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

1. 0:00 – 1:34

   Introduction

   1. LFLex Fridman0:00

      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, Cleer, 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 you could live 100,000 years, even under controlled conditions, like in a spaceship, say. Then suddenly, a trip to Alpha Centauri that is, uh, 4.37 light years away takes a single human lifespan. And on the psychological, maybe even philosophical level, as the horizons of death drifts 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 Fridman Podcast, and here is my conversation with David Sinclair.

2. 1:34 – 5:30

   Staying young at heart

   1. LFLex Fridman1:34

      I usually feel like the same person when I was 12, 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, um, I am getting older, both body and mind, and still feel like time hasn't passed at all. Do you, um, feel this tension in yourself that you're the same person and yet you're aging?

   2. DSDavid Sinclair2:01

      Yeah, I have this tension that, that I'm still a kid, um, but that helps in my career. Scientists need to have a wonder about the world and you don't want to grow up. Uh, 12-year-olds and, and even younger, I would say six, seven-year-olds, have 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 euro- six-year-old 'cause I, I am that mentally. But on the other hand, I'm getting older, right? I run a lab of 20 people at Harvard. I've got a book, I've got, uh, you know, science to do, companies to run. And so I have to, um, on most days, just pretend to be a grownup and, and be mature, but I definitely don't feel that way.

   3. LFLex Fridman2:40

      There's uh, there's something I really appreciated. In the opening of your book, you talked about your grandmother and on this kind of theme, on this kind of topic, uh, she first of all had a big influence on you. My grandma- mother 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... (laughs) . 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." Um, so this idea of being six and staying six forever, being youthful, being curious, being childlike, this and other things. What, uh, influence has your grandmother had in your thinking about life, about death, about, uh, love?

   4. DSDavid Sinclair3:53

      Yeah, I was getting misty-eyed as you read that because that, that poem was read to me very often, if not every day by my grandmother who partially raised me. Uh, 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."

   5. LFLex Fridman4:14

      (laughs) .

   6. DSDavid Sinclair4:14

      "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, uh, 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, uh, a whole group of, uh, Jewish friends in her apartment, saw what happened after the world war which was, um, there was, uh, the, the Russians were in control and locals weren't n- 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, um, 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.

3. 5:30 – 11:05

   Bringing people back to life

   1. DSDavid Sinclair5:31

   2. LFLex Fridman5:31

      You know, we mentioned offline this idea of bringing people back to life through, um, through artificial intelligence. Sort of, I don't know if you've seen videos of basically animating people back to life, meaning, uh, whether it's... For me personally, I've been working, uh, on specifically about Al- Albert Einstein but also Alan Turing, Isaac Newton, and Richard Feynman, and it's, it's an opportunity to bring people that meant a lot to others in the world and, uh, animate them and be able to have a conversation with them.... uh, at first to try to visually (sighs) visually explore the, the full richness of character that they had as they struggle with the ideas of the modern age. Sort of it's less about bringing back their mind and more bringing back the, the visual quirks that made them who they are. And then maybe in the future, it's using the textual, the visual, the, the, 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 Replika, which is a chat engine that was born out of the idea of bringing the f- the founder, uh, lost her friend, uh, to a- he, he got r- ran over by a car, and the ini- initial reason she founded the company was tr- trying to just have a conversation with her friend. She trained a machine learning, uh, 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. Uh, and it's very... uh, the, the conversation was very trivial. It was obvious that it's, uh, you know, AI, AI agent, but it gave her solace. It, it made m- her actually feel really good. In that same way, I wonder if it's possible to bring back people that are... that mean something to us personally, not just Einstein, but, um, people that we've lost, and i- in that way achieve a kind of small artificial immortality. I don't know if you think about this kinda stuff.

   3. DSDavid Sinclair7:44

      Uh, well, I definitely think about a lot of things. That, that one's a really good one. There's a great Black Mirror episode about the, the wife who brings back the, the boyfriend or husband. I think one of the challenges with bringing back Richard Feynman would be to, to capture his sense of humor, but that would be awesome. Um, but yeah, bringing back loved ones would be great, especially if, uh, if it's your... they're young and, and, uh, they, 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 going to be possible, especially when we're, we're recording, some of us, every aspect of our lives, whether it's our face or, uh, things we see, right? Eventually one day, everything we see can be recorded, and then you can, you can build somebody's experience and, and thoughts, uh, speech, and, and you will have replicas of everybody, um, at least digitally. Uh, and physically you could do that too one day. But that- that's a, 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.

   4. LFLex Fridman8:47

      (laughs) Really?

   5. DSDavid Sinclair8:47

      Well, I wouldn't go back in time. Um, 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 he... 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.

   6. LFLex Fridman9:05

      Yeah, so you're, you're thinking Benjamin Franklin the scientist, not Benjamin Franklin the political thing, 'cause he'd be very upset with Congress right now. (laughs)

   7. DSDavid Sinclair9:13

      Right.

   8. LFLex Fridman9:13

      So maybe talk to him about science and technology, not, uh, not politics, or maybe just don't get him on Twitter because he'll be very upset with human civilization. You know, I, 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 kind of... um, 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 a- a- about him from others, and then certainly you, uh... the, the sad thing about Alan Turing, for example, is there's very little, if any, uh, recording of him. In fact, I haven't been able to find a recording. Allegedly, there's supposed to be a recording of him, uh, doing some kind of, uh, radio broadcast, but I haven't been able to find anything. And so that, that's, that's, that's truly sad. It feels like it makes you realize how the upside, how nice it is to collect data about a person, uh, to, to capture that person. There's, that's the upside of the modern internet age, the digital age, that that information, uh, yeah, creates a kind of immortality. (laughs) Uh, and then you can choose to highlight the best parts of the person, maybe throw away the, the ugly parts, and, uh, celebrate them even after they're gone. So that's a really interesting opportunity.

4. 11:05 – 20:18

   Wearables and tracking health data

   1. LFLex Fridman11:05

      You, um, 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, uh, well, the whole thing. Is... what- what's most exciting to you in terms of collecting the, the, the biological, uh, data, uh, about a human being?

   2. DSDavid Sinclair11:27

      Well, so I'm a biologist. I find animals and humans as machines very interesting.

   3. LFLex Fridman11:33

      Mm-hmm.

