David Sinclair: Extending the Human Lifespan Beyond 100 Years | Lex Fridman Podcast #189 | Transcription

Transcription for the video titled "David Sinclair: Extending the Human Lifespan Beyond 100 Years | Lex Fridman Podcast #189".


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Opening Remarks

Introduction (00:00)

The following is a conversation with David Sinclair. He's a professor in the Department of Genetics at Harvard and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School. He's the author of the book "Lifespan" and co-founder of several biotech companies. He works on turning age into an engineering problem and solving it, driven by a vision of a world where billions of people can live much longer and much healthier lives. Quick mention of our sponsors, Onnit, Clear, National Instruments, NI, SimpliSafe, and Linode. Check them out in the description to support this podcast. As a side note, let me say that longevity research challenges us to think how science and engineering will change society. Imagine if we can live 100,000 years, even under controlled conditions, like in a spaceship, say, then suddenly a trip to Alpha Centauri that is 4.37 light years away takes a single human lifespan. And on the psychological, maybe even philosophical level, as the horizons of death drift farther into the distance, how will our search for meaning change? Does meaning require death, or does it merely require struggle? Reprogramming our biology will require us to delve deeper into understanding the human mind and the robot mind. Both of these efforts are as exciting of a journey as I can imagine. This is the Lex Friedman Podcast, and here is my conversation with David Sinclair. I usually feel like the same person when I was 12.

Exploring The Aspects Of Aging And Lifestyle

Staying young at heart (01:34)

Like when I, right now, as I think about myself, I feel like exactly the same person that I was when I was 12, and yet, I am getting older, both body and mind, and still feel like time hasn't passed at all. Do you feel this tension in yourself that you're the same person, and yet you're aging? - Yeah, I have this tension that I'm still a kid, but that helps in my career. Scientists need to have a wonder about the world, and you don't wanna grow up, 12-year-olds, and even younger, I would say, six, seven-year-olds. I've still got that boy in me, and I can look at things. It's a gift, I think, that I can see things for the first time if I choose to, and then explain them as I would to a six-year-old, 'cause I am that mentally. But on the other hand, I'm getting older. I run a lab of 20 people at Harvard. I've got a book, I've got science to do, companies to run. And so I have to, on most days, just pretend to be a grown-up and be mature, but I definitely don't feel that way. - There's something I really appreciated. In opening your book, you talked about your grandmother, and on this kind of theme, on this kind of topic, she, first of all, had a big influence on you. My grandmother had a big influence on me. And you also mentioned this poem by the author of Winnie the Pooh, Alan Alexander Milne. Maybe I can read it real quick, 'cause I, on the topic of being children, "When I was one, I had just begun. "When I was two, I was nearly new. "When I was three, I was hardly me. "When I was four, I was not much more. "When I was five, I was just alive, but now I am six. "I am as clever as clever, so I think I'll be six, "now, forever and ever." So this idea of being six and staying six forever, being youthful, being curious, being childlike, this and other things, what influence has your grandmother had in your thinking about life, about death, about love? - Yeah, I was getting misty-eyed as you read that, because that poem was read to me very often, if not every day, by my grandmother, who partially raised me. And she was as much a bohemian as an artist, philosopher. And she's one of those people that wouldn't talk about the little things. She said, "I hate small talk. "Don't talk to me about politics or the weather. "Yeah, talk to me about human beings and culture." So I was raised on that, and this poem was one that she read to me often, because she knew that the mind of a child is precious, it's honest, it's pure. And she grew up during the Second World War and in Hungary and Budapest, witnessed the worst of humanity. She was trying to save a whole group of Jewish friends in her apartment, saw what happened after the World War, which was, there was, the Russians were in control and locals weren't necessarily treated well if they were rebellious, which she was. And then there was the revolution in '56, which she was part of and had to escape the country. So she saw what can happen when humans do their worst. And her words to me, expressed in part through that poem, was, "David, always stay young and innocent "and have wonder about the world, "and then do your best to make humanity the best it can be." And that's who I am, that's what I live for, that's what I get up in the morning to do, is to leave the world a better place and show to whoever's watching us, whether it's aliens or some future human historian, that we can do better than we did in the 20th century. - You know, we mentioned offline this idea of bringing people back to life through artificial intelligence, sort of, I don't know if you've seen videos of basically animating people back to life, meaning whether it's, for me personally, I've been working on specifically about Albert Einstein, but also Alan Turing, Isaac Newton, and Richard Feynman.

Bringing people back to life (05:30)

And it's an opportunity to bring people that meant a lot to others in the world and animate them and be able to have a conversation with them. At first, to try to visually, visually explore the full richness of character that they had as they struggled with the ideas of the modern age. Sort of, it's less about bringing back their mind and more bringing back the visual quirks that made them who they are. And then maybe in the future, it's using the textual, the visual, the video, the audio data, to actually compress down the person for who they are and be able to generate text. There's a few companies, there's Replica, which is a chat engine, that was born out of the idea of bringing, the founder lost her friend to, he got ran over by a car. And the initial reason she founded the company was trying to just have a conversation with her friend. She trained machine learning, natural language system on the text that they exchanged with each other and try, she had a conversation with him sort of after he was gone. And it's very, the conversation was very trivial. It was obvious that it's, you know, AI agent, but it gave her solace. It made her actually feel really good. And that's the way I wonder if it's possible to bring back people that are, that mean something to us personally, not just Einstein, but people that we've lost. And in that way, achieve a kind of small artificial immortality. I don't know if you think about this kind of stuff. - Well, I definitely think about a lot of things. That one's a really good one. There's a great Black Mirror episode about the wife who brings back the boyfriend or husband. I think one of the challenges with bringing back Richard Feynman would be to capture his sense of humor, but that would be awesome. But yeah, bringing back loved ones would be great, especially if they're young and they die early. Though it may hold you back from moving on, that's another thing that could happen as a negative. But I think that's great. And I also think that it's gonna be possible, especially when we're recording, some of us, every aspect of our lives, whether it's our face or things we see. Eventually one day, everything we see can be recorded. And then you can build somebody's experience and thoughts, speech, and you will have replicas of everybody, at least digitally and physically. You could do that too one day. But that's a good idea, especially 'cause there are people that I'd like to meet, and I think it's easier than building a time machine. One person I'd love to meet is Benjamin Franklin. - Really? - Well, I wouldn't go back in time. I would, but I'd prefer to bring him into the future and say, "Can you believe we have this thinking machine "in our pockets now?" And just see the look on his face as to where humanity has come. 'Cause I think of him as a modern guy that just was before his time. - Yeah, so you're thinking Benjamin Franklin the scientist, not Benjamin Franklin the political thing, 'cause he'd be very upset with Congress right now. - Right. - So maybe talk to him about science and technology, not politics, or maybe just don't get him on Twitter because he'll be very upset with human civilization. You know, I wonder what their personalities are like. Isaac Newton, it does seem complicated to figure out what their personality is like. Even Friedrich Nietzsche, who I also thought about. Feynman is, we just have enough video where we get the full kinda, I mean, it shows you how important it is to get not the official kind of book level presentation of a human, but the authentic, the full spectrum of humanity. You mentioned collecting data about a person, collecting the whole thing, the whole of life, the ups and downs, the embarrassing stuff, the beautiful stuff, not just the things that's condensed into a book. And then with Feynman, you start to see that a little bit. Through conversations, you start to see peaks of like that genius, and then through stories about him from others. And then certainly you, the sad thing about Alan Turing, for example, is there's very little, if any, recording of him. In fact, I haven't been able to find recording. Allegedly, there's supposed to be a recording of him. They're doing some kind of radio broadcast, but I haven't been able to find anything. And so that's truly sad. That it feels like it makes you realize how the upside, how nice it is to collect data about a person, to capture that person. That's the upside of the modern internet age, the digital age, that that information, yeah, creates a kind of immortality. And then you can choose to highlight the best parts of the person, maybe throw away the ugly parts, and celebrate them even after they're gone. So that's a really interesting opportunity.

