-year-olds will still be just as active as we are in our 50s. Yeah. Your focus is in the hard science, geneticist.

But I can't help when we're having a discussion about longevity and aging, I can't help but think about the blue zones and the characteristics of these little pockets across planet Earth where we're finding populations of people that tend to live longer and be happier than others. others and what are their shared characteristics. And of course, it's certain diet protocols. It's having an active lifestyle that isn't running on the treadmill, but being kind of consistently engaged in some kind of low-grade movement throughout the day. But on top of that, there's also this aspect of faith. Most of these communities have some kind of faith that congeals them, that creates, you know, a community sensibility that, that to which they collectively adhere. And also this sense of purpose. Like I think it's, uh, Yocanawans who call it the ikigai right that they're driven by something that uh exceeds their personal ego like that that is um fueling their life with uh with meaning really that gives them a contentedness that makes them a healthier person and able to live longer

yeah 100 if you don't have a mission in life, go get one. It'll keep you happier and probably longer lived as well. You can take all the resveratrol you want, and we could talk about the genetics, but if you're aimless and you don't have purpose and you're mentally not dialed in and you're not taking care of yourself and you're not eating well, you're missing the big picture. Well, this is the problem with retirement. I mean, it's all fine to go on cruises and enjoy

some relaxation. But once you've lost your purpose, that's when things go downhill. And I saw that with my father, actually. So my father retired at a typical age of 66, 67, and spent about 10 years just flailing around. You can only, I think, go on so many cruises before you get sick of it. It wasn't until he started his new career, which is working at the university on an ethics panel for experiments, that he perked up and he was excited about life. And I've never seen him happier. Isn't that crazy that someone who's essentially 80, turning 80, has never been happier or more vigorous?

That's really, I think, inspiring and shows me what the world could be like for millions of people. Mm-hmm. Yeah, my wife's father was an engineer in Alaska. He passed away a couple years ago, but he worked well into his late 80s on gigantic construction projects in Anchorage because the community there is largely Native American, and they have a reverence and a respect for their elders that is kind of lacking in most of the rest of our culture, and they would continue to employ him.

And he kept saying, like, I can't even see anymore. They're like, but they respected his experience, and it was just like the right thing to do. And he did contribute you know in a very material way to the advancement of these projects um so he worked essentially all the way to the end and it just defies that whole paradigm of people you know this the great generation working towards their retirement their 401k so they could live out the rest of their lives and leisure, playing golf,

and hanging out at the club, only to discover that that's the thing that makes you depressed. Well, it really is. And so society would be so much better if people stayed healthy, but also were able to contribute. It's getting up in the morning and knowing that you've got something to do that's important. And on the retirement age, now I think that if you've been busting roads your whole life, you really deserve to have a second chance. So I think that as nations become wealthier and we're already finding that people are talking about what we call a living wage when people take time off work,

I would suggest that the best thing we could do is people get healthier for longer and just sitting around being healthy, that they actually have a choice to take some paid time off to start a new career. So let's say someone who's been busting roads, or that's just a catch-all term for someone who didn't like their career, gets a few years off paid by the government to do what they always wanted to do. And it can be anything, can be building model airplanes or helping out at nursing homes. But that living wage would come back in huge dividends because then you'd have people like my father who are helping society. It doesn't even have to be paid work, by the way. But I think just getting people with the wisdom

and knowledge that they've accumulated over a lifetime instead of just throwing that away into the ground or into the crematorium let's use that human capital it's worth trillions of dollars and we just throw it or throw it away yeah being able to leverage the collective wisdom of centenarians who are mentally fit enough to pass down their wisdom and experience to a younger generation and at the same time changing our perception of the elderly you know right now we warehouse them we dismiss them we want to pretend they don't exist we want them to go away we don't want to hear what they have to say i mean i think there's some cultural shifts that would have to take place as well.

Well, they would. I mean, who wasn't a 20-year-old who's guilty of don't want to hang around the old farts? Yeah, that's not going to change. That is not going to change. But, you know, I think as you get older, you realize that they're very special people, anyone who's managed to survive for 80-plus years and what they've seen, especially people who had to live through World War II, one of the worst times in human history,

what they can tell you about the meaning of life. And also what I've learned in life is it's important to learn from mistakes, not just success. And everyone's had mistakes, but if you can see what the mistakes others have had in their lives before you make those same mistakes, that's really the way to avoid the pitfalls in life. And I've really benefited from having some mentors in my life. I would love to these days sit down with people who have these stories to tell about what have

they learned in their life that they could pass on to future generations. Right. Well, in terms of passing on wisdom down the line, I think we should round this out with some practical wisdom and advice for people that are listening in terms of things that they can do in their daily lives to improve their longevity and combat aging to increase their health span? What are some of the top things? Well, here's what I do. That's how I convey advice. So every day I wake up having had a decent night's sleep, preferably, and I'll go have a yogurt that I make myself for the microbiome, try to keep my microbiome in check.