   4. DSDavid Sinclair11:33

      Um, 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, uh, 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, um, 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, you wouldn't go to the doctor and they don't know if it's... you need an antibiotic or not. Um, 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, than your physician, and would augment them, and then there'd be a human that would just tick off to see if that it's correct and they approve. Um, I also was predicting, in the book, that we would have video conferences with our doctors-

   5. LFLex Fridman12:30

      Mm-hmm.

   6. DSDavid Sinclair12:30

      ... and that medicines would be delivered, initially by courier, but eventually by drones, and get it to you, sometimes in an emergency. And that w- we could even have pills that were, were synthesized or delivered, um, in your kitchen, and combine, 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, uh, 19-

   7. LFLex Fridman12:54

      Accelerated-

   8. DSDavid Sinclair12:54

      ... accelerated that incredibly. So, where we're at now in society, is if you, if you want to 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, uh, of course do your genome very cheaply for less than $100 now. Um, there are bio-wearables already. I wear this ring from Oura, um, that I have a number of years of data. I've been doing blood tests for the last 12 years with a company called InsideTracker, 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, I use all that data to, of course, I wear a watch that, 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 I, if I really work at it, I can get my biochemistry down to early to mid-30s. Um, though I like to, you know, 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, uh, you can be wearing wearables. So, I- I'm currently wearing a- a little what's called a bio sticker. Uh, this one, um, I just put on last night, uh, it's about an inch long, a few millimeters, uh-

   9. LFLex Fridman14:18

      Yeah, for people just listening, it's, uh, it's on David's chest.

   10. DSDavid Sinclair14:21

       Yeah.

   11. LFLex Fridman14:21

       It's just, how does it attach? It just kind of ... ?

   12. DSDavid Sinclair14:24

       It sticks on.

   13. LFLex Fridman14:25

       Sticks on?

   14. DSDavid Sinclair14:25

       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, uh, the, it's called a bio button.

   15. LFLex Fridman14:36

       Mm-hmm.

   16. DSDavid Sinclair14:36

       Nice name. And there's a, there's another one that I have, that I haven't tried yet, that does EKG on your heart. Um, 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.

   17. LFLex Fridman14:48

       Wow.

   18. DSDavid Sinclair14:49

       So, there will be a day, in fact it's already here, that, uh, doctors are using these to get patients to go home and save a- a week in hospital, $2,000 at- at least for each patient. That's massive safe- um, 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 1,000 times a second is, um, my vibrations as I speak, my orientation, it can tell, already has told me this morning how I slept, where I slept, what side I slept on, uh, we've got sneezing, coughing, body temperature, heart rate, heart, other- parameters of the heart that would indicate heart health. These- these data are being used to 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. Right? This is really going to, not just revolutionize medicine, but I think extend lives dramatically. 'Cause if- if I have, if I'm going to 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.

   19. LFLex Fridman16:17

       Maybe you can talk a little bit about InsideTracker, 'cause I saw that there's some really cool things in there (laughs) . Like, it actually, so, um, maybe you can talk about, I guess, that you're collecting blood, uh, to give it the data, so, and it has like basic recommendations on how to improve your life. So, it's not, we're not just talking about diseases, right, like anticipating having a particular disease, but it's almost like guiding your trajectory through life, how to, whether it's extend your- your life or just live a more fulfilling, like improve the quality of life, I suppose is the right way to say it. What, how does InsideTracker work? Uh, what the heck? 'Cause the results were pretty cool.

   20. DSDavid Sinclair16:55

       Yeah.

   21. LFLex Fridman16:55

       What is it? Is this something other people can use (laughs) ?

   22. DSDavid Sinclair16:58

       Y- you can definitely use it. Uh, you can sign up at, it's consumer-

   23. LFLex Fridman17:02

       It's like a company, consumer-facing company?

   24. DSDavid Sinclair17:04

       It is, yeah.

   25. LFLex Fridman17:05

       Okay, cool.

   26. DSDavid Sinclair17:05

       Uh, and I also want to democratize the ability to- 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- and you'd go to a Labcorp or Quest in the US. Um, it's also available overseas. You can upload your own data for a 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, as, in terms of health and lon- longevity, bio age they call it, 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 basic- 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 in, a co-author on a paper that showed that the recommendations for food and supplements, um, was better than the leading drug for type 2 diabetes.

   27. LFLex Fridman18:18

       (laughs) 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 the, whatever the scientific paper is, to make the suggestion of how, how, like 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. (laughs)

   28. DSDavid Sinclair18:58

       Right, and, and we'll have the genome in there as well, you can upload that.

   29. LFLex Fridman19:01

       Yeah.

   30. DSDavid Sinclair19:01

       Uh, and so-
5. 20:18 – 30:22

   How to solve aging

   1. DSDavid Sinclair20:18

   2. LFLex Fridman20:18

      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, uh, from an engineering perspective, you said you like the biological machine, is that a feature or a bug of the biological machine?

   3. DSDavid Sinclair20:37

      It is both a bug and a feature. Uh, evolutionarily speaking, we only live as long as we need to to replace ourselves efficiently. Uh, if you're a mouse, you're only going to live two and a half years, three years, you're probably gonna die of starvation, predation, freezing in the winter. So, they, they di- 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, you know, 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. Uh, so, we're, we, we actually need to evolve quicker than evolution will, and that's why we can use our oversized brains-

   4. LFLex Fridman21:33

      (laughs)

   5. DSDavid Sinclair21:33

      ... and intuition to give us what evolution not only didn't give us, but took away from us. You know, we're, we're pathetic. Look at our bodies.

   6. LFLex Fridman21:40

      Mm-hmm.

   7. DSDavid Sinclair21:40

      These arms ... If, 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.

   8. LFLex Fridman21:47

      Yeah.

   9. DSDavid Sinclair21:47

      So, we're pathetic. So, we need to engineer ourselves to be healthier and longer lived. So, getting to aging, uh, we, 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, it's a word for causes of aging. So, that you probably have heard of some of these, your listeners will have. Uh, loss of telomeres, the ends of the chromosomes, like the little, uh, ends of, um, shoelaces, that kind of thing, they get too short, cells stop dividing, become senescent. They s- they become, um, they put out what are called mitogens that cause cancer and inflamma- inflammatory molecules, so that's another aspect of aging, cellular senescence. Another one is loss of the energetics of mitochondria, the battery packs wind down. Uh, there's a whole bunch, stem cells, uh, proteostasis. Well, these are our Achilles' heels that I'm talking about-

   10. LFLex Fridman22:45

       Yeah.