Wearables and tracking health data (11:05)

You've also mentioned to me offline that you're really excited about all the different wearables and all the different ways we can collect information about our bodies, about the whole thing. What's most exciting to you in terms of collecting the biological data about a human being? - Well, so I'm a biologist. I find animals and humans as machines very interesting. It's one of the reasons I didn't become an engineer or a surgeon. I wanted to understand how we actually are built. And so I think a lot about machines merging with humans. And the first of that are the bio-wearables. And so I talked a lot about this, I wrote about it in "Lifespan," the book, and pictured a future where you would be monitored constantly so that you wouldn't suddenly have a heart attack. You'd know that was coming, or you wouldn't go to the doctor and they don't know if you need an antibiotic or not. Long-term, how old are you, how to fix things, what should you eat, what should you take, what should your doctor do? These devices, I predicted, would be smarter, better educated than your physician, and would augment them, and then there'd be a human that would just tick off to see if it's correct and they approve. I also was predicting in the book that we would have video conferences with our doctors, and that medicines would be delivered, initially by courier, but eventually by drones, and get it to you sometimes in an emergency. And that we could even have pills that were synthesized or delivered in your kitchen, and combined, certainly. What's amazing about that is that, what are we now, two years since the book came out, even less, and that future is basically here already, COVID-19. - Accelerated. - Accelerated that incredibly. So where we're at now in society is, if you wanna pay for it, you can have a blood test that will detect cancer 10, 20 years earlier than it would before it forms a tumor. You can, of course, do your genome very cheaply for less than $100 now. There are bio-wearables already I wear, this ring from Aura, that I have a number of years of data. I've been doing blood tests for the last 12 years with a company called Inside Tracker, which I consult for. And so I have all of that data as well, and there's 34 different parameters on my testosterone, my blood glucose, my inflammation. And I use all that data to, of course, I wear a watch that measures things as well. I use that data to keep my body in optimal shape. So I'm now 51, and according to those parameters, I'm at least as good as someone in their early 40s. And if I really work at it, I can get my biochemistry down to early to mid 30s. Though I like to now eat a little dessert once in a while. So that's the future we're in right now. Anyone can do what I just said. But in the very near future, just in the next few years, you can be wearing wearables. So I'm currently wearing a little, what's called a bio sticker. This one I just put on last night. It's about an inch long, a few millimeters. - Yeah, for people just listening, it's on David's chest. It's just, how does it attach? It just kind of-- - It sticks on. - Sticks on. - Yeah, so on one side, you have an on button that you press. The lights come on, flashes four times. It's good to go. It immediately syncs to your phone. And this one, it's called a bio button. Nice name. And there's another one that I have that I haven't tried yet that does EKG on your heart. This is mainly for doctors to monitor patients that go home after a heart attack or surgery. But that's medical grade, FDA approved device. So there will be a day, in fact it's already here, that doctors are using these to get patients to go home and save a week in hospital. $2,000 at least for each patient. That's massive savings for the hospital. But ultimately what I'm excited about is a future that isn't that far off where everybody, certainly in developed countries, eventually these will cost a few cents and rechargeable. The only cost will be the software subscription that can be monitored constantly. And to give you an idea what this is measuring me at a thousand times a second is my vibrations as I speak, my orientation. It already has told me this morning how I slept, where I slept, what side I slept on. We've got sneezing, coughing, body temperature, heart rate, heart of other parameters of the heart that would indicate heart health. These data are being used now to predict sickness. So eventually we'll have, just in the next year or so, the ability to predict whether something, or diagnose whether something is pneumonia or just a rhinovirus that can be treated or not. This is really going to not just revolutionize medicine, but I think extend lives dramatically. 'Cause if I'm gonna have a heart attack next week, and that's possible, this device should know that, and I'll be in hospital before I even have it. - Maybe you can talk a little bit about Inside Tracker, 'cause I saw that there's some really cool things in there. Like it actually, so maybe you can talk about, I guess that you're collecting blood to give it the data. So, and it has like basic recommendations on how to improve your life. So we're not just talking about diseases, right? Like anticipating having a particular disease, but it's almost like guiding your trajectory to life, how to, whether it's extend your life or just live a more fulfilling, like improve the quality of life. I suppose this is the right way to say it. How does Inside Tracker work? What the heck is it? 'Cause I saw that there's also pretty cool. - Yeah. - What is it? Is this something other people can use? - You can definitely use it. You can sign up, it's consumer. - Take a company, consumer-facing company? - It is, yeah. - Very cool. - And I also wanna democratize the ability to just take a mouth swab eventually. We don't need to have a blood test necessarily. But for now it's a blood test and you'd go to a lab core request in the US. It's also available overseas. You can upload your own data for minimal cost and get the algorithms, the AI in the background to take that data, plot where you are against others in your age group in terms of health and longevity. Bio-age they call it, no inner age. But also it provides recommendations. And this isn't just a bunch of BS. It sounds like it might be to say, oh, go eat this or go to that restaurant and order that. But it's actually based on, they've basically, this company has entered hundreds, now it would be thousands of scientific papers into their database and hundreds of thousands of human data points. And they have tens of thousands of individuals that have been tracked over time. And anonymously that data is used to say what works and what doesn't. If you eat that, what works. If you take that supplement, what works. And I was a co-author on a paper that showed that the recommendations for food and supplements was better than the leading drug for type 2 diabetes. - That's so cool. The idea that you can connect, like skipping the human having to do this work. You can connect the scientific papers, almost like meta analysis of the science connected to the individual data. And then based on that sort of connect your data to whatever the proper group is within whatever the scientific paper is to make the suggestion of how that work applies to your life. And then that ultimately maps to like a recommendation of what you should do with your life. Like it all, like this giant system that ultimately recommends you should drink more coffee or less. - Right, and we'll have the genome in there as well. You can upload that. - Yeah, awesome. - So these programs will know us way better than we do and our doctors as well. The idea of going to a doctor once a year for an annual checkup and having males get a finger up their butt and you cough. That to me is a joke. That's medieval medicine. And that's very soon going to be seen as medieval. - Yeah, to me as a computer science person, it's always upsetting to go to the doctor and just look at him and like realize, you know nothing about me. Like you're making your like opinions based on like, it is very valuable years of intuition building about basic symptoms, but you're just like, it is medieval. They're very good at it. In fact, doctors in medieval times are probably damn good at working with very little. But the thing is, I'd rather prefer a doctor that doesn't really know what they're doing, but has a huge amount of data to work with. - Well, you're right. And many of my good friends are doctors. I work at Harvard. So I'm not against the profession at all. But I think that they need just as much help as anyone else does. We wouldn't drive a car without a dashboard. We wouldn't think of it. So why would doctors do the same?

How to solve aging (20:18)