I take a little bit of resveratrol sprinkled in that yogurt. Is there a particular brand or do you have some special Harvard lab version that no one else can get? Except for me because you're going to get it to me, right? Well, we'll talk. I fortunately have pharmaceutical-grade resveratrol in my basement, so I'd sprinkle a bit of that. And same with NMN.

And that's not commercially available? Can people get that? Not from me. Well, for you, you don't count because you're working in it. But for somebody who's listening, like they can't go to their doctor and get this prescribed and they can't go to their doctor and get this prescribed. They can't purchase it. Right.

Well, there's a lot of things sold online, which I apologize I can't endorse or talk about. I try to stay above that fray. But there are people selling things online. I'm going to use social media to be able to talk more about it. So stay tuned. I'll release what I can. I'm going to use social media to be able to talk more about it. So stay tuned. Okay. I'll release what I can. But I'm also looked out, looked over by a very large institution called Harvard University. Right.

Be careful what I say and what I do. But I also want to be able to say with authority the science. So anyway, my apologies for not being able to say go buy this product. I just am not able to say that. But I can point you in the right direction. I think you should look for, if you're going to take a supplement, make sure it's from a reputable source. And there are some reputable companies, some are not. Sometimes it's hard to know.

There's really much out there, and there's a lot of quackery. Yeah, so my dream, Rich, is to have an independent group who does these studies and leaves me out of it, but maybe I can enable that group to test things and report on it. And that would be the ideal. But I got into trouble when I used to talk about supplements. I once said on NBC or a TV show that some of the supplements I've tested don't have the product in it. And that got some people very upset. And I got dragged into a fight between two companies, and there was a lawsuit, and I lost a year's salary on legal costs.

So, you know, it was a good lesson. Don't talk about supplements if you can help it. You know, that said, look for quality brands. Look for purity. Don't take things that have a lot of mixed things in it. You just don't know what else you're getting in there. Look for clinical trials that have been tested on some products. So some products that raise NAD have been published in clinical studies.

And so you can go to PubMed. If you Google the words P-U-B-M-E-D, you can find some scientific papers and look for sirtuins, look for NAD, look for either NMN or its similar molecule, its cousin called NR. And actually, people are wondering what's NR. It stands for nicotinamide riboside. So that's as best I can do to help there. I try to do some exercise at least once a week on the weekends. My son and I go

to the gym for two to three hours. Just once a week? Well, we try to do more, but I'm traveling a lot. So hopefully twice a week at minimum. We have a gym at home actually i built a gym um adjacent to my bedroom which i can see through the windows and for a while there i figured just looking at the gym is probably helping um i was hoping at least okay yeah mentally you know if i just look at the treadmill it's probably good but no i try to use it more and more especially because i've been writing this book and i've spent hundreds, if not a thousand or more hours sitting down, which is really bad.

So I'm trying to make up for all of that. So we do that. We do high intensity running on treadmills and we also do weight training with a trainer every for an hour. And actually my trainer recently looked at my body and he said, I used to work out when you were young. And I said, yeah, I did. How do you know? And he goes, cause you're all messed up. My arms are turned inward. My palms aren't straight. I slouched to

one side. And so he's fixing that part of my body. But so I'm trying to get back into shape. Is there research on the differences between high intensity training and aerobic training in terms of longevity? Not in longevity as much. There have been some human studies that have looked at biomarkers and other things like that. And also the relationship to frailty. And as far as I can tell from reading a very complex body of literature, is that you want to do some not high impact but high intensity aerobics, get your heart rate up pretty high until you're feeling some hypoxia. You're gasping for breath.