   11. DSDavid Sinclair22:45

       ... that are common amongst all life forms, really. But if you wanted 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. Uh, and that is the basis of my research. Uh, it originally came out of discoveries in yeast cells where, well, I went to MIT in the 1990s.

   12. LFLex Fridman23:17

       You studied bread.

   13. DSDavid Sinclair23:19

       I kind of did.

   14. LFLex Fridman23:20

       (laughs)

   15. DSDavid Sinclair23:20

       I studied the, uh, the makers of bread, uh, a little yeast called Saccharomyces cerevisiae, which at the time was one of the hottest, excuse the pun, uh, organisms to work on.

   16. LFLex Fridman23:30

       Yes.

   17. DSDavid Sinclair23:30

       But they, we, 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, an amazing four years of my life. One of those genes had a name with an acronym SIR2. Now, the 2 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 live 30% longer and suppress 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, they live shorter and are cheaper to study, whether loss of information in our bodies is a root cause of aging, and I think it is.

   18. LFLex Fridman24:24

       Your boldness in viewing biology in this way is fascinating because that also leads to a kind of, uh, it's- it's almost like a- allows for a theory of aging, like- like you could boil it down to a single equation, and it leads to a, perhaps a metric that allows you to optimize aging, sort of in the fight against entropy. Uh, to figure out which mechanisms, like you said, the- the silent information regulator, which mechanisms allow you to preserve information, uh, without- like, without injecting noise, without- without creating entropy, without creating degradation of that information (laughs) . 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, uh, whether that's genetic engineering or AI, it makes it, uh, possible to, uh, create the technology that would improve the- the degradation of information and aging. Is- is there more concrete ways you think about the kind of information we want to preserve, uh, and also, is there good ideas about regulators of that information, about ways to, um, prevent the distortion or the degradation of that information?

   19. DSDavid Sinclair25:54

       Right. So, the, we have silent information regulator genes in our bodies. We have seven of them. Uh, SIRT1 through seven, they're called, and we found in- in mice, one way to slow down the loss of information is to just give more of these, um, to upregulate these genes.

   20. LFLex Fridman26:08

       Mm-hmm.

   21. DSDavid Sinclair26:08

       So, we- we made a mouse that has more of this SIRT1 gene, turned it on, and that slowed down the aging of the brain and preserved their information. The, uh, 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, uh, information, A, T, C, G, the four chemicals that make up the various sequences of the genome, billions of letters. Uh, 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.

   22. LFLex Fridman26:51

       (laughs)

   23. DSDavid Sinclair26:51

       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 is 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, um, 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- in a different cell, you'd read different music, different songs, different symphonies. Uh, and that's what gets laid down when we're in the womb and that gives- makes a skin- 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.

   24. LFLex Fridman27:42

       Mm-hmm.

   25. DSDavid Sinclair27:43

       And the kidney cells start to look more like liver cells. Um, and they, what we call X differentiate. This is a term that we use in my lab but isn't yet, uh, widely used, but we needed a term to explain this, and that, those, that process of X differentiation, the loss of the reader of the- the CD or the DVD, uh, we liken that to scratches on the DVD.

   26. LFLex Fridman28:06

       (laughs) .

   27. DSDavid Sinclair28:06

       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- or even eat them, uh, and turn on those pathways, which- which my father and I have been trying to do for about a decade to slow things down. But the question r- 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- 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. Um, his, uh, 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 TCPI proto- TCP IP protocol of the internet that stores information, in case it doesn't make it to your computer-

   28. LFLex Fridman29:04

       Mm-hmm.

   29. DSDavid Sinclair29:05

       ... it will fill in the gaps. And we've been spending about the last five years to f- try and find if there really is a backup copy in the body to reset the epigenome and polish those scratches away.

   30. LFLex Fridman29:16

       Tha- that's incredible. So, finding the backup so whenever the too many scratches pile up, you can just write a new version. Like, v- write, the- the, not a new version, but go to the backup and restore it.
6. 30:22 – 35:50

   Why do we age?

   1. LFLex Fridman30:22

      the scratches, do those come from...... are those programmed or are they failures? Meaning, is it b- uh, so, if it's m- by design, then there's like a encoded timeline schedule that the body's just, on purpose, degrading the whole thing. And then there is the just, the wear and tear of like the scratches in a disc that happen, uh, through time. Which, which one is it that's the source of aging?

   2. DSDavid Sinclair30:54

      Uh, it's more akin to wear and tear. There isn't a program. Um, getting back to evolution, there's no selection for aging. W- we're not designed to age, we just live as long...

   3. LFLex Fridman31:03

      Mm-hmm.

   4. DSDavid Sinclair31:03

      ... as we need to and then we're at the whim of entropy, basically. Second law of thermodynamics, sh- stuff falls apart. Uh, we live a bit longer than age 40 only because there are robust resilient systems. But eventually, they fail as well. Current limit till the human lifespan where they completely fail is 122. Uh, but, so it's ... And I, but I don't like to think of it as wear and tear because there's, there's two aspects to it. There's a system that's built to keep us alive when we're young, but actually goes... comes back to bite us as we get older. And we call this, this issue antagonistic pleiotropy.

   5. LFLex Fridman31:37

      Ah.

   6. DSDavid Sinclair31:37

      What's good for you when you're young can cause problems when you're older. So, we've been looking what, what is the cause of, the main causes of the noise, and we've come... we found two of them definitively. The first one is broken chromosomes. When a, 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. Uh, 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 to... they have a dual function, they actually go to the break, the chromosomal break, and fix that, and then they come back. The... 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, uh, and that's what we think is the main noise for aging.

   7. LFLex Fridman32:46

      Interesting.

   8. DSDavid Sinclair32:47

      And we've also cr-... uh, the other cause of aging that we found is, is cell stress. We damage nerves and they age rapidly. So, you... that's the other issue. There's probably others. Um, smoking, chemicals, for example, we know accelerates biological age pretty dramatically. But the question is ca- 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 found a way to do that.

   9. LFLex Fridman33:12

      Well, can you give me hints? Uh, whose fault is it in... ball's not coming back? Is it the proteins themselves? Like, uh, are they, are they starting... Again, I've been obsessed with the protein folding problem from the AI perspective. So, is it, is it the proteins or is it something else?

   10. DSDavid Sinclair33:25

       Well, we know who hits the balls, um, and recruits them so that the break, uh, is recognized by proteins who send out a signal, uh, through... phosphorylation is typical p- 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. Um, that could just be a, a flaw in the "design." I don't think that there's something saying, "Well, 1% of you, 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 lo-... Well, I sh-... We never know anything in biology, but we-

   11. LFLex Fridman34:22

       (laughs) Right.

