#27 – David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [intro music]

2. 0:04 – 7:37

   Episode Intro and Guest Background

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hi, everyone. Welcome to this week's edition of The Peter Attia Drive. I'm Peter Attia. This week my guest is Professor David Sinclair. He's a professor in the Department of Genetics at Harvard Medical School, and he is the co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging. David hails from Australia. That'll take you about 10 seconds into our interview to figure out. He did his Ph.D. in molecular genetics at the University of New South Wales in Sydney. And it was at that time that he met the man that would go on to become his mentor. We talk a lot about him, and this is a guy, Lenny, who's actually come up on other podcasts, so I won't get into him now. But nevertheless, David met Lenny and decided he wanted to come to MIT to study with him, which is what he did. And David has gone on to become one of the pioneers in a particular field of aging that focuses on a class of molecules known as sirtuins. I'm sure many of you have heard of sirtuins, but you might not entirely be clear on what sirtuins are. I won't obviously make any attempt to do that here in the intro because we spend so much time talking about that during this episode. The other thing that David is really quite famous for is his role in the discovery of a molecule or class of molecules that stimulate sirtuins. And by the time you get through this episode, you will understand why that may be a desirable thing to do. And among these, the most famous is one called resveratrol. Of course, resveratrol came to fame probably a little over a decade ago when it was noted, at least in one study, in one type of animal model, to promote a longevity phenotype. And of course, what really made it interesting, at least for the lay press, was that resveratrol is found in very low concentrations in the skin of grapes, and therefore the logic went, "Hey, grapes make wine. Wine contains resveratrol. Wine makes you live longer. Hallelujah. The French paradox has been resolved." Slight spoiler alert, that's not true, but we get into the whys that might be the case. This episode we only had... When I say only, meaning we had less than two hours, but like has happened in other podcasts, including the one with Rhonda Patrick, after we closed the podcast, because I wanted to be respectful of David's time, he had to catch a flight to New York right after we spoke. This interview took place in Boston. We ended up talking for another 15 minutes, and unfortunately, that 15 minutes was some of the most intense, detailed, nuanced discussions of it, and I left thinking, "Gosh, I wish we had more time to talk." So I suspect David and I will speak again. David has a book coming out next year, and I think that'll provide another great opportunity to sit back down with him. In this episode, we talk a lot about his postdoc at MIT. He came out of a powerhouse lab that has produced other notable folks that, including folks we've already interviewed like Matt Kaeberlein and folks we've talked about like Brian Kennedy. We talk about his contribution to the understanding of sirtuins, which was something that was coming out of Lenny's lab, and David really picked that up and ran with it. What are these things? What do they do? What's their role in aging, DNA repair, gene silencing? We go over all this stuff in detail. We talk a lot about NAD and its precursors, specifically something called NMN. So if you are listening to this and you are in the camp of trying to understand how to make heads or tails of NAD, NR, NMN, I think this episode will be helpful. Tragically, it was not until 24 hours after we did this episode that I ran into George Vlasik on an airplane who mentioned to me a paper by Josh Rabinowitz in Cell Metabolism that came out about a month before we did this interview that we will link to that I think makes a very compelling case for the futility of orally administered versions of these precursors. And that would have been a really interesting discussion to have with David because of his expertise in this. So at some point I'll probably want to interview Josh, and we'll go into that in really detail because again, unless you've been up in the Himalayas hunting Yeti, you're probably aware that these are kind of the hottest supplements out there. We talk a lot about NAD levels. What do these things mean? Where does it go? Where is it produced? We, again, as I alluded to above, talk about resveratrol and its potential in life extension. And we talk about the connection then between sirtuins and NAD. We talk about his rationale for what he does. So David is actually very open about, you know, kind of the stuff that he does personally, including he, the fact that he takes resveratrol and metformin and NMN himself. We also go into the differences between some of these molecules and again allude a little bit to his book. There's a lot of stuff in here. Again, sometimes it gets technical, sometimes it doesn't. The show notes, as always, will provide a lot of help, so if you have any questions about papers we reference, the likelihood that they're in the show notes is actually quite high. Also, if you haven't signed up for our weekly email list and you wouldn't mind getting an email from me once a week, I suggest you head on over to the website, peterattiamd.com, and sign up. Again, my promise to you is to make it as non-lame as possible. And finally, if you are enjoying these podcasts, please head on over to iTunes and write a review there. And again, I would hope that you like the podcast and leave a positive review. But I guess in the spirit of getting as much feedback as possible, if you don't like it and you have something to say that we can do to make it better, that's probably not an unreasonable place to leave that kind of feedback. So with all that said, please welcome to my interview with Professor David Sinclair. Good afternoon, David.

   2. DSDavid Sinclair6:07

      Nice to be here, Peter.

   3. PAPeter Attia6:08

      Thank you for making time today. I gathered only by the commotion in this very busy place we're in that there's a lot going on here, and making time to speak with somebody as inconsequential as I am is a big ask, so I am incredibly grateful.

   4. DSDavid Sinclair6:23

      I'm pleased to be on.

   5. PAPeter Attia6:24

      We were introduced by a mutual friend who's no stranger to people listening to this, because I've had him on before, David Sabatini. And maybe a month ago, maybe a little more than that, I said, "David, you know, I really want to know more about sirtuins, and who do you recommend that I speak with?" And he said, "Well, I think David Sinclair would be perfect." So he reached out to you, and you very graciously agreed to speak. So again, I, I, I thank you for that, and I'm really excited to talk about something that I know very little about, as you will undoubtedly learn in the next, uh, hour or so.

   6. DSDavid Sinclair6:53

      Well, uh, yeah, that's kind of David. Uh, yeah, y- you... as you know, and probably the listeners know as well, he's a bit of a superstar, so.

   7. PAPeter Attia6:58

      [laughs]

   8. DSDavid Sinclair7:00

      Uh, it's kind of him. I'll have to, uh, you know, send him a note for that. But, um, no, honestly, it's really, uh, great to be on, 'cause I, I know you delve into the details of the science more than anyone I've heard, and I'm excited to be able to share that with listeners.

   9. PAPeter Attia7:12

      Well, yeah, that's, that's the part that's got me excited. So a lot of times I've listened to talks that you've given, and I can tell you're, I don't want to use the word dumbing it down, but you're, you know, you're speaking to an audience where you realize that if you go too far in the weeds, they're, they're gonna miss the point. And so I've found myself watching talks you've given on YouTube going, "I, I wish he would elaborate on that point and that point," and-

   10. DSDavid Sinclair7:33

       Hey, it may be that I don't, I don't understand it myself.

   11. PAPeter Attia7:35

       [laughs]

   12. DSDavid Sinclair7:36

       Let's see.

3. 7:37 – 15:18

   From Australia to Lenny Guarente's Lab at MIT

   1. PAPeter Attia7:37

      So I think just for a bit of background, I know you did your undergrad, your PhD in Australia, and then somehow you wind up in Lenny's lab at MIT. How did that happen?

   2. DSDavid Sinclair7:46

      I've been interested in aging since I was four, since I realized that everybody and everything around me is gonna die. That's a pretty big shock for everybody. Most people forget about it, because you just can't function thinking about it every day. I forgot about it until my teenage years, and I realized that with the technology that was coming online, you know, these are the days of early PCR and gene sequencing, we used to call it genetic engineering, I thought maybe we're just the last generation who's going to live a normal lifespan, a regular evolved lifespan, and our children and our children's children forever are going to be able to benefit from these new technologies, and damn it, this is not right. I've got grandparents, parents, friends, and about five billion people who could really be benefited right now. So at that point I decided to seek out the best people in the world and see if I could go work with them, and I got a PhD in molecular biology, in yeast genetics, and that was a great PhD. And, uh, a real turning point for me was this guy from MIT who I knew about because he was also a yeast researcher, he was a legend, I'd read all his papers, Lenny Guarente came to Australia. And here I am, this, uh, young 20-something-year-old having dinner with Lenny Guarente and my PhD supervisor from Australia, and Lenny starts telling this story halfway through dinner about this new project that a guy called Nicanor Austriaco and Brian Kennedy had just started doing, and it was to try and find genes that controlled aging in yeast cells. And I said, "Okay, I know yeast, and I've always wanted to figure this out. Damn it, that's what I want to do. Save me a spot, Lenny. I'm coming to your lab." And he went, "Yeah, yeah, yeah, whatever," as he does to pro- most people who want to join his lab. So I wrote to him pretty soon after, maybe six months, I was finishing up, "Can I come to your lab?" And he wrote back, like he does to everybody, "Sure, you can come." But then a millisecond later I was disappointed because he said, "You have to bring your own funding."

   3. PAPeter Attia9:41

      Mm.

   4. DSDavid Sinclair9:41

      So that was no small task, and that's a story in itself. Just briefly though, this is a lesson for anyone who's listening who thinks that getting to somewhere like this is, is easy. It's, you have to be massively determined. You have to have grit. And I just wouldn't give up because there's nothing else I wanted to do in my life. I certainly was looking at patent law even, but that would-- I think I would have died, uh, if I had done that as a career. I just don't have the attention span. Anyway, I actually found funding. It turns out I applied to the Helen Hay Whitney Foundation, which is a prestigious foundation here, and they wrote to me and said, "You can't apply, you're a foreigner." And, uh, I said, "Well," this is the old days with early email, I think it might even be post, and they wrote back and they said, "Well, you're a foreigner. We can't afford to fly you out to Boston, Cambridge to, for an interview." And I said, "Well, I'll sell my car and I'll pay for the ticket." As I understand it, I was the first foreigner who was allowed to interview, and I flew here. I stayed in Nicanor Austriaco's basement. He was very kind. And my interview was with a guy who everyone was telling me is a real tough guy, super smart. I'd never heard of him. Of course, now everybody in, in science knows of Doug Melton. He's king of, well, endocrinology and stem cells at Harvard, and I was just this kid showing up for an interview, and there was a line of people outside his door waiting.

   5. PAPeter Attia11:02

      [laughs]

   6. DSDavid Sinclair11:03

      And I was fifth in line, and I went in and Professor Melton said to me, "David, tell me what you want to do." And I had literally five minutes to, to impress this guy, one of the smartest people you'll ever meet.

