The Peter Attia Drive - #27 - David Sinclair, Ph.D.： Slowing aging – sirtuins, NAD, and the epigenetics of aging

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions along the way. I've spent the last several years working with

00:00:19.840 some of the most successful top performing individuals in the world. And this podcast

00:00:23.600 is my attempt to synthesize what I've learned along the way to help you live a higher quality,

00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

00:00:33.020 and other topics at peteratiyahmd.com.

00:00:41.220 Hi everyone, welcome to this week's edition of the Peter Atiyah Drive. I'm Peter Atiyah. This week,

00:00:48.400 my guest is Professor David Sinclair. He's a professor in the Department of Genetics at Harvard Medical

00:00:54.700 School. And he is the co-director of the Paul F. Glenn Center for the Biological Mechanisms of

00:01:02.200 Aging. David Hales from Australia. That'll take you about 10 seconds into our interview to figure

00:01:06.940 out. He did his PhD in molecular genetics at the University of New South Wales in Sydney. And it was

00:01:12.480 at that time that he met the man that would go on to become his mentor. We talk a lot about him and

00:01:17.360 this is a guy, Lenny, who's actually come up on other podcasts, so I won't get into him now. But

00:01:22.000 nevertheless, David met Lenny and decided he wanted to come to MIT to study with him, which is what he

00:01:27.780 did. And David has gone on to become one of the pioneers in a particular field of aging that focuses

00:01:34.760 on a class of molecules known as sirtuins. I'm sure many of you have heard of sirtuins,

00:01:41.980 but you might not entirely be clear on what sirtuins are. I won't obviously make any attempt to do that

00:01:47.020 here in the intro because we spend so much time talking about that during this episode.

00:01:51.880 The other thing that David is really quite famous for is his role in the discovery of a molecule or

00:01:58.660 class of molecules that stimulate sirtuins. And by the time you get through this episode, you will

00:02:02.700 understand why that may be a desirable thing to do. And among these, the most famous is one called

00:02:07.720 resveratrol. Of course, resveratrol came to fame probably a little over a decade ago when it was

00:02:15.020 noted at least in one study in one type of animal model to promote a longevity phenotype. And of

00:02:21.480 course, what really made it interesting, at least for the lay press was that resveratrol is found in

00:02:25.640 very low concentrations in the skin of grapes. And therefore the logic went, Hey, grapes make wine,

00:02:32.120 wine contains resveratrol, wine makes you live longer. Hallelujah. The French paradox has been

00:02:37.040 resolved. Slight spoiler alert. That's not true, but we get into the wise. That might be the case.

00:02:41.680 This episode, we only had, when I say only, meaning we had less than two hours,

00:02:46.940 but like has happened in other podcasts, including the one with Rhonda Patrick, after we closed the

00:02:53.860 podcast, cause I wanted to be respectful of David's time. He had to catch a flight to New York right

00:02:57.640 after we spoke, this interview took place in Boston. We ended up talking for another 15 minutes. And

00:03:02.220 unfortunately that 15 minutes was some of the most intense, detailed, nuanced discussions of it.

00:03:07.660 And I left thinking, gosh, I wish we had more time to talk. So I suspect David and I will speak

00:03:13.340 again. David has a book coming out next year, and I think that'll provide another great opportunity to

00:03:18.460 sit back down with him. In this episode, we talk a lot about his postdoc at MIT. He came out of a

00:03:23.500 powerhouse lab that has produced other notable folks that, including folks we've already interviewed,

00:03:28.860 like Matt Caberlin and folks we've talked about, like Brian Kennedy. We talk about his contribution to

00:03:33.220 the understanding of Sirtuins, which was something that was coming out of Lenny's lab. And David

00:03:37.260 really picked that up and ran with it. What are these things? What do they do? What's their role

00:03:41.500 in aging, DNA repair, gene silencing? We go over all this stuff in detail. We talk a lot about NAD

00:03:47.020 and its precursors, specifically something called NMN. So if you are listening to this and you are in the

00:03:54.520 camp of trying to understand how to make heads or tails of NAD, NR, NMN, I think this episode will be

00:04:01.800 helpful. Tragically, it was not until 24 hours after we did this episode that I ran into George

00:04:10.220 Vlasic on an airplane who mentioned to me a paper by Josh Rabinowitz in Cell Metabolism that came out

00:04:17.420 about a month before we did this interview that we will link to that I think makes a very compelling

00:04:23.460 case for the futility of orally administered versions of these precursors. And that would have

00:04:29.400 been a really interesting discussion to have with David because of his expertise in this. So

00:04:32.960 at some point, I'll probably want to interview Josh and we'll go into that in really detail because

00:04:36.580 again, unless you've been up in the Himalayas hunting Yeti, you're probably aware that these

00:04:40.560 are kind of the hottest supplements out there. We talk a lot about NAD levels. What do these things

00:04:46.020 mean? Where does it go? Where is it produced? We, again, as I alluded to above, talk about

00:04:50.020 resveratrol and its potential in life extension. And we talk about the connection then between

00:04:55.060 sirtuins and NAD. We talk about his rationale for what he does. So David is actually very open about,