   12. DSDavid Sinclair34:22

       ... 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 three-fold over background levels of normal breakage. And if we're right, those mice should get old.

   13. LFLex Fridman34:38

       Mm-hmm.

   14. DSDavid Sinclair34:39

       And they do. We can actua-... we've, we've created these breaks in a way that's titratable. We can... it's like a rheostat, we can send it to 11. Uh, you know, I, I drove my Tesla here, I'm a big fan of, uh, an, uh, of, uh, Spinal Tap 2-

   15. LFLex Fridman34:51

       Yes (laughs) .

   16. DSDavid Sinclair34:51

       ... 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.

   17. LFLex Fridman35:05

       Wow.

   18. DSDavid Sinclair35:05

       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-

   19. LFLex Fridman35:18

       Wow.

   20. DSDavid Sinclair35:18

       ... than normal.

   21. LFLex Fridman35:19

       So, you can replicate the aging process in a controlled way. You can al-... I mean, in a way they, y- I mean, you could accelerate it, you, m- in, in a, 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 wh- how can we reverse this.

   22. DSDavid Sinclair35:37

       And now, we're reversing those mice.

   23. LFLex Fridman35:40

       Is there a good... (laughs) uh, I, I love what you said. I mean, in biology, you really don't know. Y- it's, it's, uh, it's such a beautiful mess.

   24. DSDavid Sinclair35:47

       (laughs)

   25. LFLex Fridman35:48

       Uh, is, is there,

7. 35:50 – 38:20

   Genetic reset switch that reverses aging

   1. LFLex Fridman35:50

      is there ideas how to do that? Is that on a gen- a genetic engineering level? Is it, uh, like, what can you mess with? Is it going to the, um, trying to discover the backup copies and restoring from them? Like, what's... if it's, it's possible to convert into natural language words? Uh, what are the ideas here?

   2. DSDavid Sinclair36:09

      What is the observer and how do we contact it?

   3. LFLex Fridman36:11

      Exactly.

   4. DSDavid Sinclair36:12

      Yeah.

   5. LFLex Fridman36:12

      How... what's the observer and how do you contact it? Or if there's other ideas how to reverse the, the, the, the balls getting lost process (laughs) .

   6. DSDavid Sinclair36:20

      (laughs) Yeah. Well, you, you can slow it down.

   7. LFLex Fridman36:23

      Slow it...

   8. DSDavid Sinclair36:23

      But we found a, a reset switch recently. We just published this, um-... uh, in the December 2020 issue of Nature. Um, and what we found is that there were 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, uh, and, uh, we're now using that to reset the age of the brain of those mice that we aged prematurely, and they're getting their ability to learn back.

   9. LFLex Fridman37:42

      This is really exciting, right? Like, what's, uh, what's the downside of this? (laughs)

   10. DSDavid Sinclair37:46

       Well, the downside is if you overdo it, uh, and you don't get it right, uh, you might cause tumors.

   11. LFLex Fridman37:52

       S-

   12. DSDavid Sinclair37:53

       But we do it, we do it very carefully, and we also know that in the eye, it's very safe.

   13. LFLex Fridman37:57

       Yeah.

   14. DSDavid Sinclair37:57

       We also injected these... We, we g- deliver them by viruses, so-

   15. LFLex Fridman38:02

       Mm-hmm.

   16. DSDavid Sinclair38:02

       ... 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-

   17. LFLex Fridman38:12

       Yeah.

   18. DSDavid Sinclair38:12

       ... 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.

8. 38:20 – 40:52

   AI in biology

   1. DSDavid Sinclair38:20

   2. LFLex Fridman38:20

      Is there a place where AI can help? Sorry to inject, uh, one of the things I'm very excited about and passionate about. So, uh, deep, uh, Google DeepMind, um, recently had a big breakthrough with AlphaFold2, but also AlphaFold, two years ago, with, um, achieving sort of a 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, um, through AI. Is there something to you, combined with this brilliant work on, uh, the biology side that you're hopeful about, where AI can be a tool to help?

   3. DSDavid Sinclair39:10

      Where isn't it 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. Uh, 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. Uh, what else? We use it to, uh, predict the longevity of a mouse based on how it reacts to certain things. Hearing, eyesight, generally frailty. So we have, we just put out a paper last year on that. Um, 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, um, Natalie, who 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 transplant, tran- liver transplant patients, to detect viruses that come out of their organs. But that's, that's another area that AI is extremely important for. Um, I, I think if you're not, in five years, if you're not using, you know, deep learning, you've got a problem, because the amount of data that we generate now, as biologists, is just terabytes, could 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, uh, bioinformaticians.

   4. LFLex Fridman40:47

      Mm-hmm.

   5. DSDavid Sinclair40:48

      Uh, a lot of our work is now just number crunching.

9. 40:52 – 48:58

   Health data

   1. DSDavid Sinclair40:52

   2. LFLex Fridman40:52

      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 let, can collect more and more data, not just on the one person level, like for you to understand your, like, various markers, but to create huge data sets to understand how we can detect certain pathogens, detect certain properties, characteristics of whether it's aging or a- all the other ways the human body can fail? It, it seems like with the, with biology, there's a kind of privacy concerns that... Well, actually not privacy concerns, it's almost like regulation, that kind of pre- prevents like hospitals from sharing data. Um, you know, I'm, I'm not sure exactly how to say it, but it seems like when you look autos- 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?

   3. DSDavid Sinclair42:06

      So, we are right in the middle. We're living through what's going to be seen as one of the biggest revolutions in human health, through the gathering of data about our bodies.

   4. LFLex Fridman42:15

      Yeah.

   5. DSDavid Sinclair42:16

      And 20 years ago, people didn't want to go on social media, they were worried about it. Now, you have to if you're a kid, that's for sure. Uh, same with medical records. These are becoming all digitized and, and expanded.Ultimately, we're going to, even if we don't want to, have to be monitored. You know, there's going to be a court case that, I, I bet two, three years from now, someone's going to say, "How come my father died from a heart attack? You had these biosensors, 20 bucks, and you didn't use it."

   6. LFLex Fridman42:45

      Mm-hmm.

   7. DSDavid Sinclair42:45

      Lawsuit right there, and suddenly all hospitals have to give you one of these.