- If we could, could we step back to the big, profound philosophical, both tragic and beautiful question about age. How and why do we age? Is it from an engineering perspective, you said you like the biological machine. Is that a feature or a bug of the biological machine? - It is both a bug and a feature. Evolutionary speaking, we only live as long as we need to, to replace ourselves efficiently. If you're a mouse, you're only gonna live two and a half years, three years. You're probably gonna die of starvation, predation, freezing in the winter. So they divert most of their resources to reproducing rapidly, but they don't put a lot of energy into preserving their soma, which is their body. Conversely, a baleen type of whale, a bowhead whale in particular, will live hundreds of years because they're at the top of the food chain and they can live as long as they want. So they breed slowly and build a body that lasts. We're somewhere in between because we've really only just come out of the savannas where we could be picked off by a cat. We were pretty wimpy going back six million years ago. So we actually need to evolve quicker than evolution will. And that's why we can use our oversized brains and intuition to give us what evolution not only didn't give us, but took away from us. Now we're pathetic, look at our bodies. These arms, if any of us, even the strongest person in the world went in a cage with a chimpanzee, the chimp could knock that person's head off, no question. So we're pathetic, so we need to engineer ourselves to be healthier and longer lived. So getting to aging, we can do better, right? Whales do way better. We're trying to learn how whales do that. And if you'd ask really anybody in the field now, professor, they'll say there are eight or nine hallmarks of aging, which are really, it's a word for causes of aging. So you probably have heard of some of these. Your listeners will have loss of telomeres, the ends of the chromosomes, like the little ends of shoelaces, that kind of thing. They get too short, cells stop dividing, become senescent. They become, they put out what are called mitogens that cause cancer and inflammatory molecules. So that's another aspect of aging, cellular senescence. Another one is loss of the energetics, so mitochondria, the battery packs wind down. There's a whole bunch, stem cells, proteostasis. Well, these are our Achilles heels that I'm talking about. They're a common amongst all life forms, really. But if you want me to jump to the chase as to where, what is the upstream defining factor? If we boil it down, what do we get? So most biologists would say you can't boil it down. It's too complex. I would say you can boil it down to an equation, which is the preservation of information and loss due to entropy, i.e. noise. And that is the basis of my research. It originally came out of discoveries in yeast cells where I went to MIT in the 1990s. - You studied bread. - I kind of did. I studied the makers of bread, a little yeast called Saccharomyces cerevisiae, which at the time was one of the hottest, excuse the pun, organisms to work on. But we figured out in the lab why yeast cells get old and found genes that control that process and made them live longer, which was an amazing four years of my life. One of those genes had a name with an acronym, SIR2. Now the two is irrelevant. The SIR is important, and the most important letter out of all of those three is I, which stands for information. Silent information regulator number two. When you put more copies of that gene in, just put in one more copy, the yeast cells lived 30% longer and suppressed the cause of aging, which was the dysregulation of information in the cell. And then, so fast forward to now, I've been looking in humans and mice, 'cause they live shorter and cheaper to study, where the loss of information in our bodies is a root cause of aging, and I think it is. Your boldness in viewing biology in this way is fascinating because that also leads to a kind of, it's almost like allows for a theory of aging, like you could boil it down to a single equation, and it leads to perhaps a metric that allows you to optimize aging, sort of in the fight against entropy, to figure out which mechanisms, like you said, the silent information regulator, which mechanisms allow you to preserve information without injecting noise, without creating entropy, without creating degradation of that information. For some reason, converting biology, which I thought was mostly impossible, into an engineering problem, feels like it makes it amenable to optimization, to solving problems, to creating technology that can, whether that's genetic engineering or AI, it makes it possible to create the technology that would improve the degradation of information and aging. Is there more concrete ways you think about the kind of information we want to preserve? And also, is there good ideas about regulators of that information, about ways to prevent the distortion, the degradation of that information? - Right, so we have silent information regulator genes in our bodies, we have seven of them, SRT1 through seven, they're called, and we found in mice, one way to slow down the loss of information is to just give more of these to upregulate these genes. So we made a mouse that has more of this SRT1 gene, turned it on, and that slowed down the aging of the brain and preserved their information. Now what information am I talking about, you might ask? Well, again, you can simplify biology. There are two types of information in the cell primarily. The one we all read about and know about is the DNA, the genome, and that's base four information, ATCG, the four chemicals that make up the various sequences of the genome, billions of letters. And that also degrades over time, but what's been fascinating is that we find that that information is pretty much intact in old animals and people. You can clone a dog, one of my friends in LA just cloned his dog three times. So this is doable, right? It means that the genome can be intact, but what's the other type of information? It's the epigenome, the regulators of the genetic information, and physically, that's really just how the DNA's wrapped up or looped out for the cell to access it and read it. So it's similar to, and excuse this analogy, but it's a good one, a compact disc or a DVD. Those pits in the foil are the digital information. That's the genome, and the epigenome is the reader of that information. And in a different cell, you'd read different music, different songs, different symphonies, and that's what gets laid down when we're in the womb and that makes a skin cell forever a skin cell and not a brain cell tomorrow. Thank God, otherwise our brains wouldn't work very well. But over time, what we see is that the brain cells start to look more like skin cells and the kidney cells start to look more like liver cells. And they, what we call X-differentiate, this is a term that we use in my lab but isn't yet widely used, but we needed a term to explain this. And that process of X-differentiation, the loss of the reader of the CD or the DVD, we liken that to scratches on the DVD so that the reader cannot fully access the information. Now we can slow down the scratches, as I mentioned. We can turn on these genes. We can even put in molecules into the cell or even eat them and turn on those pathways, which my father and I have been trying to do for about a decade, to slow things down. But the question that I've had is, is there a repository of information still in the body? Because anyone who knows anything about the loss of information or even has tried to copy a cassette tape or photocopy or Xerox anything, knows that over time you lose that information irreparably. So I've been looking for a backup copy, inspired largely by Claude Shannon's work at MIT as well in the 1940s. His theory, mathematical theory of communication is just brilliant. And so I've been looking for what he called the observer, which is the backup copy. We today might call that the TCP/IP protocol of the internet that stores information. In case it doesn't make it to your computer, it will fill in the gaps. And we've been spending about the last five years to try and find if there really is a backup copy in the body to reset the epigenome and polish those scratches away. - That's incredible. So finding the backup, so whenever there are too many scratches pile up, you can just write a new version. Not a new version, but go to the backup and restore it. - Right, that's really all we're talking about. It's not that hard once you know the trick. - And for people that actually remember like DVDs and scratches on them, how frustrating it is, that's a brilliant metaphor for aging. And then the reader is the thing that skips and then it could destroy your experience, the richness of the experience that is listening to your favorite song. - Right, but in biology, it's even worse 'cause you'll lose your memory, your kidneys will fail, you'll get diabetes, your heart will fail. And we call that aging and age-related diseases. So most people forget that diseases that we get when we get old are 80 to 90% caused by aging. And we've been trying to fix things with Band-Aids after they occur without even generally talking about the root cause of the problem. - Is there the scratches, do those come from, are those programmed or are they failures?

Why do we age? (30:22)

Meaning, is it, so if it's by design, then there's like a encoded timeline schedule that the body's just on purpose degrading the whole thing. And then there's the just the wear and tear of like the scratches in a disc that happen through time. Which one is it that's the source of aging? - It's more akin to wear and tear. There isn't a program. Getting back to evolution, there's no selection for aging. We're not designed to age, we just live as long as we need to and then we're at the whim of entropy, basically. Second law of thermodynamics, stuff falls apart. We live a bit longer than age 40, only because there are robust resilient systems, but eventually they fail as well. Current limit to the human lifespan where they completely fail is 122. But I don't like to think of it as wear and tear because there's two aspects to it. There's a system that's built to keep us alive when we're young, but actually comes back to bite us as we get older. And we call this issue antagonistic pleiotropy. What's good for you when you're young can cause problems when you're older. So we've been looking what is the cause of the main causes of the noise. And we've found two of them, definitively. The first one is broken chromosomes. When a chromosome breaks, the cell has to panic because that's either gonna cause a cancer or kill the cell. There's only two outcomes, it's pretty much a problem. And so what the cell does is it reorganizes the epigenome in a massive way. What that leads to is, think of it as a tennis match or a ping pong game. The proteins are the balls and they now leave where they should be, which is regulating the genes that make the cell type whatever it is. And they have a dual function, they actually go to the break, the chromosome will break and fix that. And then they come back. You might ask, well why is it set up that way? Well it's a beautiful system, it coordinates gene expression the control systems with the repair. You want them coordinated. Problem is as we get older, this ping pong game some of the balls get lost. They don't come back to where they originally started. And that's what we think is the main noise for aging. The other cause of aging that we found is cell stress. We damaged nerves and they age rapidly. So that's the other issue, there's probably others. Smoking chemicals for example we know accelerates biological age pretty dramatically. But the question is can you slow that down or can you reset them to get those ping pong balls to go back to where they originally started in the game? And we think we've found a way to do that. - Well can you give me hints? Whose fault is it in the balls not coming back? Is it the proteins themselves? Like are they starting? Again I've been obsessed with the protein folding problem from the AI perspective. So is it the proteins or is it something else? - Well we know who hits the balls and recruits them. So that the break is recognized by proteins who send out a signal through phosphorylation is a typical way cells talk to other proteins. And that recruits those repair factors, those ping pong balls to the break. So the cell's actively doing this to try and help itself. But we don't know who's to blame for them not coming back. That could just be a flaw in the quote unquote design. I don't think that there's something saying well one percent of you balls, proteins never go back. I just think it's hard to reset a system that's constantly changing. We have in our bodies close to a trillion DNA breaks every day and imagine that over 80 years what damage that does to our epigenomic information. Now we know that this is, well we never know anything in biology but we have strong evidence that this is true because we can mess with animals, we can create DNA breaks and tickle them with a few breaks, maybe raise it by threefold over background levels of normal breakage. And if we're right, those mice should get old. And they do. We've created these breaks in a way that's titratable. It's like a rheostat, we can send it to 11. I drove my Tesla here, I'm a big fan of Spinal Tap 2. - Going to 11. - If we go to 11 we can make a mouse old in a matter of months. We prefer to go to a level of about four and it gets old in 10 months. But it's definitely old. It's got all of the hallmarks of aging, it's got diseases, it looks old, its skin is old, it's got gray hair. But importantly we can now measure age by looking at the scratches. We can look at the epigenome, we can measure it and use machine learning to give us a number and those mice are 50% older than normal. - So you can replicate the aging process in a controlled way. You can, I mean, in a way that you, I mean you could accelerate it in a controlled way and measure how much exactly it's aging and that gives you step one of a two-step process to when you can then figure out how can we reverse this. - And now we're reversing those mice. - Is there a good, I love what you said, I mean in biology you really don't know. It's such a beautiful mess. Is there ideas how to do that?

Genetic reset switch that reverses aging (35:50)

Is that on the genetic engineering level? Is it like what can you mess with? Is it going to the, trying to discover the backup copies and restoring from them? Like what's, if it's possible to convert it to natural language words, what are the ideas here? - What is the observer and how do we contact it? - Exactly, what's the observer and how do you contact it? Or if there's other ideas, how to reverse the boss getting lost process. - Yeah, well you can slow it down. - Slow it. - But we found that a reset switch recently, we just published this in the December 2020 issue of Nature. And what we found is that there are three embryonic genes that we could put into the adult animal to reset the age of the tissues. And it only takes four to eight weeks to work well. And we can take a blind mouse that's lost its vision due to aging, neurons aren't working well towards the brain, reset those neurons back to a younger age and now the mice can see again. These three genes are famous actually because they're a set of four genes discovered by Shinya Yamanaka, who won the Nobel Prize in 2016 for discovering that those four genes when turned on at high levels in adult cells can generate stem cells. And this is I think well known now that we can create stem cells from adult tissue. But what wasn't known is can you partially take age back without becoming a tumor or generating a stem cell in the eye, which would be a disaster. And the answer is yes, there is a system in the body that can take the age of a cell back to a certain point but no further, safely, and reset the age. And we're now using that to reset the age of the brain of those mice that we age prematurely and they're getting their ability to learn back. - This is really exciting, right? Like what's the downside of this? - Well the downside is if you overdo it and you don't get it right, you might cause tumors. But we do it very carefully and we also know that in the eye it's very safe. We also injected these, we deliver them by viruses so we can control where and when they get turned on. And in this paper we've published that if we put high levels in the mouse into their veins throughout the body they don't get cancer for over a year. So I'm so optimistic that we're going into human studies in less than two years from now. - Is there a place where AI can help?