   7. PAPeter Attia11:16

      So you've sold your car, flown 22 hours for a five-minute interview.

   8. DSDavid Sinclair11:20

      Yeah, that was basically it. And so I thought about it most of my adult life, what was aging about. And a lot of people in those days, back in the late '80s, early '90s, were talking about the evolution of aging genes, death genes. And I, I studied evolutionary biology myself, and that didn't make any sense. You don't evolve death genes. And I just, I never subscribed to the group theory of selection, so every w- every person for themselves. Selfish gene, love Dawkins stuff. And so my thought was the only genes that I could understand could evolve that have relevance to aging are longevity genes. And right about that time, there was the discovery of, in C elegans, the nematode worm of the DAF-2 mutation from-

   9. PAPeter Attia12:00

      Yeah, I was about to say, this must have corresponded with Cynthia's work, right? Around the same time.

   10. DSDavid Sinclair12:04

       It's ex- it's just happening, and Lenny at the same time had just discovered a mutation that they weren't sure what it was doing, but it turns out it led to the sirtuin story. And so I said to Doug- I want to come to Lenny's lab and discover life genes, genes that give life and longevity. And I guess he liked the idea what I was saying. I was certainly very passionate. It probably didn't hurt that I brought a bottle of red wine as a present. I just thought that's what you do when you come to people's place. Later on, I learned that that's equivalent to bribing somebody-

   11. PAPeter Attia12:36

       [laughs]

   12. DSDavid Sinclair12:37

       ... but I was just a young kid. But yeah, that, that's what happened. I got the, got the-

   13. PAPeter Attia12:40

       No foreshadowing the resveratrol there, right?

   14. DSDavid Sinclair12:43

       Yeah, definitely. It was, uh, auspicious, uh, kind of a thing. But being able to come to Lenny's lab, I would have worked in Lenny's lab for free. I would have lived in the basement and done it. That's just how much I wanted to do this. So I came over, it was, uh, late nineteen ninety-four, early ninety-five, when things were just starting to take off, trying to understand what these mutations were that Brian had found.

   15. PAPeter Attia13:03

       And was Matt Kaeberlein there as well?

   16. DSDavid Sinclair13:04

       Not yet.

   17. PAPeter Attia13:04

       Matt's also a close friend. He was not there yet. So the, the, the lab has produced just a ridiculous [chuckles] amount of sort of prolific individuals in this anti-aging space.

   18. DSDavid Sinclair13:15

       It was a golden age. There w- you could definitely feel that something special was going on in those days. But I arrived-- I was the first postdoc to join to study aging specifically.

   19. PAPeter Attia13:22

       Was Brian a PhD student?

   20. DSDavid Sinclair13:24

       Yeah.

   21. PAPeter Attia13:24

       Okay.

   22. DSDavid Sinclair13:24

       So Brian-- I was this new guy on the block. Brian, "Teach me how to do yeast aging," and he taught me. But all the other postdocs, there, there were probably eighteen to twenty postdocs there, big lab, all working on transcription regulation, and that was the sexy thing. And I was told by... And I, I don't think I've told anybody publicly this, that, that the postdocs were saying, "You're crazy to work on this aging project. Lenny's lost his mind. It's a house of cards. It's gonna fall down. You can't study aging in yeast," all of these things. And within the first few weeks, I thought, m-maybe I've made a mistake. Maybe I was just fooled. Maybe Lenny isn't that smart as I thought. But I stuck with it. But I do remember at one point on the phone, nearly crying to my mother, saying, "I think I made a really big mistake." And that stands out as a point where I could have easily just quit, uh, but I stuck with it, and thank goodness I did, because Lenny was right, and Lenny is, uh, really this, the smart visionary that saw that this was the right way to go.

   23. PAPeter Attia14:19

       So you sort of alluded to it earlier, Lenny was sort of onto something, right? Was-- There was basically a new pathway. Now, if we go back in time to ninety-four, what did we know? Well, we barely knew about TOR. I mean, it was just being basically figured out that this thing that Michael Hall had figured out a year earlier, Saul is figuring out, David is figuring out. I mean, there's a-- there's still this early triangulation of what's going on with, with rapamycin. At the time, they didn't even... If I recall, I don't think we knew that there was mTORC one, mTORC two, and they were doing totally different things. AMPK is pretty well understood. Metformin's been around, but I don't think people really had a sense at the time that it was anything other than an anti-diabetic drug. So talk me through this whole sirtuin thing. That's a pretty broad question.

   24. DSDavid Sinclair15:11

       Yeah.

   25. PAPeter Attia15:12

       Let me, let me narrow it down a little bit. Talk me through what you were just about to allude to, that what was Lenny onto when you showed up?

4. 15:18 – 20:58

   Discovering SIR2: Gene Silencing and Aging in Yeast

   1. DSDavid Sinclair15:18

      Well, g-genetics is, is a fabulous tool because you don't have to go in with any hypothesis, that biology will tell you the answer. And the gene that had just been cloned by Brian turned out to be what's called SIR4. Now, SIR4 didn't turn out to be a mammalian conserved gene, so SIR4 has not been as exciting. But there was this partner of the SIR4 gene, uh, it was called SIR2. And SIR2 and SIR3 and SIR4 form this complex of proteins stick together and control, of all things, gene silencing. That's what SIR stands for, silent information regulator, in this case, number two. And that was very unexpected. In those days, if you think back, the cause of aging was thought to be DNA damage, mutations, free radicals, so we were all expecting to find genes that controlled DNA repair or, uh, antioxidants.

   2. PAPeter Attia16:07

      At that time-- 'Cause I, I go back and I think, God, at that time, I was still in college studying math and engineering. I didn't know-- I hadn't taken a biology course, so I can't think about it through the context of my own education. How well was it understood that there were introns and exons and that much of the genome wasn't even coding and stuff? Like, was that als- was that well understood at that point in time?

   3. DSDavid Sinclair16:26

      It was. In yeast, actually, they, they were ahead of, uh, anybody else, uh, in eukaryotes. We knew that there were introns. There are not many introns in yeast anyway. But we hadn't seen the full genome. It was still bits and pieces. Maybe five, ten percent was known. My PhD was sequencing three genes. That's all that could be, uh-

   4. PAPeter Attia16:43

      [laughs]

   5. DSDavid Sinclair16:44

      So things were changing rapidly, this new thing with PCR. You, you could move tubes into hot tubs and amplify genes. It was all very exciting. But what we didn't have any clue was that why a silencing gene that controlled, negatively controlled genes, other genes, why that would, would have anything to do with aging. It was totally bizarre. It led to a string of cell papers, and one after another, every few months, we were actually publishing something new, and we had a science paper, and that was the, the gold rush of this discovery because it really turned on the lights in this cave of a whole new area of biology. And we're still trying to understand actually why those silencing proteins are relevant to aging. But what we do know for sure is that these same genes, these sirtuins, in all life forms, whether they're from plants all the way to us, do play a protective role in responding to energy and nutrients, just like the AMP kinase and the mTOR pathway do.

   6. PAPeter Attia17:38

      So you alluded to SIRT2. Was that first found in yeast?

   7. DSDavid Sinclair17:43

      Yes, it was. It was known already, actually. Lenny-- and we didn't s-discover SIRT2. It was already known as a silencing protein that controlled the mating type, in other words, the sex of a yeast cell. And, uh, if you don't have the silencing, what happens is that the yeast cells get confused because they're now turning on genes for A and alpha, which means male and female. And a yeast cell that doesn't know if it's male or female will not mate, and it's become sterile. And turns out that's a hallmark of yeast aging, is sterility. So if you, you know, you-- The way you can tell whether a yeast cell is truly old is, is it sterile or is it just sick? And that's how we used to tell. But now we actually understand the cause of that sterility. It's the actual, the, the movement of SIR2 protein away from those genes that it should be at to go deal with other problems in the cell.

   8. PAPeter Attia18:33

      I see. So it's not that SIR2 becomes deactivated, it just, for lack of a better description, shifts its attention elsewhere?

   9. DSDavid Sinclair18:40

      Right. It becomes distracted by other things going on in the cell. And, and we, we had a cell paper in nineteen ninety-nine with Kevin Mills and Lenny where we discovered and a couple of other groups should also get credit for co-discovering this, is that the sirtuins are also involved in DNA repair. When you get a broken chromosome, it's the SIR2 complex that goes along, helps unwrap the DNA, we think, and put it back together and repair that. And while the SIR2 complex is doing that, it cannot be also silencing. There's not enough of it to go around. And you might ask, "Well, why would the cell do that? Why don't you just make more SIR2?" What we think is that this is a very ancient system that coordinates controlling mating and DNA repair. You don't want to be mating and dividing if you've got a broken chromosome. So this is a way of coordinating those two events, and it's very ancient. It's a very active system. You need DNA checkpoint signaling, so it's not just random. But what we also have come to realize is that this, let's call it this distraction of the sirtuins, it's conserved. We find this happens in our own aging process as well.

   10. PAPeter Attia19:43

       So there's really two roles. There's gene silencing and DNA repair. Now, sirtuins are HDACs, is that correct? Are they all HDACs?

   11. DSDavid Sinclair19:55

       So HDAC, histone deacetylases, this is the old name for protein deacetylases now. Because what we've all come to realize is histones are just one of the things that sirtuins and these other HDACs do. They can target what are called non-histone proteins, and they remove not just acetyl groups, but also other types of what are called generally acyl groups. And so that's a whole new world. That means that sirtuins, the family, there are seven of them in mammals, five of them in yeast, target other proteins, proteins that are in cytoplasm, in the nucleus, even in the mitochondria. And that's their role. It's not so much only about controlling the chromatin and histones, but also about controlling signaling and metabolism as well. And they can do that by targeting any protein theoretically in the cell.

   12. PAPeter Attia20:41

       So what are the... You know, again, thinking back to DAF-2, DAF-16 as the parallels with FOXO and IGF, were there elegant experiments in the yeast that could show you extreme conditions of lots of SIRT, no SIRT, and what that phenotype is?