   8. LFLex Fridman42:49

      There'll be a reversal, like to where (laughs) it's your fault if you don't collect the data. That's brilliant. That's, you know, and that's absolutely right. I mean, that's absolutely right. That's the frustration I feel when going to the doctor, is like you're... It's almost negligent to not collect the data, because you're, you're making... If there's something really wrong with me and you're making, uh, decisions based on very few tests, that's almost negligent when you have the opportunity to collect a huge amount more data.

   9. DSDavid Sinclair43:22

      Well, I, let me tell you something.

   10. LFLex Fridman43:23

       Yeah.

   11. DSDavid Sinclair43:23

       Like the, the, I, I've got this InsideTracker data for, 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, 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 InsideTracker." And he said, "Great, I'd love to see them." So, I share screen and we look at the graphs, look at the data, and he's loving it.

   12. LFLex Fridman44:00

       Mm-hmm.

   13. DSDavid Sinclair44:00

       'Cause he cannot order these tests willy-nilly. So, I said, "Well, let- 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." "Uh, are you... 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.

   14. LFLex Fridman44:23

       (laughs)

   15. DSDavid Sinclair44:23

       Um, but instead, you know, I, 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 and... But they'd like you to do that.

   16. LFLex Fridman44:34

       Quick human question. Maybe you can educate me. I've, I think doctors sometimes have a bit of an ego. I understand that the, the doctor is super experienced with a lot of things, but, uh, this is a fundamental question of human variability. Like, I know a lot of specific details about, like, um... I mean, it depends of course what we're talking about, but there's a... I bring a lot of knowledge, and if I have data with me, then I have a hu- like, uh, several orders of magnitude more knowledge. And I think there's an aspect to it 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 ex- j- as you said, are excited to see the data? Or is that already happening?

   17. DSDavid Sinclair45:26

       It's, it's really happening now. We've probably lost the last generation, um, that they're no-hopers, but... So, I, I teach at Harvard Medical School.

   18. LFLex Fridman45:34

       Mm-hmm.

   19. DSDavid Sinclair45:34

       And they're excited about this. They're excited about aging, which is a new aspect (laughs) to medicine. "Oh, wow, we can do something about that?"

   20. LFLex Fridman45:41

       (laughs)

   21. DSDavid Sinclair45:41

       Um, 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.

   22. LFLex Fridman45:47

       Yes.

   23. DSDavid Sinclair45:47

       But, uh, yeah, time will change their, their, uh, 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 it's, you know, I have a front row seat on all of this.

   24. LFLex Fridman46:01

       Mm-hmm.

   25. DSDavid Sinclair46:02

       Uh, I had breakfast with a, with a CEO who, uh, is making this happen, uh, just yesterday. I can tell you for sure that most people have no idea that this revolution is occurring and is happening so quickly. Uh, 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. Um, otherwise-

   26. LFLex Fridman46:24

       Mm-hmm.

   27. DSDavid Sinclair46:24

       ... you know, the hospital down the road is gonna be, uh, beating you. Um, and there, 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. For, let's say, one of these buttons on my chest cost 20 bucks, it's rechargeable, and it can predict people's health and save on antibiotics, f- prevent heart attacks. How many billions, if not trillions, of dollars will that save, uh, over the next decade?

   28. LFLex Fridman46:58

       Yeah. So, when the public wakes up to this, they'll almost demand it. Like, this, this should be, this should be accepted everywhere, this is obvious, it's gonna save a lot of money, it's gonna improve the quality of life.

   29. DSDavid Sinclair47:07

       Well, and the CFOs of hospital-

   30. LFLex Fridman47:09

       Yeah.
10. 48:58 – 56:29

    Fasting

    1. LFLex Fridman48:58

       So, there's, on a biology side, super exciting ways to, um, to slow aging, but there's also on the lifestyle side. I recently did a 72-hour fast, just an opportunity to take a pause and be, you know, appreciate life, think about li- There's something about fasting that, um, encourages you to reflect deeper than you otherwise might. Uh, 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, that takes food and produces thoughts.

    2. DSDavid Sinclair49:33

       (laughs)

    3. LFLex Fridman49:35

       And then, and then ends brief- I mean, there, you, you start to, uh, depending who you are, if, if you're like engineering-minded, you start to think of this whole thing as a kind of, yeah, as a machine. And then, also feelings fill this machine. Uh, feelings of gratitude, of love, but also, uh, the uglier things of jealousy and greed and hate and all those kinds of things, and you, you start to think, "Okay, h- how, um, 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, to fasting. I intermittent fast a lot, I eat just one meal a day most of the time. Is there, uh, something you can say about the benefits of fasting in your own life, and in general, the anti-aging process?

    4. DSDavid Sinclair50:23

       Well, you're a philosopher too. Also-

    5. LFLex Fridman50:25

       Sorry. I apologize.

    6. DSDavid Sinclair50:27

       No, I'm impressed. Uh, true Renaissance man. Uh, it's, it's a joy to be here. Uh, so when it comes to fasting, this is, you know, being abstemious is one of the, the, the oldest ways to improve health. Right? 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. 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 run, uh, chased by a cyber too- saber-toothed cat or something." Um, 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. Um, in fact, you, 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. Uh, 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.

    7. LFLex Fridman52:06

       Mm-hmm.

    8. DSDavid Sinclair52:07

       Uh, what I'm not good at is going beyond one day. But if you can do three days-

    9. LFLex Fridman52:11

       All right. Have you ever fasted longer than, uh, than the 24 hours?

    10. DSDavid Sinclair52:15

        Uh, I tried doing two days. I might have made it to the third and given up. Um, I just find that, uh, I'm, I'm not ver- I don't have a lot of willpower. I also hate exercise, so-

    11. LFLex Fridman52:26

        (laughs)

    12. DSDavid Sinclair52:26

        ... I'm not sure how long I'm going to live. Uh, but I've managed to do one meal a day. So, if I can do that, seriously, anybody can do that.

    13. LFLex Fridman52:32

        (laughs) Yeah.

    14. DSDavid Sinclair52:32

        Um, to, to your listeners and, 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. Um, that's fine, you can fill your stomach up with, with liquids. Uh, diet sodas, I get criticized for drinking, but I'm gonna continue to have those. But then, you know, I power through the day. I definitely don't feel tired, I don't have a lag anymore. But give, also give it at least two weeks 'cause you... There's a habit as well.

    15. LFLex Fridman53:04

        Mm-hmm.

    16. DSDavid Sinclair53:05

        Having something in your mouth, chewing, feeling that fullness. You can break that habit, and within two, three weeks, you'll have done it.