AI in biology (38:20)

Sorry to inject one of the things I'm very excited about and passionate about. So Google DeepMind recently had a big breakthrough with AlphaFold 2, but also AlphaFold two years ago with achieving sort of state of the art performance on the protein folding problem, single protein folding. But it also paints a hopeful picture of what's possible to do in terms of simulating the folding of proteins, but also simulating biological systems through AI. Is there something to you combined with this brilliant work on the biology side that you're hopeful about where AI can be a tool to help? - Where isn't that a tool? I mean if you're not using AI right now in biology you're getting left behind. We use it all the time. We're using it to generate these biological clocks to be able to read those scratches. We're using it to predict the folding of proteins so we can target molecules and modulate their activity. We're using it to assemble genomes of different species. What else? We use it to predict the longevity of a mouse based on how it reacts to certain things, hearing, eyesight, generally frailty. So we just put out a paper last year on that. The other thing we can use it for, which is a little off the track here, but we use it for predicting which microorganisms are in your body, actually not predicting, telling you. So our daughter, Natalie, was infected with Lyme disease a few years ago, almost went blind from it, and the test took four days, and I thought, just give me the DNA from her spinal fluid. I'll go tell you what's in it, if it's Lyme disease or not. They refused. And so at that point I said, this has to be done better. So I started a company that now can take a sample of any part of your body. It's typically done now with liver transplant patients to detect viruses that come out of their organs. But that's another area that AI is extremely important for. I think if you're not, in five years, if you're not using deep learning, you've got a problem, because the amount of data that we generate now as biologists is just terabytes, can be terabytes per week, it'll eventually be terabytes per day, and then we just go from there. And I actually have trouble recruiting enough bioinformaticians. A lot of our work is now just number crunching. - A part of that is collecting the data, which is kind of something we've talked a little bit about, but is there something you can say about how we can collect more and more data, not just on the one person level, like for you to understand your various markers, but to create huge data sets to understand how we can detect certain pathogens, detect certain property characteristics of whether it's aging or all the other ways that the human body can fail.

Health data (40:52)

It seems like with biology, there's a kind of privacy concerns that, well, actually not privacy concerns, it's almost like regulation that kind of prevents like hospitals and sharing data. I'm not sure exactly how to say it, but it seems like when you look at autonomous vehicles, people are much more willing to share data. When you look at human biology system, people are much less willing to share data. Is there a hopeful path forward where we can share more and more data at a large scale that ultimately ends up helping us understand the human body and then treat problems with the human body? - So we are right in the middle. We're living through what's gonna be seen as one of the biggest revolutions in human health. Through the gathering of data about our bodies. And 20 years ago, people didn't wanna go on social media, they're worried about it. Now you have to if you're a kid, that's for sure. Same with medical records. These are becoming all digitized and expanded. Ultimately, we're going to, even if we don't want to, have to be monitored. There's gonna be a court case that I bet two, three years from now someone's gonna say, how come my father died from a heart attack? You had these biosensors, 20 bucks, and you didn't use it. Lawsuit right there and suddenly all hospitals have to give you one of these. - There'll be a reversal. It's your fault if you don't collect the data, that's brilliant. That's absolutely right. That's absolutely right. That's the frustration I feel when going to the doctor. It's almost negligent to not collect the data because you're making, there's something really wrong with me and you're making decisions based on very few tests that's almost negligent when you have the opportunity to collect a huge amount more data. - Well, let me tell you something. Lex, I've got this inside tracker data for myself over a decade and you'd think my doctor would roll his eyes at this, oh, he's gone to a consumer company, blah, blah, blah. I had my first checkup in a year with him through video conference and he was running blind. He really didn't know what was going on with me. He asked the usual things, how am I sleeping, how am I eating, these kind of usual things. And I said, well, I've got new tests back from inside tracker and he said, great, I'd love to see them. So I'd share screen and we'd look at the graphs, look at the data, and he's loving it 'cause he cannot order these tests willy-nilly. So I said, well, let's order a HbA1c blood glucose levels because I'm very interested in that. That tracks with longevity. And he said, well, I have no reason to order that. Do you have a family history? No. Do you have any symptoms of diabetes? No, well, I can't order the test. I almost wanted to reach through the computer and strangle him, but instead, I pay a little bit to get these tests done and then he looks at them. So that's now the way consumer health is going is that you can get better data than your doctor can, but they'd like you to do that. Quick human question, maybe you can educate me. I think doctors sometimes have a bit of an ego. I understand that the doctor is super experienced with a lot of things, but this is a fundamental question of human variability. Like I know a lot of specific details about like, I mean, it depends, of course, what we're talking about, but I bring a lot of knowledge and if I have data with me, then I have like several orders of magnitude more knowledge and I think there's an aspect to where the doctor has to put their expert hat, like take it off and actually be a curious, open-minded person and study and look at that data. Do you think it's possible to sort of change the culture of the medical system to where the doctors are almost, as you said, are excited to see the data? Or is that already happening? It's really happening. Now, we've probably lost the last generation. There are no hopers, but so I teach at Harvard Medical School and they're excited about this. They're excited about aging, which is a new aspect to medicine. Oh wow, we can do something about that? And then, yeah, all this data, what do we do with it? There's still the traditional pathology and all that stuff, which they need to know. But time will change their mindset. I'm not worried about that and like we were discussing, this isn't a question of if. It's just a matter of when. And I have a front row seat on all of this. I had breakfast with a CEO who is making this happen just yesterday. I can tell you for sure that most people have no idea that this revolution is occurring and is happening so quickly. If you're running a hospital and you can save $2,000 per cardiac patient, what are you gonna do? You have to use it. Otherwise, the hospital down the road's gonna be beating you. And there are large hospital aggregations, so there's Ascension and others that just have to go this way for budgetary reasons. And right now, the US spends, what is it, 17% of their GDP on healthcare. Let's say one of these buttons on my chest costs 20 bucks, it's rechargeable. And it can predict people's health and save on antibiotics for prevent heart attacks. How many billions, if not trillions of dollars will that save over the next decade? - Yeah, so when the public wakes up to this, they'll almost demand it. Like this should be accepted everywhere. This is obvious. It's gonna save a lot of money. It's gonna improve the quality of life. - Well, and the CFOs of hospital groups will have to. And insurance companies are gonna wanna get in on this. So now that gets to privacy, right? Should an insurance company have access to your data? I would say no, but you could voluntarily show them some of it if they give you a discount. And that's also being worked on right now. - I hope we do create kind of systems where I can volunteer to share my data and I can also take the data back. Meaning like delete the data, request deletion of data. And then maybe policy creates rules to where you can share data, you could delete the data. And I think if I have the option to delete all my data that a particular company has, then I'll share my data with everyone. I feel like if, because that gives me the tools to be a consumer, an intelligent consumer of giving, of awarding my data to a company that deserves it and taking it back when the company is misbehaving. And in that way, encourage as a consumer in the capitalist system, encourage the companies that are doing great work with that data. - Well yeah, healthcare data security is number one. On my mind, Inside Tracker made sure that that was true. But these buttons on your chest, there's very private stuff. They can probably tell if you're having sex one night, right? So this is not the kind of stuff you want leaked. So I don't know whether it's blockchain or something. - Speak for yourself, I don't want this public. Live streamed. - Well I guess it depends on how you go, but there's a lot of stuff you don't want out there. So this definitely has to be number one 'cause it's one thing to have your credit card information stolen, it's another thing your health records are permanently out there. - Yeah, so there's on the biology side, super exciting ways to slow aging.

Fasting (48:58)