5. 20:58 – 25:37

   Yeast Experiments: Werner Syndrome, rDNA and Sirtuin Overexpression

   1. DSDavid Sinclair20:58

      Oh, yeah. These were the first experiments. So I'll, I'll try to take you through them correctly in sequence. So the-- what we showed with Brian, first of all, and this is a nineteen ninety-six cell paper, was that we were looking for this movement. There was this so-called age locus. We didn't know what it was. We didn't know where they were going. We just know that they knew that they left the silent mating type locus. So what we did was we stained it. So Brian had moved on actually to his postdoc, and Kevin Mills and I, a student at the time, our job was to find where are the SIR proteins going. So we stained them, and we could look at them under the microscope. And what we saw was they were going to this little place in the nucleus, which we eventually figured out was the nucleolus, which is what makes the rRNA, which makes the, the ribosomes. It's a, a really important part, and the DNA that's within the nucleolus is called the ribosomal DNA or the rDNA. And that's where they were going, not just during normal aging, but also during an accelerated form of aging. So there's a whole story that was lost in history actually that maybe I'll just quickly touch on. One of the first things I did when I got to Lenny's lab was to work on Werner syndrome, which is a premature aging disease.

   2. PAPeter Attia22:07

      And these are kids that die in their teens or twenties, aren't they?

   3. DSDavid Sinclair22:10

      No, that, that's a different Hutchinson Gilford syndrome. This one, Werner's, they live till forty.

   4. PAPeter Attia22:14

      They live to their forties, yeah.

   5. DSDavid Sinclair22:15

      Yeah.

   6. PAPeter Attia22:15

      Yeah.

   7. DSDavid Sinclair22:16

      But the gene was just cloned by George Martin and his team out there, and the homologue in yeast is called SGS1. And I, I picked up the paper, it was in Science, I recall, went into Lenny's office and I said, "I've just been scooped, but there's a yeast homologue. I'm going to work on that. Is that okay?" And he said, "Yeah, go for it." And, uh, so we, we worked on SGS1 for a little bit, and what we found was that they were going through accelerated aging as well. So we had a science paper on that. And what was exciting about that was that they were also becoming sterile and the SIR2 complex was moving as well, just like the normal aging. So we had this model, rapid aging model, and you might say, "Well, so what, what's the big deal? You've got a rapid aging model." But A, that told us that there was some universal process that results in premature aging in humans, probably in yeast the same thing, and we could also study this much more easily than an old yeast cell. Consider that to find a single old yeast cell, it's really hard, especially if you're just studying replicative aging, which is the number of times they divide. Each mother cell produces on average ten to the power of twenty-five offspring.

   8. PAPeter Attia23:23

      Wow.

   9. DSDavid Sinclair23:24

      Okay. So that's, by my calculations, about thirty million offspring, and you have to pull out that one cell and study it biochemically.

   10. PAPeter Attia23:32

       Wait, you said ten to the twenty-five.

   11. DSDavid Sinclair23:33

       Yeah.

   12. PAPeter Attia23:34

       That's m-

   13. DSDavid Sinclair23:34

       Oh, sorry, two to the twenty-five.

   14. PAPeter Attia23:35

       Oh, okay. Okay. [chuckles]

   15. DSDavid Sinclair23:37

       Yeah. But in any case, that's, that's way more... Uh, so what we used to do is to sort out the old cells. We'd label them with a chemical and pull them out with magnetic beads. But it was a real-- We couldn't get many of them. You'd just get a handful. But with these SGS1 as proteins-

   16. PAPeter Attia23:51

       You could get a bunch of them

   17. DSDavid Sinclair23:53

       ... the mutants, we could get a lot more. And so we, we'd made a lot of progress using that. But every time we made a discovery with the SGS protein, uh, mutants, we went back to the normal yeast cells and verified. Uh, but we were actually able to figure out with that mutant what the distracting problem was for the SIR complex, and that was actually DNA breaks and DNA recombination that was occurring at the most repetitive regions, the most unstable region of the genome, which is the rDNA, which is in the nucleolus. And that was what was distracting those proteins.

   18. PAPeter Attia24:22

       Interesting. When you knock out SIR2 Is it easy to knock it out?

   19. DSDavid Sinclair24:26

       Yeah, so that was the next experiment.

   20. PAPeter Attia24:28

       Okay.

   21. DSDavid Sinclair24:28

       So then we wanted to know-- The prediction is if you knock out Sirtuin, you should get a lot more of this instability at the RNA.

   22. PAPeter Attia24:34

       Yes. And the question is does it translate to accelerated aging or not necessarily accelerated aging, but more cancer or some other phenotype, right?

   23. DSDavid Sinclair24:41

       Well, in yeast it led to accelerated aging through the process I was telling you about.

   24. PAPeter Attia24:44

       Mm-hmm.

   25. DSDavid Sinclair24:44

       Genomic instability, DNA repair went, went down. And also that happens in animals, although it's a little more complex because it's embryonic lethal in a lot of y- in a lot of mice. So you can't easily do that experiment. What you can do is the opposite. You can turn on or overexpress the Sirtuin gene in a yeast cell and if we're right, you should get a few things that are gonna happen. You'll have more genomic stability at this, particularly at this rDNA locus in the nucleolus, and the yeast cells should live longer. And that experiment was done by an incoming graduate student, Matt Kaeberlein, and what an, what a fantastic project to get when you walk in. He did it, and the day that he got lifespan extension with extra Sirtuin was a very good one for him and the lab.

   26. PAPeter Attia25:27

       So what's the next step from there? The most obvious thing is how do you develop a compound that would do this without the genetic mutation that empowered it?

6. 25:37 – 32:34

   Sirtuins, Calorie Restriction and Evolutionary Conservation

   1. DSDavid Sinclair25:37

      Yeah. That, that was the issue because you can't easily genetically manipulate humans. So the question was how do you turn on these genes? Now we, we spent about three, four years working on caloric restriction in yeast and then in mammals. And my lab and some others were leading the charge in showing that sirtuins both in yeast and mammals were not only necessary but were sufficient when you overexpress them to mimic calorie restriction. Put another way, if you knock out Sirtuin-

   2. PAPeter Attia26:04

      Mm-hmm

   3. DSDavid Sinclair26:04

      ... you don't get the benefits of calorie restriction.

   4. PAPeter Attia26:06

      You don't get the benefits of CR.

   5. DSDavid Sinclair26:07

      Right. And that's also now been shown by others to be true in mice as well. So that, that led to the idea that-

   6. PAPeter Attia26:13

      Is that true in all mice?

   7. DSDavid Sinclair26:15

      I couldn't say. You know, there's-- Even in yeast you can get around-

   8. PAPeter Attia26:18

      Mm-hmm

   9. DSDavid Sinclair26:18

      ... the need for sirtuins if you stress the yeast really intensely with very little amount of calories. But there are, you know, there are aspects of, of calorie restriction benefits such as a lifespan extension that are ameliorated, lessened by a Sirtuin knockout. But it's still complexified by the fact that it's lethal in embryos and you have to knock it out in the adult to do a real experiment.

   10. PAPeter Attia26:41

       Yeah, it's the same sort of issue that Cynthia had with the DAFs, which was if you do it too early you, the C elegans doesn't make it into an intermediate stage.

   11. DSDavid Sinclair26:48

       You know what? Somebody hasn't even done the proper experiment, which is to take a, a mouse that you can knock out Sirtuin one in an adult whole body and then calorie restrict. Something that we probably should have done years ago. We didn't, but the technology's there to do that. But what, what we did learn actually was both in yeast and in mammals was that it's not just one of these genes that's important, it's the whole family, and that if you knock out, take yeast for example, if you knock out Sirtuin in yeast you lose the ability to respond to some mild calorie restriction. But if you really calorie restrict them, they'll still live longer. And there was a big debate actually between Brian, Matt, myself about that and where we settled on was that these other Sir- Sirtuin-related genes, uh, were also helping and they work as a family and if you knock one out the others can compensate.

   12. PAPeter Attia27:37

       The yeast only have one?

   13. DSDavid Sinclair27:39

       Yeast have five.

   14. PAPeter Attia27:39

       Yeast have five. And humans have a whole family, like-

   15. DSDavid Sinclair27:41

       Seven

   16. PAPeter Attia27:41

       ... eight or something, right?

   17. DSDavid Sinclair27:42

       Just seven.

   18. PAPeter Attia27:42

       Seven.

   19. DSDavid Sinclair27:43

       Yeah.

   20. PAPeter Attia27:43

       Oh, okay. So only two more. That's interesting.

   21. DSDavid Sinclair27:46

       Little known fact, most people ignore the other yeast sirtuins, but they're just as interesting, and what we've found is they also can extend lifespan as well.

   22. PAPeter Attia27:54

       So when you-- Actually it's funny, I was gonna go back to something else you said a second ago, but what's the teleologic explanation for why caloric restriction and sirtuins would move hand-in-hand? I'm just-- Like from an evol- You, you talked earlier about your appreciation for sort of evolutionary biology. So an organism is, you know, in a nutrient-deprived environment, it still has to be able to do a bunch of things if it's going to be fit. Do we believe that that's an environment where we need to see more stabilization of the genome or repair or silencing or what do we think is the biggest insult during that period of time?

   23. DSDavid Sinclair28:29

       Yeah, the, so the biggest insult to any life form is a broken chromosome. That's lethal if you don't fix it. That's a-

   24. PAPeter Attia28:34

       And do we see that more likely happening during nutrient deprivation?

   25. DSDavid Sinclair28:38

       I-

   26. PAPeter Attia28:38

       I would see that as-- I would have assumed-- To be honest with you, I would have assumed that was independent of nutrient exposure or at least if anything inversely co- correlated.

   27. DSDavid Sinclair28:45

       Well, if, if you don't have enough nucleotides to complete replication you're gonna break a lot of times.

   28. PAPeter Attia28:49

       I see.

   29. DSDavid Sinclair28:49

       So they, they do go hand-in-hand. But the bigger picture is that the sirtuins evolved, we believe, what are we talking about, three and a half billion years ago in the first life forms, early life forms. Maybe just after the first f- one of the first proteins to actually evolve we think would be a sirtuin and its job is to sense stress, biological stress in the environment, whether it's DNA damage or it's, you know, a burst of cosmic rays, change in temperature, or a lack of nutrients, and their job is to allow that organism to hunker down and survive. Stop mating, stop breeding, we can do that in another day. If we don't survive this, our offspring are gonna, gonna die anyway. So they control-- We think we, they control which genes to turn on and off in response to adversity and they allow those organisms to survive. But they're also talking to other pathways, so they're gonna talk to mTOR, they're gonna talk to Cynthia's DAF pathway and t- collectively these are the, the genes that we've settled on as the longevity pathways. But they didn't evolve for longevity, they evolved for survival of during adversity.