    17. LFLex Fridman53:12

        Absolutely. So, I'm not actually even that strict about... (laughs) you said diet soda. Uh, yeah, people are very kind of weirdly strict about fasting, the rules in fasting. Like, for example, I, I drank LMNT electrolytes when I was fasting, and that has like five calories. And so technically, it's, uh, 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 caffe-" 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 (laughs) especially, uh, I've gained quite a bit of weight, uh, like maybe even like 15 pounds, something like that, since I moved to Austin, Texas. (laughs) And I, I s- I still keep the same diet, but I eat a lot of meat, uh, in that one, just because it's delicious, because it's also the, the a- the amazing people I met in Texas. It's just, there's like a comradery, a friendship, a love to the people that like makes you really enjoy the, uh, the atmosphere of eating the brisket and the meat.

    18. DSDavid Sinclair54:29

        Is this Joe Rogan insisting?

    19. LFLex Fridman54:31

        Joe is... I mean, he's very different. Uh-Joe loves bread and pasta. Like, he knows that his body feels best doing keto or carnivore, so that's what he usually d- tries to stick to, but he also does not hold back and he'll just eat pasta when he needs his 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 I, I know my body ultimately does not feel good with pasta. So, it's, it's a funny kind of dichotomy is, I, I would like to, um, cheat, I guess, by eating more meat than I... You know, like overeating, uh, 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, I tend to, um, I tend to find happiness in overeating the good stuff versus eating the bad stuff. And, uh, th- that's the kind of balance. Him, he's like, "Fuck it." (laughs) Every once in a while, you got to enjoy it. And, and then also coupled with that for him, uh, is just exercise, like, and then face his demons the next day and just, like, burn a huge amount of calories which is... I mean, whatever, whatever is up with that guy's mind, (laughs) there's an, uh, there's a 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, and running, the hills, and all those kind of stuff that he does. That takes a lot out of you doing that kind of insane exercise. And, um, I think I'm more like you, or at least towards your direction as, like, I really hate exercise. So I do it, but I really hate it.

    20. DSDavid Sinclair56:26

        (laughs)

    21. LFLex Fridman56:26

        And so, it, it's a balance that you have

11. 56:29 – 1:04:40

    Diet

    1. LFLex Fridman56:29

       to strike. Is there something you could say about the diet side of that? Uh, 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 been, 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?

    2. DSDavid Sinclair57:01

       Well, sure. Uh, 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, uh, 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... If we're... 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?

    3. LFLex Fridman58:00

       (laughs) Exactly.

    4. DSDavid Sinclair58:01

       Uh, but you got to live life, right? What's, what's a long life if it's not enjoyable anyway?

    5. LFLex Fridman58:05

       Yes.

    6. DSDavid Sinclair58:05

       But what I've, I also have found, and this is... I'll, I'll get to your question in a second, but my microbiome right now is... 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, a, a chicken, uh, a fried chicken specifically. Uh, 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, I just can't. It just feels bad. Um, but what, what do I recommend? Well, what the data says, which I try to follow, is, uh, that plant-based foods will, 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... There's a few facts. One is that people who live a long time tend to eat those type of diets. Mediterranean, Okinawa diet. They're eating mostly plants with a little bit of meat, and not a lot of red meat. Uh, and the other fact is that in animals we know that there's a, there's a mechanism that's called mTOR, little M, capital TOR, 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, uh, in, mostly in meat, then it extends lifespan. And there, there's a drug called rapamycin which some people are experimenting with that does that. So you might be able to... And I'm just saying this here. From all, 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-

    7. LFLex Fridman59:32

       Mm-hmm.

    8. DSDavid Sinclair59:32

       ... on, in the long run. Don't know... We should try that actually. We could do that in the lab. But, uh, 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, um, 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.

    9. LFLex Fridman59:57

       Well, this is actually something I worry about in terms of long-term effects, or the, the cost in terms of longevity. It's very difficult to know how your choices affect your longevity because the im- impact is down the line. Like, 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.

    10. DSDavid Sinclair1:00:22

        Well, think about what I, 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.... um, Kirkwood just, uh, proposed that in the '70s. What meat probably does is put you in the, the mouse category, super fertile, grow fast, heal fast. And then, but if you want to be a whale, you should restrict meat, uh, and do things that promote the preservation of your body.

    11. LFLex Fridman1:00:53

        Is it, uh, difficult to eat a plant-based diet that, uh, you perform well under? So, uh, mentally and physically, just almost, I'm asking, uh, almost like, um, anecdotal question. Uh, unless you know the science.

    12. DSDavid Sinclair1:01:09

        Uh, well, the science is still being worked out.

    13. LFLex Fridman1:01:12

        Yeah.

    14. DSDavid Sinclair1:01:12

        But from the synthesis of everything I've read, uh, I try to eat a diet that's definitely full of leafy greens, uh, particularly spinach is great 'cause it's got the iron that we need, plenty of vitamins. I also, um, try to avoid too much, uh, fruit and, uh, 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 are called, what we call xenohormetic molecules. Let me unpack that 'cause it's a terrible name, and I take full responsibility with my friend, uh, Conrad Howitz. The xeno means cross-species, and hormesis is the term that what doesn't kill you makes you live longer.

    15. LFLex Fridman1:01:58

        Mm-hmm.

    16. DSDavid Sinclair1:01:59

        And, and, and, and be healthier. And so we're getting cross-species health improvements by molecules that plants make, and plants make these molecules when they're also under adversity or perceived adversity. For instance, uh, I, I understand if you want really healthy ar- good oranges, you can drive nails into the, 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, and that's because these plants make these colorful and xenohormetic molecules that make themselves stress-resistant, turn on their sirtuin defenses, the SIR 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 supply is, 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, uh, practically speaking, if it's full of color or if there's been some chewing by a caterfel- caterpillar, organic, grown locally in local farms, I'll eat that versus a watery, insipid, uh, light-colored, um, lettuce that's been, been grown in California.

    17. LFLex Fridman1:03:12

        So, you want vegetables that have suffered. You want the David Gogginses of vegetables.

    18. DSDavid Sinclair1:03:16

        (laughs)

    19. LFLex Fridman1:03:16

        That's the xenohormetic molecules.

    20. DSDavid Sinclair1:03:19

        I love that term.

    21. LFLex Fridman1:03:20

        (laughs)

    22. DSDavid Sinclair1:03:20

        I'm gonna take that one with me, thank you.