But there's also on the lifestyle side. I've recently did a 72 hour fast. Just an opportunity to take a pause and appreciate life. Think about, there's something about fasting that encourages you to reflect deeper than you otherwise might. The time kind of slows and you also realize that you're human because your body needs food and you start to see your body's almost as a machine that takes food and produces thoughts. And then ends, breathes. I mean, you start to, depending who you are, if you're like engineering minded, you start to think of this whole thing as a machine. And then also feelings fill this machine. Feelings of gratitude, of love, but also the uglier things of jealousy and greed and hate and all those kinds of things. You start to think, okay, how do I manage this body to create a rich experience? All of that comes from fasting for me. Anyway, but there's also health benefits to fasting. I intermittent fast a lot. I eat just one meal a day most of the time. Is there something you could say about the benefits of fasting in your own life and in general the anti-aging process? - Well, you're a philosopher too. - Sorry, I apologize. - No, I'm impressed. True renaissance, man. It's a joy to be here. So when it comes to fasting, this is, being abstemious is one of the oldest ways to improve health. Probably they knew this 5,000 plus years ago. So that's not new. But what we're figuring out is what is optimal and how does it work? And one of the things we help contribute to, which I can speak to with some authority, is that these longevity genes we work on, we showed back in the early 2000s, are turned on by fasting. And at least in yeast, we were the first to show that how calorie restriction fasting works to extend lifespan. And that was the first for any species. Something similar happens in our bodies. When we're hungry or put our bodies under any other perceived adversity, such as running, our bodies think, wow, we're getting chased by a saber-toothed cat or something. If we're really hot or cold, these probably also work to put our bodies in this defensive state to activate these genes in the way that whales do and mice don't. And so hunger is the best way to do that. In fact, I don't think you have to feel hungry. You can get used to it. But if there was one thing I would recommend to anybody to slow down aging would be to skip a meal or two a day. Now it doesn't mean you don't have to live well. You can go out. I go to restaurants. I eat regular food. I try to be as healthy as possible. But I've gone from skipping breakfast most of my life, now to skipping lunch as well. And I have my physique back that I had when I was 20. I feel 20 mentally. I'm much sharper. I don't feel tired anymore. I sleep well. So I'm a huge fan of the one meal a day thing. Where I'm not good at is going beyond one day. But if you do it three days-- - Have you ever fasted longer than 24 hours? - I tried doing two days. I might've made it to the third and given up. I just find that I don't have a lot of willpower. I also hate exercise. So I'm not sure how long I'm gonna live. But I've managed to do one meal a day. So if I can do that, seriously, anybody can do that. To your listeners and viewers, I would say, don't try to do it all at once. You can't go from snacking and eating three meals a day to what I do easily. Work your way up to it. But also compensate with drinking. If you like tea, if you like coffee, put some milk in it. That's fine. You can fill your stomach up with liquids. Diet sodas, I get criticized for drinking. But I'm gonna continue to have those. But I power through the day. I definitely don't feel tired. I don't have a lag anymore. But also give it at least two weeks. 'Cause there's a habit as well. Having something in your mouth, chewing, feeling that fullness. You can break that habit. And within two, three weeks, you'll have done it. - Absolutely. So I'm not actually even that strict about it. You said diet soda. Yeah, people are very kinda weirdly strict about fasting the rules. And fasting, like for example, I drank Element Electrolytes when I was fasting. And that has like five calories. And so technically it's not fasting. Or people will say like, if you drink coffee, there's caffeine, and they'll say, that's technically not fasting 'cause there's some kind of biological effects of caffeine, but whatever. Of course, there's like biological benefits that you can argue about. But there's also just experiential benefits. Just calorie restriction broadly has a certain experience to it that, like for me personally, just as you said, has made me feel really good. That said, like especially, I've gained quite a bit of weight. Like maybe even like 15 pounds, something like that, since I moved to Austin, Texas. And I still keep the same diet. But I eat a lot of meat in that one, just because it's delicious, because it's also the amazing people I met in Texas. It's just there's like a camaraderie, a friendship, a love to the people that like makes you really enjoy the atmosphere of eating the brisket and the meat. Is this Joe Rogan insisting? - Joe is, I mean, he's very different. Joe loves bread and pasta. Like he knows that his body feels best doing keto or carnivore. So that's what he usually tries to stick to. But he also does not hold back. And he'll just eat pasta when he does pasta. And he sort of enjoys life in that way. I can't, I don't know how to enjoy life in that way. I also love pasta, but I'm just not going to enjoy it, because I know my body ultimately does not feel good with pasta. So it's a funny kind of dichotomies. I would like to cheat, I guess, by eating more meat than I, you know, like overeating on the things that I know my body feels good on, as opposed to eating stuff I shouldn't, like cake and all those kinds of things. I tend to find happiness in overeating the good stuff versus eating the bad stuff. And that's the kind of balance. Him, he's like, fuck it. Every once in a while, you got to enjoy it. And then also coupled with that for him is just exercise, like then face his demons the next day and just like burn a huge amount of calories, which is, I mean, whatever's up with that guy's mind, there's an ability to fully experience life, which is represented by the pasta and the ability to just like fight the demons, which is represented by all the crazy kettle balls and running the hills and all this kind of stuff that he does. That takes a lot out of you doing that kind of insane exercise. And I think I'm more like you, or at least towards your direction is like, I really hate exercise. So I do it, but I really hate it. And so it's a balance that you have to strike.

Diet (56:29)

Is there something you could say about the diet side of that? For you personally, but in general, in order to achieve calorie restriction, like for me eating, I know it may not sound healthy, but eating carnivore, eating mostly meat has made me feel really good, both mentally and physically. Is there something you could say about the kinds of diets that may improve longevity, but also enable calorie restriction? - Well, sure. I mean, the first thing that's important to know is that while many people are interested/obsessed with what they eat, the data that's come out of animal studies at least is it's far more important when you eat than what you eat. And this was a fantastic study a few years ago by my friend, Rafael de Cabo at the National Institutes of Health in Bethesda. And he had 10,000 mice on different diets hoping to find the perfect mix of carbs, protein, and fat. And it turns out that the only ones that lived longer were the ones that only ate once a day. And so that, we're not mice, but I think that we're close enough to mice that this tells us a lot. But okay, but I still think the best bang for the longevity buck is to do both well. Eat less often and eat the right things. Now I'll preface this to say I'm not a nut about this. I will eat occasional, very occasionally a dessert. Usually I steal from others, which doesn't count, right? - Exactly. - But you gotta live life, right? What's a long life if it's not enjoyable anyway? But what I also have found, and this is, I'll get to your question in a second, but my microbiome right now and stomach is at a point where if I try to overeat on a steak, which I did a couple of days ago, I actually had a chicken, a fried chicken specifically, for two days I felt terrible. I couldn't sleep, it wouldn't go down. So I'm now at a point where even if I want to binge on meat and fried foods, I just can't, it just feels bad. But what do I recommend? Well, what the data says, which I try to follow, is that plant-based foods will be better than meat-based foods. And I know that there are a lot of people who disagree. But one of the facts is, well, there's a few facts. One is that people who live a long time tend to eat those type of diets, Mediterranean or Canara diet. They're eating mostly plants with a little bit of meat and not a lot of red meat. And the other fact is that in animals we know that there's a mechanism that's called mTOR, little m, capital T-O-R, that responds to certain amino acids that are found in more abundance in meat. And when it responds, it actually shortens lifespan. And the converse, if you starve it of those three amino acids, mostly in meat, then it extends lifespan. And there's a drug called rapamycin, which some people are experimenting with, that does that. So you might be able to, I'm just saying this here from all my colleagues, we don't know the results here, but you could potentially take a rapamycin-like drug and counteract the effects of meat in the long run. Don't know, we should try that, actually. We could do that in the lab. But getting to the bottom of this, what I think is going on is that, just like testosterone and growth hormone, you will get temporary, maybe not temporary, immediate health benefits. You'll feel great, you'll get more muscle energy. But the problem is, I think it's at the expense of long-term health and longevity. - Well, this is actually something I worry about in terms of long-term effects or the cost in terms of longevity. It's very difficult to know how your choices affect your longevity because the impact is down the line. Just because something makes me feel good now, like eating only meat makes me feel good now, I wonder what are the costs down the line. - Well, think about what I was saying about the trade-offs between growth and reproduction, which is what a mouse does, and a whale that grows slowly, reproduces slowly, lives a long time. It's called the disposable soma theory. Kirkwood proposed that in the '70s. What meat probably does is put you in the mouse category, super fertile, grow fast, heal fast, and then if you wanna be a whale, you should restrict meat and do things that promote the preservation of your body. - Is it difficult to eat a plant-based diet that you perform well under, so mentally and physically? Just, I'm asking almost like a anecdotal question, unless you know the science. - Well, the science is still being worked out, but from the synthesis of everything that I've read, I try to eat a diet that's definitely full of leafy greens. Particularly spinach is great, 'cause it's got the iron that we need, plenty of vitamins. I also try to avoid too much fruit and berries, particularly fruit juice. Definitely avoid that sugar high. Spiking your sugar is not healthy in the long run. The other thing that's interesting is we discovered what we called xenohormatic molecules. Let me unpack that, 'cause it's a terrible name, and I take full responsibility with my friend Conrad Howitz. The xeno means cross species, and hormesis is the term that what doesn't kill you makes you live longer and be healthier. So we're getting cross species health improvements by molecules that plants make. Plants make these molecules when they're also under adversity or perceived adversity. For instance, I understand if you want really healthy or good oranges, you can drive nails into the bark of the tree before you harvest. Same with wine, you typically want them to be dry before you harvest or covered in fungus. That's because these plants make these colorful and xenohormatic molecules that make themselves stress resistant, turn on their sirtuin defenses, the sora genes, remember? And when we eat them, we get those same benefits. That's the idea, and we've evolved to do so. This isn't a coincidence. It's my theory, our theory, that we want to know when our food supplies is under adversity because we need to get ready for a famine. And so we hunker down and preserve our body. And by eating these colored foods, so practically speaking, if it's full of color, if there's been some chewing by a caterpillar organic grown locally in local farms, I'll eat that versus a watery, insipid, light-colored lettuce that's been grown in California. - So you want vegetables that have suffered. You want the David Goggins' of vegetables. That's xenohormatic molecules. - I love that term. I'm gonna take that one with me, thank you. - Yeah, I follow him on Instagram. He's always screaming. So you want that he's basically the xenohormatic version of a human. I like it. So these are the molecules that are representative of the stress that a plant has been under. - Yeah, the best example of that is resveratrol, which many people, including myself, take as a supplement. Grapes, grape vines produce that in abundance when they're dried out or they have too much light or fungus and that we've shown activates the SIR2 enzyme in our bodies, which remember is what extends lifespan in yeast and slows down aging in the brain. - That's beautiful. Yeah, I tend to avoid fruit as well. So green veggies, anything that's not very sweet. So would you say you're relatively low, like you try to avoid sugary things as well? - Yeah, I'm fairly militant about that. I rarely would add sugar to anything. Occasionally I would eat a slice of cheesecake, but that would be maybe once or twice a year. You have to give in occasionally. But yeah, anything that's sweet, I would rather substitute something like Stevia if I need a sugar hit. - What about exercise, your favorite topic?