   30. PAPeter Attia29:55

       How conserved are these across, let's, y- you know, use the big four models of eukaryotes from yeast, worms, flies, you know, larger mammals like mice and rodents. Is this relatively well conserved the way the TOR pathway is conserved or does it have more bends in the road?
7. 32:34 – 38:48

   Moving to Harvard and the NAD Connection

   1. PAPeter Attia32:34

      So now you're in your, in the process of kickstarting your own lab, which comes with its own stresses, right? You've got to secure funding and all those other things. And then what's happening in the, on the front of, uh, of this stuff?

   2. DSDavid Sinclair32:46

      Yeah, so 1999 a few major things happened. One was this, uh, DNA repair connection. The second one was Lenny's lab, uh, published that NAD was a requirement for sirtuin activity. And Shin Imai, who's at Wash U now, was the postdoc who made that somewhat serendipitous but brilliant, uh, discovery. And then, uh, the third thing was the connection to calorie restriction was happening around that time too.

   3. PAPeter Attia33:08

      Going back to the second thing, we talk about it now today like it's in textbooks, it's so obvious, right, that sirtuins are NAD-dependent deacetylase. Okay. NAD is so ubiquitous in cells that if the quantity you could have in a cell varies on a scale from one to 10, what is sufficient to produce this deacetylase activity? Is it anywhere from two to 10, or does it have to be, you know, quite a high concentration?

   4. DSDavid Sinclair33:36

      It can be two to 10. You can actually get very low levels in some disease conditions and the org- the animal is still alive.

   5. PAPeter Attia33:42

      So it's basically only saying that NAD is necessary for sirtuins to work.

   6. DSDavid Sinclair33:48

      Right. Well, without NAD, we'd be dead in 30 seconds, but we don't know-

   7. PAPeter Attia33:52

      By, by other reasons as well.

   8. DSDavid Sinclair33:53

      Exactly.

   9. PAPeter Attia33:53

      I mean, wouldn't we be dead just from not being able to do electron transports?

   10. DSDavid Sinclair33:56

       We would, and there's more than 500 reactions that you-

   11. PAPeter Attia33:59

       Yeah, yeah

   12. DSDavid Sinclair33:59

       ... we need, uh, to, just to survive. But what we didn't know in the 2000s, and it w- it was actually quite a crazy thing to think that NAD was regulating anything, and that was actually what we first worked on in my lab, was the control of sirtuins with NAD levels. The reason it's crazy is you read textbooks and NAD is the, the most ubiquitous, important molecule in the cell. How could it possibly be varied during aging, let alone during the day when you eat something or your circadian rhythm? Now it's obvious. We know NAD goes up and down. It changes with age. But in those days, people thought if you changed NAD levels, you'd probably die. And that's not true.

   13. PAPeter Attia34:37

       Was it known at the time that doesn't complex one of the mitochondria basically convert NADH to NAD?

   14. DSDavid Sinclair34:44

       Mm-hmm.

   15. PAPeter Attia34:45

       So the, you would at least know that in the mitochondria, the concentration of NAD must go up and down, or else you couldn't actually respire.

   16. DSDavid Sinclair34:53

       Well, locally it goes up and down, but the steady state level's pretty constant.

   17. PAPeter Attia34:57

       And, and when you say going up and down, are you talking cytoplasmic, nuclear, plasma? What, what, where are we talking about?

   18. DSDavid Sinclair35:04

       Yeah, we had a paper, I think it was 2007, where we had a, quite a surprising result which told us that it's not just the cytoplasm that it goes up and down. It was the, also the mitochondria going up and down. And we, we didn't know that. We actually, we stumbled upon it. We found that if we kept cells with high amounts of NAD, they would survive better DNA damage, other insults. And we could deplete NAD in the cytoplasm, but they still, the cells still lived, and we didn't understand that.

   19. PAPeter Attia35:33

       How did you do that, by the way? How do you deplete NAD?

   20. DSDavid Sinclair35:35

       Actually, come to think of it, we could either overexpress NAD-depleting enzymes... But actually, the way we found it was that when you damage cells with a DNA-damaging agent, say chemotherapy drug, the cells themselves deplete NAD naturally with this enzyme called PARP1, which is an NAD-consuming enzyme. And that, actually, that's very well known that if you hit a cell with a DNA-damaging agent, the reason that it dies is NAD depletion. So we were measuring the NAD depletion in the context of-

   21. PAPeter Attia36:04

       And, and that's because the cell is trying to utilize that NAD to repair the damage you've just caused?

   22. DSDavid Sinclair36:09

       Right. Right. So PARP-

   23. PAPeter Attia36:10

       Or you didn't know that at the time?

   24. DSDavid Sinclair36:11

       No, that was well known. So PARP1 is a known DNA repair protein, and that's, if you block PARP, you also protect cells. But what was interesting was that we could overexpress, give more copies of a gene that made NAD, and, uh, this is called an MPT, which is the equivalent of the PNC1 gene in yeast, which we found was important for lifespan in those organisms. So we were overexpressing this MPT. Cells had more NAD. Hit them with the toxin, they'd survive better than the regular cells, but the NAD was still being almost completely depleted from the cytoplasm.

   25. PAPeter Attia36:45

       And sorry, just because this is, this is sort of at the crux of it. Did they survive because they were unable to deplete their NAD?

   26. DSDavid Sinclair36:52

       No, we, we, we saw that NAD just disappeared from the cell, but they survived.

   27. PAPeter Attia36:56

       But they still survived.

   28. DSDavid Sinclair36:57

       But there was a place we weren't looking at the time, and we tracked it down to the mitochondria. So this begs the term the mitochondrial oasis hypothesis. So myself and Anthony Sauve from Cornell coined this term because what we found was that as long as the mitochondria stayed active with their NAD, it didn't matter. The cell could survive and recover from that stress. And actually, it turns out that the levels in mitochondria, NAD levels, are even more important than cytoplasmic NAD levels for survival.

   29. PAPeter Attia37:24

       That makes sense. And of course, that's a hard thing to measure, isn't it?

   30. DSDavid Sinclair37:27

       It was extremely hard. That's where Anthony came in. Anthony is a chemist and a biochemist at heart, and, uh, it was extremely hard to isolate these mitochondria, preserve the NAD in them. We had to use, uh, new technologies to be able to do that.
8. 38:48 – 49:41

   PNC1, Nicotinamide Inhibition and the Path to Resveratrol

   1. PAPeter Attia38:48

      ... size, yeah. Okay, so now you've made this, these three discoveries, the second of which we just went into in a little bit more detail. How does the story unfold now you've got your spanking new lab?

   2. DSDavid Sinclair39:01

      Well, we worked for a little while on the SGS1 won- oneness protein-

   3. PAPeter Attia39:05

      Yes

   4. DSDavid Sinclair39:05

      ... and telomeres. Put out a paper on that. And we didn't work on sirtuins for about a year because Lenny said, "I don't want you working on sirtuins," when I left the lab, which was a bit of a shock.

   5. PAPeter Attia39:14

      Why?

   6. DSDavid Sinclair39:15

      He doesn't want, didn't want the competition, I suppose. But I thought a year was enough to give him a head start, but we quickly started working back on that.

   7. PAPeter Attia39:23

      Is that a common request of people when postdocs leave their labs?

   8. DSDavid Sinclair39:26

      No, of course not, but what am I gonna do? I mean, the guy, the guy trained me.

   9. PAPeter Attia39:30

      Yeah, yeah, yeah.

   10. DSDavid Sinclair39:30

       I owe him my career. But in those days, it was very competitive.

   11. PAPeter Attia39:33

       Mm-hmm.

   12. DSDavid Sinclair39:33

       And so, uh, you know, the Lenny of today is not the Lenny of previous years, and he's a wonderful friend and mentor to me. But that's how it was in those days. It was very cutthroat.

   13. PAPeter Attia39:41

       I see, but if it were to, up to you, you would've continued to work on sirtuins.

   14. DSDavid Sinclair39:45

       Right.

   15. PAPeter Attia39:45

       So then now we're basically back to 2001, 2002. You're, the moratorium is up. You're now back to working on it, and nobody at this point in time has yet figured out a way to exogenously manipulate sirtuins more than the stuff that we've already talked about, which is nutrients, stress, and things like that.

   16. DSDavid Sinclair40:03

       Yeah, we, we were trying to feed yeast NAD, and we, we gave them nicotinamide, which is a precursor to NAD, vitamin B3. And actually, Kevin Bitterman, who's now a very successful venture capitalist, w- my first student, he put nicotinamide on yeast, and we could measure the SIRT2 activity by the color, and if SIRT2 was more active, they'd turn red. And he walked into my office, one of his first experiments when we s- worked on sirtuins, and he said, "David, something's weird. We didn't get activation. We got inhibition." So the yeast had gone red. And I said, "Kevin, doesn't matter what happens. As if it's unexpected, that's even better." So that led to a paper that said that vitamin B3 high doses is inhibitory of sirtuins, and now the labs around the world use nicotinamide as an inhibitor for sirtuins, and I wouldn't recommend taking really high doses of nicotinamide.

   17. PAPeter Attia40:49

       Why is that?

   18. DSDavid Sinclair40:50

       There's a, a few answers. Biochemical answer is that there's a, a s- an evolved pocket in the sirtuin structure that measures nicotinamide levels, and it's a feedback loop. So nicotinamide is, to get nerdy, is the product of the reaction. It takes NAD, cleaves it-

   19. PAPeter Attia41:06

       Oh, I got it. So it's just a negative feedback loop.

   20. DSDavid Sinclair41:08

       It's a negative feedback loop.

   21. PAPeter Attia41:08

       It's seeing too much B3, and it's saying, "I have too much of my output."

   22. DSDavid Sinclair41:13

       Slow down.