    23. LFLex Fridman1:03:23

        (laughs) Yeah. Oh, I follow him on Instagram. He's, he's always screaming. So, you want the... That he's basically, uh, the, the, the xenohormetic version of a human. Um, I, I like it. So, the- these are the molecules that are representative of the stress that's been, um, that, uh, a plant has been under?

    24. DSDavid Sinclair1:03:44

        Yeah. The best example of that is resveratrol, which many people, including myself, take as a supplement. Grapes, well, grapevines produce that in abundance when they're dried out or they have too much light or fungus. Uh, 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.

    25. LFLex Fridman1:04:05

        That's beautiful. Yeah, I, 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 a- avoid sugary things as well?

    26. DSDavid Sinclair1:04:19

        Yeah, I'm fairly militant about that. Um, I rarely would add sugar to anything. Occasionally, I would, um, eat a, a slice of cheesecake, but that would be, you know, maybe once or twice a year. You know, you have to give in occasionally. But yeah, ev- anything that's sweet, I would rather substitute something like stevia if I need a sugar hit.

12. 1:04:40 – 1:10:01

    Exercise

    1. LFLex Fridman1:04:40

       What about exercise, your favorite topic? (laughs) Is there, uh, is there-

    2. DSDavid Sinclair1:04:46

       I don't mind talking about it. (laughs)

    3. LFLex Fridman1:04:48

       (laughs) Yeah, okay, great. Is there benefits to longevity, uh, from exercise?

    4. DSDavid Sinclair1:04:53

       Well, no doubt. That's, that's proven. Um, just like fasting, it's pretty clear that that works. Uh, 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, 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. Um, 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, getting your- lose your breath, get hypoxic, as it's called, seems to be very beneficial for long-term health. Um, and that's the kind of exercise that I like to do, aerobic. Though I, I do enjoy, uh, 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, um, I want to be able to counteract the effects of sitting for most of the day.

    5. LFLex Fridman1:05:53

       Yeah.

    6. DSDavid Sinclair1:05:53

       And as you get older, you lose muscle mass. It's a percent or so a year. And I don't want to be frail when I'm older and fall over and break my hip, which is, which happens every 20 seconds in this country.

    7. LFLex Fridman1:06:04

       So, maintaining that strength, but also doing the cardio for the, for the longevity, for the avoiding the heart disease. Yeah, I, I definitely, just like with fasting, have the philosophical benefit of running long and running slow. I enjoy, 'cause it, it kind of clears the mind and allows you to think, and actually listen to brown noise as I run. It really helps remove myself from the world and just like zoom in on particular thoughts.

    8. DSDavid Sinclair1:06:28

       What is brown noise?

    9. LFLex Fridman1:06:30

       It's like white noise but deeper. So, like white noise is like, "Shh," and then brown noise is more like...... like ocean.

    10. DSDavid Sinclair1:06:40

        That sounds great. I might try that.

    11. LFLex Fridman1:06:41

        Yeah. Yeah. It's, uh...

    12. DSDavid Sinclair1:06:43

        More soothing probably.

    13. LFLex Fridman1:06:45

        I'm not sure. There could be science to this. I need to look this up. I've been meaning to. But I- when I started, uh, this is maybe like five years ago, I started listening to brown noise when I work, and, uh, the first time I listened to it, something happened to my mind where it just went like (swoosh noise) zoomed in to like, in a way that it felt like really weird, like, how- 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. Um, 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, um, an encouraging and motivating of 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. Like, I 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- of that nature that, um, they're yet to be discovered. So it pays to explore.

    14. DSDavid Sinclair1:08:31

        Yeah. Though you have a different mind. You have quite a beautiful mind. So, I- I suspect brown noise helps you focus and because you're probably all over the place if you don't control it.

    15. LFLex Fridman1:08:40

        Yeah, exactly. I mean, it's something about it. It's a programmer thing. I don't... The programming is a really difficult, um, mental journey because you have to keep a lot of things in mind. You have to, uh, 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, the 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, uh, I've been very much exploring how to do. Like, I do it really well in the morning, coffee's involved, all those kinds of things. You're trying to optimize, uh, keeping very positive, inspired, no social media, all those kinds of things, and trying to optimize for it. 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, (laughs) uh, sometimes it pays off to be wild.

13. 1:10:01 – 1:18:29

    Sleep

    1. LFLex Fridman1:10:01

       What about, uh, sleep? How important is sleep for longevity?

    2. DSDavid Sinclair1:10:06

       I would guess, based on the evidence, that it's really important, and because we- 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. Um, 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- 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- is a disaster in your old age, which is, um, right, you're aging, you can't, at this moment, totally prevent that. And then it's disrupting your sleep, then you get not enough sleep and then that's going to accelerate your aging process. Um, and so it's knowing that- that people who are shift workers are more susceptible to certain age-related diseases. So, bottom line, you definitely want to 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. (laughs)

    3. LFLex Fridman1:11:30

       (laughs) I see you're still carrying the burdens of that decision. But is... Yeah. You know, sleep is one of those things that's making me wonder about the variability between humans a little bit and how science is often focused on... Like 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, like 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- 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...... in private, usually, a smile on my face, that's when I'm doing good as opposed to getting a perfect amount of sleep, uh, according to whatever the l- 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 w- you know what it is. The reason I pull all-nighters isn't for like, um, I'm playing Diablo III or something, it's because I'm doing something I'm truly passionate about. Well, I can also love video games, but I'm doing something I'm truly passionate about. And it's almost like there's the Jocko Willink feeling of when I'm up at 7:00 AM and I haven't slept all night and still am working on it, there's a kind of a celebration of the human spirit that I really enjoy it. Like, uh, and that's happiness, and to sort of then... And I usually don't tell that kind of stuff to people because th- 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."

    4. DSDavid Sinclair1:13:48

       (laughs) That's right.

    5. LFLex Fridman1:13:50

       (laughs) So, but that said, in aggregate, when you look at the full span of life, is probably you should be getting a- a- a consistent amount of sleep, and it- it seems like it's in that seven, eight-hour range.

    6. DSDavid Sinclair1:14:05

       Yeah, but it's similar to food. It- it's the quality, not the quantity.

    7. LFLex Fridman1:14:09

       Yeah.

    8. DSDavid Sinclair1:14:09

       Right? And- and when you get it. So, I- I look at my- my data pretty often, and what makes a difference to me is not the amount of hours but the quality-

    9. LFLex Fridman1:14:18

       Quality.