And that hypoxic response is a hormetic response it will stimulate your body to fight back so get get your heart rate up they say as little as five minutes is is sufficient um i don't know i go a little bit further i don't see any harm in doing that so you know 10-15 minutes of panting but then i slow down and then i do a bit of jogging as well. But it's that really what you just want to do a bit of jogging, a bit of sprinting, bit of jogging, bit of sprinting, but it doesn't seem to have to last for that long to be good for you. Just to get that, that stimulus response. Yeah. Because your body has an epigenetic memory of those exercises uh and so it lasts for days and what about training 25 to 30

hours a week for ultra distance triathlons and marathons yeah it's i'm digging my early grave i don't think so i've seen data on on bicyclists this is not the same thing, but bicyclists who, I think they were riding over 80 miles a week, their chance of getting a heart disease was reduced by 40% in old age. And 40% is a massive number. And so I think that if you're not wearing body parts out, certainly your organs are going to be younger for longer. Yeah. Although there's some research out there. There's some research out there that says long-term like super, uh, you know, a lot of aerobic exercise,

ultra marathoners, marathoners have scarring in their heart tissue and there's some cardiac implications that don't look so great for that I'm always getting tweets from people all the time telling me that I'm harming myself well I think you're gonna live longer than someone who sits on the couch and eats potato chips all the time so I can't speak for the fibrosis in the heart it's other than to say we're also working on that where I have a sena lytics company with some real experts in the field like Manuel Serrano in Spain who cloned the senescence gene P16.

And so we're trying to figure out how to fix problems like that that accumulate over time. Right. Okay, so exercise. What's your specific fasting protocol look like then i don't have one i do try to eat smaller meals i try to not overeat and i try to skip meals which is pretty easy because i'm not hungry when i wake up other than that little yogurt which is just for residual solubility and then i'm so busy i usually skip lunch um. So I'm practically eating one, maybe two meals a day by default.

I'm never able to literally go a whole day without eating for some reason. It's just too hard. I'd like to. I think that would be a great thing. I know Peter Atiyah does it really well and others. But I'm unable to. I think I've got to fuel my brain. Without my brain, i've got no job

so that's gotta be able to think straight right sometimes i think better when i haven't eaten you know you get the brain fog after the lunch and the lull and the energy sometimes it's better to be without food in terms of focus for me personally yeah i agree with that 100 but then you get to a point after diminishing, then it starts to go down. So you're not super hardcore about these kinds of practices? No, I probably should be better about it. But as I've said, I'm not so worried about my longevity. I mean, I'm hoping not to die in the next few years because I've got some work to do.

I try to be a role model for others, but I'm not obsessive about it. I do have some bad genes that I inherited. So I'm trying to live at least 80 to 90 years. I'd like to live longer. I'd love to be able to continue working and doing good. I'd like to see where the world goes with all of this research. I'd like to figure out what we have in our pockets besides computers 20 years from now. But to your point, I do what I can within reason. Most of my mental energy and dedication is devoted to this cause, which is finding cures for diseases, improving people's lives, getting the word out that this is coming and this is important for the world to know about.

lives, getting the word out that this is coming and this is important for the world to know about. One last question. Sleep. If so much of what we've talked about is trying to get the body to get into its reparative state, isn't sleep the ultimate example of that? Is this not something that we should be really trying to enhance and focus on if we're concerned about longevity yeah well the first of all the the longevity genes that i work on are central to the circadian rhythm which is the sleep-wake cycle and if you're out of whack you don't get enough sleep that we think has negative effects on the sirtuins and NAD levels. NAD levels will precisely cycle with the day. So just before you wake up or before you have breakfast,

your NAD levels will start to spike and get you ready for the meal. So if you start to miss sleep and you get your, if you have a lot of jet lag like I do, it's not good. We mice when you mutate their body clock they get signs of premature aging and in fact if you prevent a rat from sleeping it'll pretty quickly develop diabetes so it's really important to maintain a good cycle and reset your body clock if you're traveling and then the the other problem um is that without a proper sleep um you're not clearing out a lot of the the toxins that accumulate in your brain and we just recently a scientific world has realized that as you're sleeping and dreaming one of the things that's happening is that those canals in your brain are getting rid of what's built up during the day. And if you wake up early and you haven't had enough sleep, your brain is still clogged with that stuff. And so

you can't think well during the day, which is lethal to someone like me, who's supposed to be at peak performance mentally. So let me tell you about what I do, because I missed out on sleep for more than a couple of decades. I'm an insomniac actually oh wow and with kids it didn't help that at all so what I managed to do was to calm myself down at night I do a little bit of meditation avoid the screens the blue light I wear those light blocking glasses yeah if if I'm traveling I'll take a little bit of a sleeping pill which I need to just calm down but I don't eat the whole thing I just nibble on the pill and that's enough to calm me down so I finally get