   23. PAPeter Attia41:13

       "Turn it, turn it down."

   24. DSDavid Sinclair41:14

       Exactly. So we, we struggled with that. We couldn't get NAD to go into cells. It's too big. Even with mammalian cells, it's difficult. Uh, so we were looking at ways to make more NAD in the cell.

   25. PAPeter Attia41:23

       Mm-hmm.

   26. DSDavid Sinclair41:23

       That was our original thesis before resveratrol was on the radar. And we were turning on and discovering the genes that made NAD in yeast, and we cloned some of the genes in that pathway, and there was one particular one that was called PN, is called PNC1, and it had been studied in the context of tuberculosis. And what we found was that when we calorically restricted yeast cells, this was one of the most highly upregulated genes in the whole yeast cell, which was very unusual. People had discovered this before in their own lab, but they were wondering, what the heck is this NAD synthesis pathway got to do with calorie restriction, got to do with stress? But we knew exactly what was happening. This is a stress response that was turning on NAD production and activating sirtuins. So we had a, our first nature paper actually on that, 2002, I think, 2003, and we found that PNC1 could mimic caloric restriction and raise NAD availability, and then if we knocked out the PNC1 gene, yeast cells didn't live longer when we calorie restricted them. And what's really interesting about that, I think, is that PNC1 doesn't just get turned on by caloric restriction. It's turned on by heat, low amino acids, salt, high salt. And so this is a gene that senses the environment And turns on the sirtuins. Exactly what I was explaining earlier about those early life forms on the planet sense their environment and through NAD and other ways, they can turn on these pathways for defense.

   27. PAPeter Attia42:52

       So where did you go from PNC1 to resveratrol?

   28. DSDavid Sinclair42:56

       Well, we, we teamed up with a company at the time, they were called Biomol, and they were making reagents for HTAC assays, this kind of thing, and Konrad Howitz was a scientist there and he had invented, it wasn't even available yet, an assay for sirtuin activity in vitro. I forget why he reached out to me, but he said, "Hey..." Or maybe I, I wrote to him, but whatever happened, he sent me some kits to test and, uh, they worked and it looked great.

   29. PAPeter Attia43:23

       And what, what was the gold standard prior to these kits?

   30. DSDavid Sinclair43:26

       Oh, gosh. A measure- measuring sirtuin activity w- required Western blotting, which is detecting these-
9. 49:41 – 57:00

   The 2006 Mouse Study and Resveratrol Dosing

   1. PAPeter Attia49:41

      So it was the mouse paper in '05, '06 that was the one that kind of brought this to everybody's attention out- even outside of the aging community, correct?

   2. DSDavid Sinclair49:52

      Right. Well, so the, the resveratrol story in yeast was one thing, but when it, the mouse paper came out in Nature in 2006, it went global, and it was... caught the attention of probably most people on the planet. Certainly, those who drank wine paid attention. The wine industry sales, I, I'm told, went up 30% and have stayed up and, uh... But that, yeah, that was 2006, very interesting time, and what's not well known in history is that we didn't know if this was gonna work. I mean, it was a real Hail Mary pass of experiment.

   3. PAPeter Attia50:23

      But, but going back to that experiment, those were not wild-type mice. Those were overfed mice, correct? They were metabolically ill?

   4. DSDavid Sinclair50:30

      We had both experiments running in parallel.

   5. PAPeter Attia50:32

      Okay.

   6. DSDavid Sinclair50:32

      But we got the results earlier for the fat mice.

   7. PAPeter Attia50:35

      And that was what? So the, you had the control mice and you had the treatment mice. The control mice... B- both mice were fed the same, which was a sort of high-fat, high-sugar, metabolically disruptive diet, presumably the usual-

   8. DSDavid Sinclair50:46

      Yeah, w- the so-called Western diet, correct.

   9. PAPeter Attia50:48

      Yeah, yeah. And in that... So what was the outcome of that experiment? How much longer did the resveratrol-treated animals live, approximately?

   10. DSDavid Sinclair50:56

       I think it was 20%, something like that, 25% memory.

   11. PAPeter Attia50:59

       And that was initiated at what age?

   12. DSDavid Sinclair51:01

       A year.

   13. PAPeter Attia51:02

       So those are pretty mature mice. They're middle-aged mice almost, right? They're what?-

   14. DSDavid Sinclair51:05

       That's right

   15. PAPeter Attia51:06

       ... 30, 40 years old equivalent?

   16. DSDavid Sinclair51:07

       Yeah, exactly.

   17. PAPeter Attia51:08

       What dose, do you remember?

   18. DSDavid Sinclair51:09

       I'm gonna guess. I think it was, uh, 200 milligrams per kilogram.

   19. PAPeter Attia51:14

       Per day?

   20. DSDavid Sinclair51:15

       Per day, but we also had a group on feeding every other day as well, and those, those turned out to be pretty interesting as well.

   21. PAPeter Attia51:22

       That's a pretty high dose relative to... Did the ITPs that came out that, uh, following use doses that high?

   22. DSDavid Sinclair51:28

       So we, we've done it now in two different doses. We've done 200 and 10 times less.

   23. PAPeter Attia51:33

       Okay.

   24. DSDavid Sinclair51:34

       And, uh, it actually, it works in both. And what we find actually is that the higher dose is acting on other pathways, including the AMP kinase metformin-related pathway.

   25. PAPeter Attia51:45

       Activating it? So it's synergistic with metformin?

   26. DSDavid Sinclair51:48

       We don't know that, but part of the, the debate about resveratrol is that if you give cells in culture or mice too much resveratrol-

   27. PAPeter Attia51:56

       Mm-hmm

   28. DSDavid Sinclair51:56

       ... then it kicks in other pathways. And in this case, it was activating AMP kinase as well. We published that in our first paper in 2006 in the supplemental that most people haven't read. But we knew it was activating AMP kinase at that high dose, and that, what that means is that when you're activating multiple pathways, it's very hard to dissect that. So we, we, these days, both in cell culture and in mice, we're very careful to use the minimum dose to get an effect, not overdose, because it just makes things much more complicated.

   29. PAPeter Attia52:27

       So the, you mentioned that you had a parallel experiment that was done in presumably mice that were not overfed. What did that experiment show?

   30. DSDavid Sinclair52:35

       So the fat mice, they were healthier. That goes without saying, I think. Most people know that. In the thin mice, they also were healthier. They had better cardiovascular system, less cancer, a whole variety of things that were exciting. It didn't reach statistical significance when they ate resveratrol every day. But if we gave it to them in their diet every other day, we saw a lifespan extension. That tells me a couple of things. One-
10. 57:00 – 1:00:12

    Resveratrol Clinical Trials and Sinclair's Personal Regimen

    1. DSDavid Sinclair57:00

       Well, what was going on in the commercial side was screening of more molecules. So there was a whole bunch of synthetic molecules that we can talk about. Resveratrol itself was considered a proof of concept molecule largely. If it ended up in the clinic, it would've, I mean, as a drug it would've been great. But we, what we were trying to do-

    2. PAPeter Attia57:16

       And your intuition was m, it might be, it might not be.

    3. DSDavid Sinclair57:19

       Well, we knew it was a terrible molecule.

    4. PAPeter Attia57:20

       Because of the solubility alone.

    5. DSDavid Sinclair57:22

       Yeah. Right. But we-

    6. PAPeter Attia57:23

       And was it millimolar? Like, what kind of concentrations were needed once it was in the plasma to reach its... Is it a, is it a micromolar or a millimolar drug?

    7. DSDavid Sinclair57:30

       Yeah, it's a micromolar, which is... It really, that's not a drug you'd want-

    8. PAPeter Attia57:33

       Yeah. Yeah

    9. DSDavid Sinclair57:33

       ... you'd want to go ahead with. But it allowed us to, to get into humans and see what would happen. Do we see the same kinds of things or could we deliver it on the skin or on the eye? So that was a goal and there was some very good formulation chemists who were trying to, and succeeded in work- working out ways to make resveratrol absorbable in the body. And there were some clinical trials that were initiated, uh, under an IND and, uh, there was one, uh, that was looking at blood sugar levels and that one I think is published now.

    10. PAPeter Attia58:05

        And what kind of doses were they using in the phase one? Do you remember?

    11. DSDavid Sinclair58:08

        It was massive levels because the scientists that were running the studies, they were worried that there wasn't enough avail- bioavailability. So they were giving I think 10 grams a day, which is-

    12. PAPeter Attia58:19

        Was there any toxicity at 10 grams?

    13. DSDavid Sinclair58:21

        Unclear. Unclear. There, there was some... In, in regular people, there was nothing. There was, uh, a couple of patients in a cancer study that had renal failure, which happens anyway in these late stage patients. So that, but that was enough to say this is not worth it 'cause this isn't a blockbuster drug anyway. It's a probe at, at best, at least according to the company that was running the trials. So they, uh, you know, exercised an abundance of caution and stopped that trial in the cancer patients.

    14. PAPeter Attia58:51

        That's odd. Why was it being done in cancer patients?

    15. DSDavid Sinclair58:54

        Well, part of it was that, trying to remember, but the person who was running the trials had a lot of experience in it, but I, I recall that there was some animal data or at least some in vitro data that resveratrol could help there.

    16. PAPeter Attia59:06

        I see. So I didn't, I didn't actually realize that at all. I didn't... So you're saying it was in a phase one that they had this questionable outcome and thought, "Well, maybe it's not worth pursuing this and we'll move on to the second and third generation variants of these?"

    17. DSDavid Sinclair59:19

        Well, right. So the company was, was bought by a large pharmaceutical company and a large pharmaceutical company looks at resveratrol and they say, "This is not a drug. This is not something that we want to continue with." Uh, and so that was certainly part of the decision I'm imagining. But what was, they really were excited about were the, the new chemical entities. There were hundreds of them made that were very potent drug-like, uh, molecules that they wanted to take further, and they did take those into humans as well. And, uh, I should mention that those molecules have been in mice and Rafal Tabarok deserves a lot of crevit- credit for doing that. And so he's taken the same molecule that went into humans, put them into mice, these same one-year-old mice, and found that those do live longer, uh, even on a regular diet. So that's why I think maybe it's just resveratrol wasn't as potent as we needed it and these other molecules succeeded.