    10. DSDavid Sinclair1:14:18

        ... the depth, and the deep sleep is what- 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, you know, barely remembering stuff. So that, like you say, if you're happy and contented and you're not... 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.

    11. LFLex Fridman1:14:45

        Yeah. Yeah, th- that's beautiful. I... and some of that could be genetic. For me, I just... (snaps fingers) I fall asleep like this, uncoo-... if you want me to fall asleep right now, I can do it. It's (laughs) it's no, um... I have no problem with it, combined with coffee, I just had two energy drinks, I can probably, uh, sleep. So that, I don't know if that's genetics or it's kind of, um, I don't know what it is. Or maybe that I don't have kids and I'm single, so I don't have, uh... 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 ph- go to sleep wh- whenever I feel like going to sleep.

    12. DSDavid Sinclair1:15:20

        Well, that's 'cause you're, uh, self-employed.

    13. LFLex Fridman1:15:22

        Self-employed.

    14. DSDavid Sinclair1:15:23

        Most people don't have that luxury.

    15. LFLex Fridman1:15:24

        (laughs)

    16. DSDavid Sinclair1:15:24

        But w- we're lucky, the two of us, that we can make our own hours.

    17. LFLex Fridman1:15:27

        Yeah.

    18. DSDavid Sinclair1:15:28

        Um, but yeah, it- it's super important and- and those people who have shift work, I mean, they- they really need to- to change the way that works because they're- they're literally killing those people.

    19. LFLex Fridman1:15:39

        Is there something you could say about the- the mind and stress, uh, in- in terms of effect on, uh, longevity? Sort of, um, 'cause wh... (sighs) 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 don't c-... are not necessarily directly connected to the brain-

    20. DSDavid Sinclair1:16:00

        Mm-hmm.

    21. LFLex Fridman1:16:01

        ... or the operation of the brain. Like, what's the role about stress and happiness and, uh, yeah, the sort of higher cognitive things going on in the brain on longevity?

    22. DSDavid Sinclair1:16:14

        Right. Well, that's a great point, that the brain is- is the center for longevity actually. We- we- we do know that. Uh, first off, when- when I'm stressed, I can see, mentally stressed, then I can see it in my body.

    23. LFLex Fridman1:16:26

        Mm-hmm.

    24. DSDavid Sinclair1:16:27

        Heart rate, hormones, it- it's clear, you know, that's no true surprise. So, you've got to work on your brain first and foremost. If- if you are totally freaked out, agitated, uh, all the time, you will live shorter, I'm- I'm certain of it. You know, I- I keep fish, I'm, um, a- a big, uh, aquarium guy, and you can see the difference between the- the fish that's having a good time and dominant and the one that gets picked on.

    25. LFLex Fridman1:16:52

        Yeah.

    26. DSDavid Sinclair1:16:53

        It just looks like crap.

    27. LFLex Fridman1:16:54

        Yeah.

    28. DSDavid Sinclair1:16:55

        You don't want to be that... the little fish getting picked on if you can help it. So, I- I used to be extremely stressed as a kid. I was a perfectionist, very shy, always worried about being a failure. Um, if I didn't get an A+, you know, I was crying in my bedroom, that kind of sad existence. I got into my 20s p-... 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... I've never gotten angry in my life. I've got 20 kids, sometimes it's like a... most of the time it's like a kindergarten. Um, I haven't lost my temper, I... very calm. But that- that's intentional, um, 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.

    29. LFLex Fridman1:17:42

        Mm-hmm.

    30. DSDavid Sinclair1:17:42

        Don't worry about it. Um, but the- the... 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 SIR- SIRT gene that I mentioned, SIRT1, we... a good friend of mine at WashU, Shin Imai did this, they up-regulate the... up-regulated 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, uh, called the hypothalamus, which leaches a lot of chemicals into the body, uh, and proteins m- most of which we don't know yet, but just changing the inflammation of that little organ, um, 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.

14. 1:18:29 – 1:24:00

    Data

    1. DSDavid Sinclair1:18:29

    2. LFLex Fridman1:18:29

       So, you kind of mentioned this, uh, with the InsideTracker, there's a ability to take blood measurement and then infer from that, um, a bunch of different things about your body and how you can improve... ho- how you can improve the longevity.And you've also mentioned saliva and more efficient ways, uh, to, uh, to get data. Uh, what does that involve? What's the future of data collection (laughs) look like-

    3. DSDavid Sinclair1:18:57

       Yeah.

    4. LFLex Fridman1:18:57

       ... for the human biological system?

    5. DSDavid Sinclair1:18:59

       Right. Well, yeah, the, the, the issue with, with blood is you need someone to take it. It's, it... or you prick your finger, which hurts.

    6. LFLex Fridman1:19:05

       Yes.

    7. DSDavid Sinclair1:19:06

       So you got to 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, it'll do that for you. But we're not there yet. So the intermediate, um, future that, that I'm building right now is that you would take a, 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 called a buccal swab. Um, I think we, we became very used to that, right? Right now, because of COVID, people don't like going to the doctor as much. They don't like going out. They just want to 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 cheek, stick it back in an envelope, send, send it off, and, you know, a week later, you have either a doctor's report or a, a health recommendation. And what can you get off a cheek swab? Well, you can get anything. You can get hormones, stress levels, um, stress hormones, blood glucose levels. You can also tell your age, uh, 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 chrono- chronological age.

    8. LFLex Fridman1:20:19

       Mm-hmm.

    9. DSDavid Sinclair1:20:19

       I mean, uh, 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-

    10. LFLex Fridman1:20:27

        Mm-hmm.

    11. DSDavid Sinclair1:20:27

        ... and how fast. So I could take a cheek swab from you today, Lex, take it back to my lab-

    12. LFLex Fridman1:20:32

        (laughs)

    13. DSDavid Sinclair1:20:32

        ... uh, and within, by tomorrow, tell you how old you are biologically based on what we call the epigenetic clock. Um, 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. Um, without that knowledge, you're flying blind.

    14. LFLex Fridman1:20:58

        Mm-hmm.

    15. DSDavid Sinclair1:20:58

        But I like the idea of a swab 'cause it's, it's just so easy. We've... a lot of us have done something like that for COVID tests. It's not a big-

    16. LFLex Fridman1:21:03

        Yeah, I've been doing a nonstop a rapid antigen test. So let, let me say, that particular one, rapid antigen test, they've been a source of frustration for me because like everybody should be doing it. It's so easy.

Episode duration: 1:41:33