to sleep because my brain is so active it would keep going all night and then waking up in the morning I find that that combination of the resveratrol and NMN a little bit of coffee really kickarts the day and I'm ready to go. And by the way, please don't criticize me, colleagues, for saying this because it's an N of one, as we call it. But I find that jet lag is ameliorated a lot less when I travel. And I use the NMmn to reset that body clock which you know we now know at least in mice that cycle of nad through the day is probably what's driving jet lag as well if it's just so it helps you get over the jet lag well i find it does for me and i travel a lot and i've i experiment a lot on myself um with this these things and that's one thing that

i i am pretty sure is true, is that the anime helps with that jet lag. When's the book coming out? Well, it's set for later. Do you have a title for it? Yeah, it's called Lifespan. Oh, Lifespan. Okay, cool.

Yeah, so I'm just finishing it up. It's an illustrated book. It's got some beautiful drawings, illustrations from one of the best illustrators in the country. And some of these concepts like the epigenome and the compact disc, they're beautiful when they're drawn out on the page. And so Katie Delphia has been working for a year on this book as well. And I have a co-author Matt

LaPlante who has written a book about the epigenome so the three of us have created what I think is a unique book unique it's science-based but it covers everything from the beginnings of life on the planet to human history and life in London in the 1830s what we can learn what we I give the readers a front-row seat on what the cutting edge of technology is today what's just around the corner because i can see it already and what does life look like in the future for our families for our family members including our four-legged ones and project into the far future of what uh the future is going to be like if we don't succeed

and if we do it's gonna be interesting either way it is but we've got to stick around to see it yeah yeah yeah well I really look forward to the book please send it to me when it's ready and hopefully I can entice you to come back and talk to me a little bit more when the book comes out sounds good rich thanks for having me on Thank you so much for the work that you're doing. It's inspiring, it's fascinating. We really are creating a world beyond anything we could have imagined as young people.

And it's a privilege and an honor for me to speak to somebody who's really at the cutting edge of all of that. So thank you for your time and best of luck with all of this, man. Doing amazing work. Oh, thanks, I appreciate it. Cool. So if people wanna connect with you

or learn more about your world and what you do, what's the best place for them to go? So I'm active on Twitter and I talk about some of the research in my lab. We've got the immortal jellyfish, gonna just tweet out a new transgenic jellyfish we made last week so that that'll be the way so that my twitter handle is david a sinclair uh and so we're gonna launch a book website soon but i'll uh i'll let everyone know when that's ready cool good talking to you thanks richard feel good uh i always feel good

good i want to always feel good. We'll talk more. All right. Thanks, man. Peace. Mind officially blown. This conversation, which incidentally transpired a couple of months ago, really deeply and profoundly impacted how I think about my personal longevity, my aging. It shaped some

new daily habits that I've been ascribing to, including daily intake of resveratrol, which we talked about during the podcast. For those interested in that product, I'll put a link up into the show notes. And I really hope you guys enjoyed it. Please do me a favor, let David know what you thought about today's conversation. You can find him on Twitter at David A. Sinclair. And don't forget to pre-order his new book, Lifespan, The Revolutionary Science of Why We Age and Why We Don't Have To, which hits bookstores on September 10th. If you'd like to support the work we do here on the podcast, just tell your friends about the show. Share your favorite episode on social media. You can subscribe to the show.

That's probably the most important of all of these things. If you hit that subscribe button on Apple Podcasts, on Spotify, on YouTube, super helpful. Leave a review on Apple Podcasts and you can support us on Patreon at richroll.com forward slash donate. I want to thank everybody who helped put on the show today. Jason Camiolo for audio engineering,

production, show notes, interstitial music, Blake Curtis and Margo Lubin, who traditionally video and edit the video version of the podcast, although this one was audio only, Jessica Miranda for her beautiful graphics, and DK, David Kahn, hashtag DKGoals for advertiser relationships. Theme music, as always, by Analema. Thank you for the love, you guys. I will see you back here in a couple days with another special edition, hotly anticipated edition of Coach's Corner

with Chris Houth, my coach, Chris Houth. Until then, take care of yourselves. Embrace life. It's not necessarily the length of time we spend here on the planet, but the quality of that time. So be mindful about it. Appreciate it. Be grateful and give back.

Peace. Plants. Namaste. Thank you.