11. 1:00:12 – 1:14:59

    NR, NMN and the Supplement Landscape

    1. PAPeter Attia1:00:12

       Now, you mentioned, and I want to come back to this at the end because it's, it's interesting you're one of the few people in this space who speaks openly about, you know, look, in the presence of incomplete information, I still take compound XY. You alluded to a moment ago you still take resveratrol. Without having any certainty, is it your hypothesis that you might not be taking enough, but it's unlikely that there's any harm and you said you take how much? About a gram?

    2. DSDavid Sinclair1:00:34

       Well, the, so my calculation is this. First of all, I'm, I like experimenting. That's, you know, I'm, I'm not afraid of death, that's for sure, but I want to be the first person to know if there's a problem. So I'm also keenly aware that what's gonna happen to all of us if we don't do anything is not pretty either.

    3. PAPeter Attia1:00:50

       Mm.

    4. DSDavid Sinclair1:00:50

       And so what have I got to lose? It's cheap. I've got buckets of it in my, in my basement. There's been never any sign of toxicity. It's been in humans for, for a long time now. So there, there's no downside here.

    5. PAPeter Attia1:01:00

       But if, but the bigger risk it would seem is what if you're not taking enough?

    6. DSDavid Sinclair1:01:03

       Sure. But you know, one, one gram, I think if it's not, if it's not working at a gram, then it's not working. I don't think it's worth going higher. But you know, the, what's important is that we've made advances since then. We're talking about discoveries from a decade ago.

    7. PAPeter Attia1:01:18

       Yeah.

    8. DSDavid Sinclair1:01:18

       We've got much better things now. So I still take my resveratrol because I've seen enough data in humans as well that it can protect the heart. You know, is it gonna make me live 10 years longer? Probably not, not even five. But will it potentially delay cardiovascular ze- disease? Absolutely. So why not?

    9. PAPeter Attia1:01:36

       Now, you mention in a talk that you... I think you mention this in the talk, but you take metformin as well.

    10. DSDavid Sinclair1:01:41

        Yeah, quite recently. Probably at least half my colleagues that I talk to.

    11. PAPeter Attia1:01:44

        Yeah. Now, you're only taking a pretty low dose, if I recall from at least what you said in that talk. Is that because of y- the additive effects potentially of resveratrol also activating AMPK?

    12. DSDavid Sinclair1:01:55

        Yeah, you're exactly right. If you're starting to take combinations of molecules, uh, like I do, you wanna ramp it up. We're going into unknown territory. So I'm, I mean, I'm not-

    13. PAPeter Attia1:02:03

        Especially if there's overlap in these pathways, right? As you-

    14. DSDavid Sinclair1:02:05

        And, and there-

    15. PAPeter Attia1:02:05

        As you've alluded to

    16. DSDavid Sinclair1:02:06

        ... there absolutely is overlap. Anyone who says there isn't is myopic or, or lying. These are pathways that are additive, so it could be that taking two grams of metformin plus I'm taking two other molecules would be overdosing it, and I don't want to do that. So what I, what I do is I start on a reasonable low dose based on all the data that I've read, and then I make sure that I'm okay, I feel okay, my blood tests are okay. And then, you know, I talk to the experts, they're all my friends, and I say, "What do you think about going up to one gram, one half gram?" So actually recently I have gone up to one and a half grams given advice from people who shall remain nameless.

    17. PAPeter Attia1:02:45

        [chuckles] Yes, we'll keep everybody nameless. So let's fast-forward to some of these other molecules because th- this story is just so interesting and, and feel free to go back and patch pieces of history if it makes things b- to where we are today. But today we are in a place where there's a company, there are two companies out there that are selling NR, precursor to NAD. They're packaging it with... Is it, uh, pterostilbene?

    18. DSDavid Sinclair1:03:10

        Right.

    19. PAPeter Attia1:03:11

        Tell me what that molecule does specifically and why it would make sense to include that with NR.

    20. DSDavid Sinclair1:03:16

        Yeah. So pterostilbene is essentially just resveratrol with some methyl groups on it. It's a more novel, sexier version of resveratrol, but that's the summary.

    21. PAPeter Attia1:03:24

        But is it any more active in your opinion?

    22. DSDavid Sinclair1:03:26

        So Lenny has told me that it is, but I, I don't know enough to be able to give a sensible answer.

    23. PAPeter Attia1:03:31

        Okay. So you now have a SIRT activator with an NAD precursor that are both basically over the counter, right?

    24. DSDavid Sinclair1:03:40

        That's right.

    25. PAPeter Attia1:03:41

        So tell me about the excitement in that space. I don't want to get too much into the politics of the companies 'cause they're, at the time of this recording, they are in World War III, so let's, let's just talk about the science [chuckles] and not sort of all the other stuff.

    26. DSDavid Sinclair1:03:54

        Yeah. Well, it's-- If you, if you take the 40,000-foot view of this, uh, so, so Lenny is in his 60s now and I'm in my 40s, late for- very late 40s, and you gotta do a calculation, how many years do you have left to not only see what happens but potentially even be vindicated, and I'm sure that's part of what Lenny's thinking.

    27. PAPeter Attia1:04:13

        What would Lenny be vindicated for?

    28. DSDavid Sinclair1:04:15

        For finding that the sirtuins are important for health longevity in humans.

    29. PAPeter Attia1:04:20

        Oh, I see. Meaning that following this discovery, some of the air left the balloon and now there's a resurgence of, "Hey, no, it really did matter." Is that what you mean by being vindicated?

    30. DSDavid Sinclair1:04:32

        Uh, well, I think there's a race to see whose pathway is more important.
12. 1:14:59 – 1:19:42

    Drug Development: Fertility, Life Biosciences and Name Misuse

    1. PAPeter Attia1:14:59

       And is there a type of infertility that this seems most amenable to? Because going back to your evolutionary argument, under periods of stress, we see fertility as one of the first things to go for obvious reasons. But infertility comes in so many flavors, right? There could be an inability to release an egg. There can be aneuploidy even when the eggs are secreted. There can be uterine hostility. There's so many things that can result in infertility. What does this particular thing target?

    2. DSDavid Sinclair1:15:25

       Well, so what, what we find in the... So the biochemical pathway we've figured out, and we've published a little bit on this, is that there's a, a protein called BubR1, which is a kinase that regulates spindle quality. And one of the problems with old eggs is that they don't have nice spindles, and they rip their chromosomes apart when they form an egg.

    3. PAPeter Attia1:15:41

       Hence the aneuploidy.

    4. DSDavid Sinclair1:15:42

       Exactly. So Down syndrome, et cetera, abortion, aborted fetuses. But, uh, what we found is that this BubR1 is regulated by the Sirt2 protein, which requires NAD. And what we think is going on after chemotherapy or during aging is that the levels of NAD in the ovary and in the egg are low and we're li-- it's getting this an-aneuploidy, and that explains why when we give NAD to, or NAD precursors to eggs in vivo-

    5. PAPeter Attia1:16:11

       Mm.

    6. DSDavid Sinclair1:16:11

       -the eggs come out healthier, more numerous, and, uh, are much better at allowing for fertilization and healthy offspring.

    7. PAPeter Attia1:16:17

       I don't know much about fertility, as this next question will illustrate, but presumably you can still see aneuploidy on the male side. So is there a male fertility opportunity here as well? I realize it's not as, probably as, as common a problem, but presumably you still have to have a perfect split of the chromosome in the sperm.

    8. DSDavid Sinclair1:16:37

       Yeah. Uh, possibly. It's an area that we're looking into. I don't have anything solid enough to be able to say if it works or not, but it, in theory, yeah.

    9. PAPeter Attia1:16:46

       And just going back to something earlier, is NMN available over the counter?

    10. DSDavid Sinclair1:16:49

        It is. More recently, yeah, I can see it on the internet.

    11. PAPeter Attia1:16:53

        Okay.

    12. DSDavid Sinclair1:16:54

        But I-- One of the things that I want to bring up is you can find my name all over these products. Not Basis, they're, they're reputable, but there are others that use my name all over the place.

    13. PAPeter Attia1:17:03

        Meaning without your permission?

    14. DSDavid Sinclair1:17:05

        Correct. And, and Harvard's permission. And so I've sent more cease and desist letters you can, than you can imagine, and they keep popping up.

    15. PAPeter Attia1:17:11

        So that's an important point. So if a listener after this talk is saying, "Hey, David Sinclair sounds like a smart, reputable guy. If his name's on something, I should take it," what can your name be associated with right now that is, you know, with your permission?

    16. DSDavid Sinclair1:17:24

        Nothing.

    17. PAPeter Attia1:17:25

        Okay. So basically anything that's out there that's over the counter that has your name on it is not endorsed by you.

    18. DSDavid Sinclair1:17:30

        Correct.

    19. PAPeter Attia1:17:30

        Okay. Thank you for clarifying that. That would be frustrating. [laughs]

    20. DSDavid Sinclair1:17:34

        Uh, yeah, it is, but I try to stay, uh, above the fray. Um-

    21. PAPeter Attia1:17:37

        It's nice when you can stand on Harvard's shoulders and let their lawyers send those cease and desist letters.

    22. DSDavid Sinclair1:17:42

        It would be nice if that were true, but I spend a portion of my salary every year on this.

    23. PAPeter Attia1:17:46

        Really? That's a shame. I'm, I'm sorry to hear that. So fertility is a super interesting angle. I would have never thought about that. That strikes me as highly testable as well, which, you know, one of the challenges of longevity research, as you know better than I do, is if you want to make claims in humans, you, you better buckle up because it's going to be... I mean, it's, it's almost untestable. So when you look at what other companies are doing, like Restore Bio going down the mTOR pathway, they're not going after longevity, right? They're going after very, very specific indications that are testable in shorter periods of time, you know, respiratory failure, things like that. What are the other disease states that you think would be most exciting if you don't already have plans to go down that from your pharmacologic standpoint?

    24. DSDavid Sinclair1:18:32

        Well, we, we've been targeting diseases that are rare and have a high unmet need. So I can't divulge all of those because that's all, that's company stuff.

    25. PAPeter Attia1:18:41

        Mm-hmm.