Exercise (01:04:40)

Is there a-- - I don't mind talking about it. - Yeah, okay, great. Is there benefits to longevity from exercise? - Well, no doubt, that's proven. Just like fasting, it's pretty clear that that works. For example, there are studies of cyclists. It was something like people that cycle over 80 miles a week have a 40% reduction in a variety of diseases, certainly heart disease. So that's not even a question, but what's interesting is that we're learning that you don't need much to have a big benefit. It's an asymptotic curve. And in fact, if you overdo it, you probably have reduced benefits, particularly if you start to wear out joints, that kind of thing. But just 10 minutes on a treadmill a few times a week, lose your breath, get hypoxic as it's called, seems to be very beneficial for long-term health. And that's the kind of exercise that I like to do, aerobic. Though I do enjoy lifting weights, so that is what I call my exercise, which has other benefits, including maintaining hormone levels, male hormone levels, but also really why I do it is I want to be able to counteract the effect of sitting for most of the day. And as you get older, you lose muscle mass. It's a percent or so a year. And I don't wanna be frail when I'm older and fall over and break my hip, which happens every 20 seconds in this country. - So maintaining that strength, but also doing the cardio for the longevity for avoiding the heart disease. Yeah, I definitely just stick with fasting, have the philosophical benefit of running long and running slow. I enjoy it 'cause it kind of clears the mind and allows you to think, actually listen to brown noise as I run. It really helps remove myself from the world and just like zoom in on particular thoughts. - What is brown noise? - It's like white noise, but deeper. So like the white noise is like, shh, and then brown noise is more like, like ocean. - That sounds great. I might try that. - Yeah, yeah, it's a-- - More soothing probably. I'm not sure, there could be signs to this. I need to look this up. I've been meaning to. But when I started, this is maybe like five years ago, I started listening to brown noise when I work. And the first time I listened to it, something happened to my mind where it just went like, zoomed in to like, in a way that it felt like really weird, like how precisely it was able to sort of remove the distractions of the world and really help my mind. Obviously, like the mind is trying to focus and then it just enabled that process of trying to focus on a particular problem. I don't know if this is generalizable to others. People should definitely try it if you're listening to this. Maybe it's just my own mind, but it's funny like, it made me, brown noise made me realize that there's probably hacks out there that work for me that I should be constantly looking for. It's almost like an encouraging and motivating event that maybe there's other stuff out there. Maybe there's other brown noise like things out there that truly like almost immediately make me feel better. I don't know if it's generalizable to others, but it does seem that it's the case that there's probably for many others, things like that that could be discovered. And so it's always disappointing when I find things in life that I wish I would found earlier. I had got LASIK eye surgery a few years ago, and the first thought I had like the next day when I woke up is like, "Damn it, why didn't I do this way earlier?" There's other stuff of that nature that are yet to be discovered, so it pays to explore. - Yeah, though you have a different mind. You have quite a beautiful mind. So I suspect brown noise helps you focus and 'cause you're probably all over the place if you don't control it. - Yeah, exactly. It means something about it. It's a programmer thing. Programming is a really difficult mental journey 'cause you have to keep a lot of things in mind. So you're constantly designing things, then you have to be extremely precise by making those things concrete in code. You also have to look stuff up on the internet to sort of feed like information and looking up stuff on the internet. Internet is full of like distracting things, so you have to be really focused in the way you look stuff up in pulling that information in. So it requires a certain discipline and a certain focus that I've been very much exploring how to do. Like I do it really well in the morning, coffee is involved, all those kinds of things. You're trying to optimize, keeping very positive, inspired, no social media, all those kinds of things and trying to optimize for. And everybody has their own kind of little journey that they try to understand. You get this from like writers. When you read about the habits of writers, like the habits they do in the morning, they usually write like two, three, four hours a day and that's it. It's like they optimize that ritual. And then there's always Hunter S. Thompson. So sometimes it pays off to be wild. What about sleep?

Sleep (01:10:01)

How important is sleep for longevity? - I would guess based on the evidence that it's really important and because we don't know for sure. But what we know from animal studies is the following. If you restrict sleep from a rat for just two weeks, it'll develop type two diabetes. It's that important. So that's the main thing. What we also know is at the molecular level that if you disrupt your sleep-wake cycle, so we actually have proteins that go up and down that control our sleep-wake. All of us, most of our cells do that. If you disrupt that, you'll get premature aging. And guess what? The opposite is true. That as you get older, that cycle, the amplitude becomes diminished. And this is why it's harder to get to sleep as you get older and then you got all sorts of problems. And I think what's going on is this positive feedback loop which is a disaster in your old age, which is you're aging. You can't at this moment totally prevent that. And then it's disrupting your sleep and you get not enough sleep and then that's gonna accelerate your aging process. And so it's known that people who are shift workers are more susceptible to certain age-related diseases. So your bottom line, you definitely wanna work on that. It's one of the reasons I have this ring on my finger which helps me optimize my sleep and learn what I do the day before if it was a bad idea and I'll stop doing that like eating a fried chicken. - I see you're still carrying the burdens of that decision. But yeah, sleep is one of those things that's making me wander about the variability between humans a little bit and how science is often focused on, it's not often focused on high performers in a particular way. And it's looking at the aggregate versus the individual cases. For example, for me, I don't know what the exact hours are but like power naps are incredible. I tend to look at the metric of stress and happiness and joy and try to optimize those. So decreasing stress, increasing happiness and using sleep as just one of the tools to do that because like hitting the five, six, seven, eight, nine hour mark or whatever the correct mark is, I find that to be stress inducing for me versus stress relieving. Like thinking about that, I feel best if I sleep sometimes for eight hours, sometimes for four hours and then power nap and as long as I have a stupid, private usually, smile on my face, that's when I'm doing good as opposed to getting a perfect amount of sleep according to whatever the latest blog post is. And I also pull all nighters still. I also think there's something about the body, like as long as you do it regularly, it's not as stress inducing, like you know what it is. The reason I pull all nighters isn't for like, I'm playing Diablo 3 or something is because I'm doing something I'm truly passionate about. Well, I'm also a love leader of games but I'm doing something I'm truly passionate about. And it's almost like there's the Jocko Willing feeling of when I'm up at 7 a.m. and I haven't slept all night and still I'm working on it, there's a kind of a celebration of the human spirit that I really enjoy it. And that's happiness. And to sort of then, and I usually don't tell that kind of stuff to people because their first statement will be like, you should get more sleep. It's like, no, I'm doing stuff I love. You should get more love in your life, bro. That's right. So, but that said, in aggregate, when you look at the full span of life, it's probably you should be getting a consistent amount of sleep. And it seems like it's in that seven, eight hour range. Yeah, but it's similar to food. It's the quality, not the quantity, right? And when you get it. So I look at my data pretty often and what makes a difference to me is not the amount of hours but the quality, the depth and the deep sleep is what'll do it. So if I have a lot of alcohol before going to sleep and I can see my heart rate being different, but what really kills me is that I don't get a lot of that deep sleep and I wake up, barely remembering stuff. So that, like you say, if you're happy and contented and you don't have these cortisol chemicals going through your body, you will more naturally get into that deep state. And even if you just get four hours, way better than eight hours of none of that. Yeah, that's beautiful. And some of that could be genetic. For me, I just, I fall asleep like this. If you want me to fall asleep right now, I can do it. It's no, I have no problem with it. Combined with coffee, I just had two energy drinks. I can probably sleep. So that, I don't know if that's genetics or it's kind of, I don't know what it is or maybe that I don't have kids and I'm single. So I don't have, I'm almost listening to some kind of biological signal versus societal signal on when I'm supposed to go to sleep. So I just go to sleep whenever I feel like going to sleep. Well, that's 'cause you're self-employed. - Most people don't have that luxury, but we're lucky, the two of us, that we can make our own hours. But yeah, it's super important and those people who have the shift work, I mean, they really need to change the way that works because they're literally killing those people. - Is there something you can say about the mind and stress in terms of the effect on longevity? Sort of, 'cause I don't know if you think about it this way, but when you talk about the biological machine, it's always these mechanisms that are not necessarily directly connected to the brain or the operation of the brain. Like what's the role about stress and happiness and yeah, the sort of higher cognitive things going on in the brain on longevity? - Right, well, that's a great point. That the brain is the center for longevity, actually. We do know that. For a start, when I'm stressed, I can see, mentally stressed, then I can see it in my body. Heart rate, hormones, it's clear. That's no true surprise. So you've gotta work on your brain first and foremost. If you are totally freaked out, agitated all the time, you will live shorter. I'm certain of it. I keep fish. I'm a big aquarium guy. And you can see the difference between the fish that's having a good time and dominant and one that gets picked on. It just looks like crap. You don't wanna be the little fish getting picked on if you can help it. So I used to be extremely stressed as a kid. I was a perfectionist, very shy, always worried about being a failure. If I didn't get an A+, I was crying in my bedroom, that kind of sad existence. I got into my 20s, then in my 30s and realized that's not the way to live. So I've worked very hard to get to this point where I almost never get stressed, never. There's nothing that, I've never gotten angry in my lab. I've got 20 kids. Sometimes it's like a, most of the time it's like a kindergarten. I haven't lost my temper. I'm very calm. But that's intentional. And I don't worry about stuff. Millions of dollars, billions of dollars at stake sometimes. Keep it cool. It's only life. We're all headed to the same place anyway. Don't worry about it. But to answer your question, I think, in a better way, if you manipulate the brain of an animal, I'll give you an example. If we turn on this SIRT gene that I mentioned, SIRT1, we, a good friend of mine at Wash U, she and I did this. They upregulated that gene just in the neurons of the animal. It lived longer. So that's sufficient to extend lifespan. We also know that you can manipulate the part of the brain called the hypothalamus, which leeches a lot of chemicals into the body and proteins, most of which we don't know yet. But just changing the inflammation of that little organ or part of the brain is sufficient to make animals live longer as well. So get your brain in order first before you tackle anything else, I would say. - So you kind of mentioned this.