    26. DSDavid Sinclair1:18:41

        But, uh, the fertility part, that's very clear. I'm able to tell you that, that those trials will begin, uh, next year in IVF clinics, and that will be the first way that-- first time a doctor looks at those eggs from a woman, she'll, he'll probably or she'll probably know that it's working or not. So that's a very clear outcome.

    27. PAPeter Attia1:18:58

        company, we're... So we're sitting right now in a headquarters that is the name of, it's-- What's it called? Is it Life Bioscience?

    28. DSDavid Sinclair1:19:05

        Yes.

    29. PAPeter Attia1:19:05

        And that's a parent company or sort of a... Tell me how that fits into a number of the scientific entities that you're involved in.

    30. DSDavid Sinclair1:19:12

        So Life Biosciences is a family of companies that uses shared resources and knowledge. There are eight of us right now that work on different aspects of aging, not just NAD biology, but the usual suspects, all the major hallmarks of aging-
13. 1:19:42 – 1:24:01

    Hallmarks of Aging and the Epigenetic Information Theory

    1. PAPeter Attia1:19:42

       Earlier you spoke about sort of eight or nine central tenets of aging. We've covered some of them, but I n- and I'm guessing that your book is gonna go into this in greater detail, but c- can you rehash what you, or at least as many of those as y- you're gonna recall on the spot? [laughs] Not to put you on the spot. That's a long list.

    2. DSDavid Sinclair1:20:02

       Uh, yeah, sure. There, there's epigenetic change, there's cell-to-cell communication and inflammation. There's... Let me count. There's senolytics, so senescent cells build up.

    3. PAPeter Attia1:20:10

       Mm-hmm.

    4. DSDavid Sinclair1:20:11

       There's protein misfolding, there's telomere loss and genomic instability. There's metabolic changes, so AMP kinase and m- um, metformin would address that. And then there's, uh, responses to, what do you call it? Amino acids and other nutrient inputs, and those collectively go awry during aging. But what causes all of those to happen? That's something that we've been working on for quite a while.

    5. PAPeter Attia1:20:35

       And you think those are more coupled than they are uncoupled, those pathways? Or do you think that, uh... I mean, there are clearly situations in which external stressors can perturb more than one of those. But, like, senescence seems somewhat uncoupled from nutrient sensing, doesn't it?

    6. DSDavid Sinclair1:20:51

       Uh, it may, but I-

    7. PAPeter Attia1:20:52

       And I'm not asking that rhetorically. Like, I just, I just don't know.

    8. DSDavid Sinclair1:20:55

       Well, the, no, the, the answer is we, we think that we've found an explanation for all of these things to happen.

    9. PAPeter Attia1:21:01

       A unifying theory?

    10. DSDavid Sinclair1:21:02

        Right. Uh, so I've kept it close to my vest for a number of years, but it actually goes all the way back to the sirtuin story in yeast. And hopefully the, the listeners who've stuck with this podcast, uh, are still with us because this is the punchline.

    11. PAPeter Attia1:21:16

        They, they will. Uh, yeah, they, I promise you they are with us.

    12. DSDavid Sinclair1:21:17

        So the punchline is that... So this is all off, off the top of my head here. We haven't published this yet, but I'm, I'm gonna tell you my, my thoughts and your listeners. So the genome is digital information. It's, uh, very easy to preserve. It's the reason we went from analog to digital in the 2000s. DNA is four letters. It's digital. It's easy to replicate. It's easy to store. You can boil it. It's very robust. And so what we've actually come to discover is that the genome is fairly intact in old people and old animals. We've sequenced the genomes of lots of old mice, and all the genes are still largely intact. So what's going wrong? Well, the other part of information that you inherit from your parents is the epigenetic information, okay? And I use that term loosely, but basically it means what's the pattern of gene expression, which genes are turned on and off at which time, and that is analog information, okay? That has to be analog because instead of just being a single code, it has to operate in three dimensions, actually four if you count time, and so that's an analog system, and it's constantly adapting to what we eat, what we, what we drink, if we run, when we sleep, and you have to turn genes on and off all the time. But that pattern of gene expression that's set down when we're young, because it's analog, analog information doesn't last very long. Anyone who's had a record player or magnetic tape knows that these things don't last, and that's the problem I think with aging is that we don't lose the digital information, so the compact disc of our lives is still intact when we're old, but it's as if we've got a scratched CD and the cells don't read the right genes at the right time anymore, and they lose their identity. In fact, if we-- there's an analogy which is called Waddington's landscape where in the 1950s Waddington drew a picture. It's a beautiful picture of some hills. It's a mountainscape, and cells actually roll down the mountainscape and land in different valleys down below. And that's to-- You know, before we had, he had access to the genome, that was his way of saying this is how cells know what they are. They land in these valleys and they stay there. But what I think is happening during aging is due to the vibration of noise over time, we lose that pattern of gene expression. We lose that information, epigenetic information, and those cells or those marbles in Waddington's landscape, they jump over into different valleys and lose their identity. So your neurons are not functional like neurons anymore. Your liver cells are more like neurons. And we see that in our lab. We're just writing up a couple of papers right now for this, and we're able to actually manipulate the epigenome in cells and in mice and have a look what happens to those animals. And the prediction is that you get all the hallmarks of aging.

    13. PAPeter Attia1:24:01

        You know,

14. 1:24:01 – 1:33:50

    Future Outlook: Human Trials and Combined NMN-Sirtuin Results in Old Mice

    1. PAPeter Attia1:24:01

       the challenge with this entire space is you think back to the time in the 1950s when he made, when he created that analogy and it's, in some ways it's amazing that it could still be relevant 75, 80 years later, whatever it is. On the other hand, it, it humbles you to realize how much more has been learned about that process in that time. And sometimes I think about it because you and I are interested in the same problem that I'm worried I just don't know anything. You know, I'm worried that in 10 years I'll look back at my hypotheses and my un- or not even my hypotheses, just my understanding of the current state of the art today and think, "You know what? That was directionally right, but it was so oversimplified and oh my goodness," like, you know. So, so it's sort of like we're back in this problem of time, like we're gonna run out of time and, I mean, how confident are you that in-- 'cause you and I are almost the same age. Like, how confident are you that in our lifetime we will see step function changes in human longevity? And to put this in context There really hasn't been a step function change in human longevity probably since the introduction of sanitation. I mean, everything has been quite incremental. Maybe antibiotics. Vaccinations, antibiotics have probably been the last step function change. Will we see one in our lifetime? How confident are you?

    2. DSDavid Sinclair1:25:20

       I'm, I'm getting more and more confident. Honestly, when I, I started in this field, I thought we'd probably not see the type of technologies that I'm seeing now. It's making my head spin, not just in the technologies, but also the, uh, the investment and the number of people working on this now. This was the backwater of biology when we started. And there's been some new results, which I'll just hint upon because, um, we haven't published and it's very early, but I've seen... It sounds like a, a scene out of Blade Runner, but I've seen things you wouldn't believe. No, it's-

    3. PAPeter Attia1:25:49

       [laughs]

    4. DSDavid Sinclair1:25:49

       ... it's maybe not that dramatic, but let me go back to the compact disc analogy. You've got the scratched CD. How do you find the polish? What is that? Let's go back to the yeast analogy. What causes those scratches? Why do you get loss of gene regulation? Anyone who was paying attention earlier on in this conversation will remember that these DNA breaks in the chromosome, broken chromosomes, distract the SIR complex, and they m- move away, and you get the expression of genes that have no right being on in this context.

    5. PAPeter Attia1:26:18

       Because the sirtuins have lost their-- they're distracted from the deactivation function and they're dealing with the repair function.

    6. DSDavid Sinclair1:26:25

       Exactly. So using that, what we've got a lot of evidence for now is that something very similar, if not essentially identical in principle, happens in mammals as we age. And what that means is that insults to the genome, and one of the major insults is a double-strand break, but there are probably others, cause these proteins, sirtuins and other factors, I'm not saying only sirtuins, but factors that control gene expression, silencing and other things, have a dual role, we know, in DNA repair and other things, such as responding to stresses, heat, whatever. But this is the cell's way of coordinating gene expression changes, hunkering down during times of adversity, and going off to repair the system, which in this case we study DNA breaks. And that's a beautiful system when you're young. It works great. You get exposed to cosmic rays or you go out in the sun, you got lots of DNA breaks. Eventually, these proteins will go repair those breaks and then go back to where they came from to settle down the response, to turn off the inflammation, to turn off the DNA repair when it's not needed. But the problem we think is it's antagonistic pleiotropy. Okay, so Peter Medawar and the other brilliant scientists in the '50s speculated, I think correctly, is that things that are really good for you when you're young come back to bite you in the ass when you're older. And I think that's what's happening here, is that this response to these stresses like a break end up not just distracting these proteins, but end up disrupting the actual structure of our chromatin, and these proteins don't always go back to where they came from 100%. Do that for 70 or 80 years, and it's not surprising that the genes that were once perfectly programmed and turned on at the right time lose their ability to do that. And we've got remnants of that program when we're age 70 and 80. But what's exciting is that information is still there to be accessed. The question is, how do you get the cells to remember to access at the right time? What's that polish? And I think we're pretty close to finding that.

    7. PAPeter Attia1:28:20

       If you had unlimited resources, and not just financial resources, but sort of metaphysical resources, like any experiment would be ethical, you could do something that no- today no IRB would approve. Is there an experiment that you would wish to see done that could accelerate our knowledge in this space log fold?

    8. DSDavid Sinclair1:28:40

       Uh, you mean staying within, within, within ethical, uh, boundaries?

    9. PAPeter Attia1:28:43

       Yeah, but, but, but, you know, for example, like, you know, to do a human experiment in longevity would be ethical but impractical because of the duration-

    10. DSDavid Sinclair1:28:51

        Oh, sure

    11. PAPeter Attia1:28:51

        ... of time. But if you-- if I gave you like a time machine and an infinite amount of resources, tell me what the most elegant experiment you can think of that would, again, just leapfrog our knowledge.

    12. DSDavid Sinclair1:29:00

        Okay. So the experiment that needs to be done, whether it's with mo- metformin or other drugs in development, including these rapalogs, um, and the NMN, NMN, and NAD precursors, is to take a group of five thousand people, that would be sufficient, and just give them the medicine and wait three, four years, and you'd know from that number of people that you're changing the hazard ratio, the mortality rate. You'd have to start with people probably in their seventies. I think that was the calculation that I did. But you don't need to wait a whole lifetime to know that these things work.

    13. PAPeter Attia1:29:33

        So this is basically Nir's argument.

    14. DSDavid Sinclair1:29:35

        Yeah, exactly. But Nir's not doing mortality as much as he's doing healthspan. But it's exactly right. You do enough people... I mean, it's going to cost tens of millions of dollars, but think of the trillions of dollars that would be saved if we can prove this.

    15. PAPeter Attia1:29:47

        But, but if I'm going to play devil's advocate for a moment, what if by doing that experiment, we're missing the opportunity, the window of opportunity for these drugs to act? In other words, you know, we know that caloric restriction w-- is less and less effective the longer you wait in the organism, at least within mice, and that's what made rapamycin so interesting, is you could-- it was-- it blew everybody away that you could start this drug on mice that were six hundred days old and they still had, you know, nine percent, fourteen percent increase in li- in lifespan. W-- If you had more time, do you think we could get a more clear answer starting earlier? Acknowledging that you'd have to wait longer if you wanted to use a hard outcome. Like, do you worry that we would risk doing this in people in their eighth decade that it might not work, but that just tells us that it doesn't work late, not that it doesn't work, period?

    16. DSDavid Sinclair1:30:36

        I don't worry about that. Uh, we, we could, with enough capital, we-- and money invested, we could do multiple different experiments. We could do people in their fifties, sixties, seventies, and eighties. So l- you know, dream with me. The other thing that makes me optimistic is it's not just rapamycin that works late in life. We've got results in my lab now that we'll be publishing that if we start Even later than 600 days in a mouse, which is, what, closer to a 75-year-old

    17. PAPeter Attia1:31:02

        Like 70, yeah

    18. DSDavid Sinclair1:31:03

        We can still extend lifespan

    19. PAPeter Attia1:31:05

        Using what? I know you won't name the compound

    20. DSDavid Sinclair1:31:06

        This is... No, I can tell you. We- we're using the NMN

    21. PAPeter Attia1:31:09

        Okay

    22. DSDavid Sinclair1:31:10

        So there are multiple ways to activate

    23. PAPeter Attia1:31:11

        And sorry, when you use NMN in the lab, are you also using like a PT analog or a, a resveratrol analog, or are you able to just use NMN and see-

    24. DSDavid Sinclair1:31:21

        Just the, the natural molecule will work. We're now gearing up to do the drug substance

    25. PAPeter Attia1:31:25

        And this is not in high-fat, overfed animals. This is in wild-type animals.

    26. DSDavid Sinclair1:31:29

        We just put it in their drinking water

    27. PAPeter Attia1:31:31

        Oh, because NMN is more soluble.

    28. DSDavid Sinclair1:31:33

        Exactly

    29. PAPeter Attia1:31:34

        Interesting

    30. DSDavid Sinclair1:31:35

        Yeah, but we've got better molecules that we're now testing. We think that we can beat, or again, try to beat rapamycin, and maybe a combination together
15. 1:33:50 – 1:41:28

    Mortality, Family, the Book and Closing

    1. PAPeter Attia1:33:50

       You mentioned at the outset of this discussion that you were four years old when you became aware of mortality. Was there something that occurred that made you aware of mortality at such a young age?

    2. DSDavid Sinclair1:33:59

       I had an unusual grandmother who was brutally honest, uh, with me. She would never lie. And any question I asked, and I was quite a-

    3. PAPeter Attia1:34:06

       And you were probably very precocious and curious

    4. DSDavid Sinclair1:34:08

       I suppose I was, but yet she would never lie. So my question that most kids have is, "Are you always going to be around?" She didn't even... y- I couldn't call her Grandma. She wanted to use her first name, which is Vera. So, "Vera, are you going, always going to be around?" "Of course not, I'm going to die." "Yeah, but what about Mom and Dad?" "Yeah, they're going to die." "What about my cat?" "It's going to die." And then of course you're thinking, "If they're all going to die, what's going to happen to me?" You know. And then, uh, but it turns out all kids go through this. It's been studied extensively that between the ages of four and seven, kids understand that there's death. And f- at first they're in denial. They say, "Well, maybe those adults will die, but my teachers and my parents, they're not going to die." But then by age seven, it's undeniable. All kids know that everything around them that's living one day will die, including themselves. But what's very interesting that happens at age seven is it's buried deep in the subconscious, and you very rarely think about it until you have to. 'Cause I don't think as a species we could get by if we're all running around, "Oh my God, we're going to die one day." So seven-year-olds onward till about 50, you try not to think about it. That's pretty common. You start looking at yourself in the mirror at 50. You notice your teeth are wearing out. You're starting to feel a little bit of age. You see some wrinkles. You think, "Oh, yeah. Crap. This is really happening." Uh, and, you know, you think more and more about it. I'm unusual 'cause I work on this every day, so I'm, I'm always thinking about it. But I think on average, when I talk to people, especially in their 20s and 30s, it's not something that is on their radar 'cause it's going to s- be something that happens in the distant future that they're not even looking at

    5. PAPeter Attia1:35:37

       Do you have kids?

    6. DSDavid Sinclair1:35:38

       I have three

    7. PAPeter Attia1:35:39

       How old are they?

    8. DSDavid Sinclair1:35:39

       Uh, they are 15, 13, and 11

    9. PAPeter Attia1:35:42

       How do you explain what you do to them?

    10. DSDavid Sinclair1:35:43

        I was just as brutal to them as my grandmother was to me

    11. PAPeter Attia1:35:47

        As Vera was to you, yeah

    12. DSDavid Sinclair1:35:48

        Yeah, and actually I saw my, my eldest daughter go through this. Actually, all my kids, but it was more dramatic to see it for the first time myself, and I gave a TED Talk about this. When I told her that I was going to die, uh, she burst out crying, and for a week couldn't sleep. It was traumatic. And, you know, maybe I'm a cruel parent, but I also try not to BS my kids either. But what I saw with her was what even I think most kids do, including myself, was you, you just can't think about it. It drives you nuts. You won't sleep. So she forgot about it, and we've never talked about it ever again. And ev- if I talk about death, she says, "Shut up. Don't want to hear about it." And she probably won't think about it in a big way until I'm old or her grandparents are dying

    13. PAPeter Attia1:36:28

        David, this has been a, a really interesting discussion. I want to be sensitive to your time. I think the listeners of this podcast will be upset to know that we're only going for about, you know, an hour and 40 minutes instead of the usual three or four hours. But where can people find you on social media, and what, how do you like to interact with people that have questions besides adding to the list of the thousands of emails you get a day?

    14. DSDavid Sinclair1:36:49

        Yeah, emails I, I can't reply to everyone, but, um, on social media, I, I'm now on social media. I, I find that's a good way to communicate with people. And, uh, so I have a, a Twitter handle, which is, uh, @davidasingclair Oh, and I'm also on LinkedIn, but we're putting together a social media page so we can have a discussion. It's now, there's so many people interested in this.

    15. PAPeter Attia1:37:11

        Yeah.

    16. DSDavid Sinclair1:37:11

        And the information that's locked in my head seems to be on demand. So that's how I want to reach people. This book is coming out, which has me regurgitating and vomiting on the page everything from what we've learned in my life with my kids all the way through to understanding why we age and this universal hypothesis that we're putting, I'm putting forward. And then the consequences of what happens when we do this. Now, it's not a question of if anymore. It's a when it's going to happen. What happens to planet Earth? What happens to humanity? What happens to your family as this starts to come out? And some good, some bad, what do we have to get ready for economically, socially? And it's all going to be in there.

    17. PAPeter Attia1:37:51

        Well, I really look forward to reading it. You know, I'm in the midst of writing a book as well. And I'm guessing you struggled with the same thing I'm struggling with, which is not just the writing of it, but more importantly, you almost don't want to hand the thing in because you know that the day you hand it in, there's something new that you're going to want. You're going to know something more. And so as we were talking about it before we started the podcast, like you submit these books a full year before they hit the press. And then, of course, it basically is a static document until, you know, sure, you could have an online updated to information or, but did you struggle with that? Especially I think, you know, people like us, I think, have a little bit of a humility around the half-life of facts. And that's, and that sounds like a very, you know, sort of pompous thing for us to say. But I just think we have the luxury of knowing that basically whatever we know today is, you know, quite likely to not be entirely true tomorrow. How did you cope with that? This is now just a very personal question for me as I'm struggling with this phenomenon.

    18. DSDavid Sinclair1:38:48

        Well, yeah, you're a perceptive guy, Peter. So I'm also one of those guys that I'm at the podium about to give a talk to a thousand people and I'm still changing my PowerPoint slides. I'm just obsessed with perfection. And that's one of my downfalls. Same thing with the book. I've been writing it for 10 years and it's needed updating, of course, even to the point that last night I was editing it. I've already turned it into my editor three weeks ago.

    19. PAPeter Attia1:39:13

        You're a nightmare to the editor.

    20. DSDavid Sinclair1:39:14

        And she's received probably seven updates already.

    21. PAPeter Attia1:39:17

        Ugh.

    22. DSDavid Sinclair1:39:18

        And I'm going to stop, I promise. But every time I wake up, there's something more really interesting to add that I want to put in there. And, you know, a year from now, I think it's going to be an even better book than it is now. But I'm really happy with everything I've gotten down on the page because when I talk to people, people write to me every day, I'm able to answer questions that I think are burning in a lot of people's minds.

    23. PAPeter Attia1:39:38

        Well, David, this has been great. I find it's sometimes hard to talk to people you don't know until the day of the podcast, which is the case here. But I found there's a common language that we speak or maybe a common passion, not a common language. This is a topic that's new to me. But anyway, this has been really exciting and I can't thank you enough for your time.

    24. DSDavid Sinclair1:39:55

        Well, I appreciate the opportunity and I've really enjoyed it too. Thanks.

    25. PAPeter Attia1:40:00

        You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at peterattiamd.com. What's a Nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peterattiamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or advise, please visit peterattiamd.com/about.

Episode duration: 1:41:31