Longevity And The Concept Of Immortality

Data (01:18:29)

With the Inside Tracker, there's ability to take blood measurement and then infer from that a bunch of different things about your body, how you can improve the longevity. And you've also mentioned saliva and more efficient ways to get data. What does that involve? What's the future of data collection look like for the human biological system? - Right, well, yeah, the issue with blood is you need someone to take it. I mean, or you prick your finger, which hurts. So you gotta have something better. So I think what the future looks like is that you'll spit onto a little piece of paper and stick it in a machine and it'll do that for you. But we're not there yet. So the intermediate future that I'm building right now is that you would take a swab of the inside of your mouth, which is the easiest way to take cells out of your body, and just ship them off. Okay, so it's called a buckle swab. I think we became very used to that. Right now, because of COVID, people don't like going to the doctor as much. They don't like going out. They just wanna have home tests. And so that, I think, is the next 10 years where you'll get a kit in the mail, you'll swab your cheeks, stick it back in an envelope, send it off, and a week later, you have either a doctor's report or a health recommendation. And what can you get off a cheek swab? Well, you can get anything. You can get hormones, stress levels, stress hormones, blood glucose levels. You can also tell your age reasonably accurately doing that, actually quite accurately. And those clocks cannot just tell you how you're doing over time, but can be used to give you recommendations to slow that process down. 'Cause some people sometimes are 10 years older biologically than their actual chronological age. I mean, why does it matter how many times the Earth's gone around the sun, seriously? Who cares about birthdays? It's how long your body's clock has been ticking and how fast. So I could take a cheek swab from you today, Lex, take it back to my lab, and we then, by tomorrow, tell you how old you are biologically based on what we call the epigenetic clock. And you might be freaked out, you might be happy, but either way, we can advise you on how to improve the trajectory. 'Cause we know that smoking increases the speed of that clock. We also know that fasting and people who eat the right foods have a slower clock. Without that knowledge, you're flying blind. But I like the idea of a swab 'cause it's just so easy. A lot of us have done something like that for COVID tests. It's not a big deal. - Yeah, we've been doing a nonstop rapid antigen test. So let me say that particular one rapid antigen test, they've been a source of frustration for me because everybody should be doing it. It's so easy. - We've also been working in my lab on democratizing these tests to bring them down from a few hundred bucks to a dollar. - So just to clarify, you're talking about not research, you're talking about company stuff, like actual consumer-facing things? - Well, right. The research on bringing the price down has occurred in my lab at Harvard, and then that intellectual property is being licensed and has been licensed out to a company that will be consumer-facing. So anybody for a small amount of money can do this. - Well, you got subscriber number one obsessed. I think that's a beautiful, beautiful idea. So somebody who maybe I would have been more hesitant about it until COVID, but home tests are super easy. I almost wanted to share that data with the world, like in some way, not the entirety of the data, but some visualization of how I'm doing. It's almost like when you share, if you had a long run or something like that, I wish I could share, 'cause it inspires others, and then you can have a conversation about, well, what are the hacks that you've tried, and have a conversation about how to improve lifestyle and those kinds of things that's grounded in data. - That's exactly, that's what's gonna happen. Now, everything's anonymous, of course. We talked about security there. But once it's anonymized, you can then plot these numbers. And I've plotted my epigenetic age versus hundreds of other people who have taken this test now. And I can tell you where I fit relative to others in terms of my biological age. And I'm happy to share that with you all 'cause it's been pretty low. You can choose to share it, of course. Not everyone wants to share that. But when you go to the doctor, first of all, your doctor does treat you as though you're an average person, and none of us are average, there's no such thing. But second of all, we never know how we're doing relative to others 'cause we all, most of us, we don't share our information. So we might have this number and that number. But do you know that your numbers are good for your age or not? You have no idea. Even your doctor probably doesn't even know. So this graph that I'm talking about is the beginning of a world where you can say, how am I doing? I'm a, for the two of us, we're white, and we're male, and we're this age. And we do this. Are we good, are we doing the right things, or the wrong things? Do we need to fix certain things? And this is what the future is. Forget about just experimenting and not knowing the result. I mean, who doesn't experiment and doesn't look at the data? No one, it makes no sense. So we're gonna enter a world where we have a dashboard on our body, the swabs, the blood tests, the biosensors, where our doctors can look at that, but we can also look at it, and they can recommend. Go to this restaurant down the road, they've got this great meal. It's high in whatever you need today 'cause you're lacking vitamin D and vitamin K2. Go for it. - Ridiculous question, or perhaps not.

Extending lifespan (01:24:00)

If you look maybe 50 years from now, or 100 years from now, a person born then, what do you think is a good goal in terms of how long a person would live? Like, what is the maximum longevity that we can achieve through the methods that we have today of, or are developing some of the things we've been talking about in terms of genetics, in terms of biology? Is there a number? - Right, well, so it changes all the time because technology's changing so quickly. I keep revising the number upward. But I would say that if you do the right things during your life and start at an early age, let's say 25, we don't want malnutrition, starvation, that's not what I'm talking about, but in your 20s, start eating the kind of diets that I talked about, skipping meals. In animals, that gives you an extra 20 to 30%. We don't know if that's true for humans, and that would, even 5% more would be a good, a big deal for the planet. I think that we should all aim to at least reach a century. I'm a little bit behind. I was born too early to benefit the most from all of this discovery. Those of you who are in your 20s, you should definitely aim to reach 100. I don't see why not. Consider this, this is really important. The average lifespan of a human that looks after themselves but doesn't pay attention is about 80, okay? Japan, that's the average age for a male, a bit higher. If you do the right things in your life, which is eat healthy food, don't overeat, don't become obese, do a bit of exercise, get good sleep and don't stress, that gives you on average 14 extra years. That gets you to 94. So getting to 100, if you just focus on what I'm talking about, it's not a big deal. So what's the maximum? Well, we know that one human made it to 122 and a number of them make it into their teens. I think that's also the next level of where we can get to with the types of technologies that I'm talking about. Medicines, like I mentioned rapamycin, there's one called metformin, which is the diabetes drug which I take. That in combination with these lifestyle changes should get us beyond 100. How long can we ultimately live? Well, there's no maximum limit to human lifespan. Why can a whale live 300 years but we cannot? We're basically the same structure. We just need to learn from them. So anyone who says, oh, you max out at X, I think is full of it. There's nothing that I've seen that says biological organisms have to die. There are trees that live for thousands of years and their biochemistry is pretty close to ours. - What do you think it means to live for a very long time?

Immortality (01:26:42)

Let's say if it's 200 years we're talking about or a thousand years. There's some sense you could argue that there is immortal organisms already living on Earth, like there's bacteria. So there's certain living organisms that in some fundamental way do not die because they keep replicating their genetic, they keep like cloning themselves. Is it the same human? If we can somehow persist the human mind, like copy clone certain aspects and just keep replacing body parts? Do you think that's another way to achieve immortality? To achieve a prolonged sort of increased longevity is to replace the parts that break easily and keep, 'cause actually from your theory of aging as a degradation of information, so an information theory view of aging, like what is the key information that makes a human? Can we persist that information and just replace the trivial parts? - Yeah, I mean the short answer is yes. We're already replacing body parts, but what makes us human is our brain. Everything else is suboptimal except our brain. The ability to replace actual neurons is really hard. I think it might be easy to upload rather than replace neurons because they're so tight, it's such a network, and just perturbing the system. It's Frodenker's cat. You change everything once you get in there. The problem is, well I guess the solution, let me go to the solution, that's more interesting. What we're learning is that if you reverse the age of nerve cells, it looks like they get their memories back. So the memories are not lost. They're just that the cells don't know how to interpret them and function correctly. This is one of the things we're studying in my lab. If you take an old mouse that has learned something when it was young but forgotten, does it get that back? And all evidence points to that being true. So I'd rather go in and rejuvenate the brain as it sits rather than replace individual cells, which would be really hard. - What do you think about efforts like Neuralink, which basically you mentioned uploading, are trying to figure out, so creating brain-computer interfaces that are trying to figure out how to communicate with the brain, but one of the features of that is trying to record the human brain more and more accurately. Do you have hope for that to, of course it will lead to us better understanding from a neuroscience perspective of the human mind, but do you have hope for it increasing longevity in terms of how it's used? - I think that it can help with certain diseases, but I see, at least within our lifetime, that's the best use of it, is to be able to replace parts of the body that are not functioning, such as the retina and other parts, the visual cortex back here. That's going to be doable. In terms of longevity, maybe we could put something on the hypothalamus and start secreting those hormones and get that back. Ultimately, I think the best way to preserve the brain is gonna be to record it, but also, I think it's gonna require death, unfortunately, to then do very detailed scans, even if you have enough time and money, atomic microscopy, and rebuild the brain from scratch. - Rebuild from scratch, yeah. We are living more and more in a digital world. I wonder if the scanning is good enough for the critical things in terms of memories, in terms of the particular quirks of your cognitive processes. - They're not, they're not. We're not close, yes, but we've made quite a bit of progress, so it's, if you're an exponential type of person. - Yeah, well, let's dream a little here. - Yes, that's the point. - The way it would work, that I could see it working, is you take a single cell slice through your dead brain, and we can now, the problem with the engineering aspect is that the engineering is, the physical aspect of the brain is not even half the problem. The problem is which genes are switched on and off. This experience that we're having here is altering certain genes in neurons that will be preserved, hopefully, for a number of decades, but you cannot see that with a microscope easily. But there are technologies invented, actually just down the hall in the building I'm at, George Church invented a way, his lab invented a way, to look at which genes are switched on and off, not only in a single cell, which any lab can do these days, but in situ, where it's situated in the brain. So you can say, okay, this nerve cell had these genes switched on and these switched off, we can recreate that. But just scanning the brain and looking how the nerves are touching each other is not gonna do it. - Wow, okay, so you have to scan the full biology, the full details. - And look at the epigenome. - And the epigenome too. - Yeah, which genes are on and off. It's just easier to reset the epigenome and get them to work like they used to. - True, true. - We're doing that now. - Use the hardware we already have, just figure out how to make that hardware last longer. - Right, ultimately information will be lost. Even genetic information degrades slowly through mutation. So immortality is not achievable through that means, though I think we could potentially reset the body hundreds of times and live for thousands of years. - Okay, so we talked about biology.

Denial of death (01:32:28)

Let's, forgive me, but let's talk about philosophy for just a brief moment. So somebody I've enjoyed reading, Ernest Becker wrote "The Denial of Death." There's also Martin Heidegger. There's a bunch of philosophers who claimed that most people live life in denial of death. Sort of, we don't fully internalize the idea that we're going to die. Because if we did, as they say, there will be a kind of terror of, I mean, a deep fear of death. The fact that we don't know what's, like we almost don't know what to do with non-existence, with disappearing. Like our, the way we draw meaning from life seems to be grounded in the fact that we exist and that we, at some point, will not exist is terrifying. And so we live in an illusion that we're not going to die and we run from that terror. That's what Ernest Becker would say. Do you think there's any truth to that? - Oh, I know there's truth to that. I experience it every day when I talk to people. We have to live that way, although unfortunately I can't. But for most people, it's extremely distressing to think about their own mortality. We think about it occasionally. And if we really thought about it every day, we'd probably be brought to tears. How much we'd not just miss ourselves, but miss our family, our friends. We are of, all living life forms have evolved to not want to die. And when I mean want, biochemically, genetically, physically. That yeast cell, the cells that I studied at MIT, they were fighting for their lives. They didn't think. But our brain has evolved the same survival aspect. Of course, we don't want to die. But the problem for us, unfortunately, it's a curse and a blessing, is that we're now conscious. We know that we're going to die. Most species that have ever existed don't. That's a burden, that's a curse. And so what I think's happened is we've evolved certainly to want to live for a long time, perhaps never want to die. But the thought about dying is so traumatic that there is an innate part of our brains, and it's probably genetically wired to not think about it. I really think that's part of being human. Because, you know, think about tribes that obsessed with longevity every day and that were going to die. They probably didn't make much technological progress 'cause they were just crying in their huts every day or on the savanna. I really think that we've evolved to naturally deny aging. And it's one of the problems that I face in my career, and when I speak publicly and on social media, is that it's shocking. People don't want to think about their age, but I think it's getting better. I think my book has helped. These tests that we're developing should help people understand it's not a problem to think about your long-term health. In fact, if you don't, you're going to reach 80 and really regret it. - And the other side of it, so again Ernest Becker, but also Viktor Frankl, I recommend to highly man-search for meaning.

Contemplating Life And Death

Meaning of life without death (01:35:45)

Bernard Williams, he's a moral philosopher. They kind of argue that this knowledge of death, even if we often don't contemplate it, we do at times. And the very, what you call the curse, which I agree with you, it's a curse and a blessing that we're able to contemplate our own mortality. That gives meaning to life. So death gives meaning to life. As what Viktor Frankl argues, I would probably argue the same, there's something about the scarcity of life and contemplating that that makes each moment that much sweeter. Is there something to that? - I think it's individual. In my case, it's completely wrong. - I appreciate you saying that. - I don't get joy out of every day because I think I'm gonna die. I get joy out of every day 'cause every day is joyous and I make it that way. And even if I thought I was gonna live forever, I would still be enjoying this moment just as much. And I bet you would too. - Well, I think about that a lot. I think it's very difficult to know. I'm almost afraid that I wouldn't enjoy it as much if I was immortal. I'm almost afraid to want to be immortal or to live longer because it perhaps is a kind of justification for me to accept that I'm going to die. It's saying like, oh, if I was immortal, I wouldn't be able to enjoy life as much as I do. But it's very possible that I would enjoy just as much. Of course, enjoying life, whether you're mortal or not, takes work. It requires you to have the right kind of frame of mind. You can discover, you can focus your mind on the ugliness of life. There's plenty of ugly things in this world and you can focus on them. You can complain. Whenever, if it's raining outside, you can focus on the fact that you have shelter and enjoy the hell out of it, or you can enjoy running in the rain when it's warm and the beauty of nature, just being one with nature. Or you can just complain in this fucking weather again in Boston. And then it's either always raining or freezing, damn it. And the same thing with wifi going out on airplanes. You can either complain about stupid wifi on JetBlue or something, or you could say how incredible it is that I can fly through the sky and in a matter of hours be anywhere else in the world. And then it could also on occasion check email and even watch movies while connecting through satellites that are flying through space. So it's a matter of perspective and perhaps there's an extra level of work required when you're a mortal, because it's easier when you're a mortal or live longer to be lazy, to delay stuff. But if you're not, you can still derive the same amount of joy. It's possible, it's possible. - It's definitely possible. In my life, I went from being the nothing's working to every day's great to wake up to. And I think even if you think you're gonna live forever, you can enjoy every day. What I do is everything's relative. We can compare ourselves to our neighbor who has more money or to the flight that should have had wifi or which is what I do, I'm still six years old, remember. What a six year old does, says, "Look, when I tell my fingers to form a fist, "they actually do that." That's really cool. That's how I live my life. I can pick up on your desk here this metal object. It's a metal cube, about an inch by an inch by an inch. And I tell myself not about cubes, but about inanimate objects. Probably once a day I'll say, "I'm a living thing. "I can think, I can move, I can eat. "I am full of energy." And there's that leaf or this cube here that will never be alive. That's what I look at and compare myself to. And for as long as I live, if it's forever, of course it won't be, but even if it was forever, the relative to this lump of metal on this table here, we are wondrous things in the universe. And probably the most wondrous things in the universe. Yeah, we're able to deeply appreciate the leaf or the cube and deeply appreciate ourselves, which is, it can be a curse, but it's mostly a gift. Especially when you're, it's such a beautiful poem. Now I'm six, I'm as clever as clever. So I think I'll be six now forever and ever. That's a good thing to aspire to. Your grandmother was onto something. David, this is a incredible conversation. I'm a huge fan of your work. So thank you for wasting your valuable time with me today. I really, really appreciate it. This was awesome. Thank you for having me on, Lex. Appreciate it. Thanks for listening to this conversation with David Sinclair. A thank you to On It, Clear, National Instruments, SimpliSafe, and Linode. Check them out in the description to support this podcast. And now let me leave you with some words from Arthur Schopenhauer. "All truth passes through three stages. "First, it is ridiculed. "Second, it is violently opposed. "Third, it is accepted as being self-evident." Thank you for listening and hope to see you next time. . Please like and subscribe Our channel Because we really love you

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