00:05:01.780 you know, kind of the stuff that he does personally, including the fact that he takes resveratrol and

00:05:05.900 metformin and NMN himself. We also go into the differences between some of these molecules. And

00:05:10.460 again, allude a little bit to his book. There's a lot of stuff in here. Again, sometimes it gets

00:05:15.600 technical. Sometimes it doesn't. The show notes, as always, will provide a lot of help. So if you have

00:05:21.660 any questions about papers we reference, the likelihood that they're in the show notes is

00:05:25.560 actually quite high. Also, if you haven't signed up for our weekly email list and you wouldn't mind

00:05:30.420 getting an email from me once a week, I suggest you head on over to the website, PeterTiaMD.com

00:05:35.980 and sign up. Again, my promise to you is to make it as non-lame as possible. And finally, if you are

00:05:41.920 enjoying these podcasts, please head on over to iTunes and write a review there. And again, I would hope

00:05:48.260 that you like the podcast and leave a positive review. But I guess in the spirit of getting as

00:05:51.600 much feedback as possible, if you don't like it and you have something to say that we can do to make

00:05:55.160 it better, that's probably not an unreasonable place to leave that kind of feedback. So with all

00:06:00.040 that said, please welcome to my interview with Professor David Sinclair. Good afternoon, David.

00:06:07.600 Nice to be here, Peter. Thank you for making time today. I gathered only by the commotion in this very

00:06:13.780 busy place we're in that there's a lot going on here and making time to speak with somebody as

00:06:18.920 inconsequential as I am is a big ask. So I am incredibly grateful. I'm pleased to be on. We were

00:06:24.580 introduced by a mutual friend who's no stranger to people listening to this because I've had him on

00:06:28.940 before, David Sabatini. And maybe a month ago, maybe a little more than that, I said, David, you

00:06:33.940 know, I really want to know more about Sirtuins. And who do you recommend that I speak with? And he

00:06:39.160 said, well, I think David Sinclair would be perfect. So he reached out to you and you very graciously

00:06:43.920 agreed to speak. So again, I thank you for that. And I'm really excited to talk about something that

00:06:48.240 I know very little about as you will undoubtedly learn in the next hour or so. Well, yeah, that's

00:06:54.020 kind of David. As you know, and probably the listeners, though, as well, he's a bit of a

00:06:58.320 superstar. So it's kind of him. I'll have to, you know, send him a note for that. But no, honestly,

00:07:04.480 it's really great to be on because I know you delve into the details of the science more than anyone

00:07:09.660 I've heard. And I'm excited to be able to share that with listeners. Well, yeah, that's, that's

00:07:13.600 the part that's got me excited. So a lot of times I've listened to talks that you've given and I can

00:07:18.020 tell you're, I don't want to use the word dumbing it down, but you're, you know, you're speaking to

00:07:21.880 an audience where you realize that if you go too far in the weeds, they're, they're going to miss

00:07:26.220 the point. And so I found myself watching talks you've given on YouTube going, I wish he would

00:07:31.460 elaborate on that point and that point. And hey, it may be that I don't, I don't understand it

00:07:35.080 myself. Let's see. So I think just for a bit of background, I know you did your undergrad,

00:07:41.040 your PhD in Australia, and then somehow you wind up in Lenny's lab at MIT. How did that happen?

00:07:46.360 I've been interested in aging since I was four, since I realized that everybody and everything

00:07:51.320 around me is going to die. That's a pretty big shock for everybody. Most people forget about it

00:07:56.200 because you just can't function thinking about it every day. I forgot about it until my teenage years.

00:08:01.540 And I realized that with the technology that was coming online, these are the days of early PCR

00:08:06.660 and gene sequencing. We used to call it genetic engineering. I thought maybe we're just the last

00:08:11.820 generation who's going to live a normal lifespan, a regular evolved lifespan. And our children and

00:08:18.180 our children's children forever are going to be able to benefit from these new technologies. And

00:08:22.540 damn it, this is not right. I've got grandparents, parents, friends, and about 5 billion people who

00:08:30.420 could really be benefited right now. So at that point, I decided to seek out the best people in

00:08:36.800 the world and see if I could go work with them. And I got a PhD in molecular biology, in yeast genetics,

00:08:42.300 and that was a great PhD. And a real turning point for me was this guy from MIT who I knew about

00:08:49.220 because he was also a yeast researcher. He was a legend. I'd read all these papers. Lenny Guarenti came

00:08:53.860 to Australia. And here I am, this young 20-something-year-old having dinner with Lenny Guarenti and my PhD

00:08:59.980 supervisor from Australia. And Lenny starts telling this story halfway through dinner about this new

00:09:05.620 project that a guy called Nicanor Austriaco and Brian Kennedy had just started doing. And it was to

00:09:12.140 try and find genes that control aging in yeast cells. And I said, okay, I know yeast. And I've always

00:09:19.200 wanted to figure this out. Damn it. That's what I want to do. Save me a spot, Lenny. I'm coming to

00:09:23.960 your lab. And he went, yeah, yeah, yeah, whatever, as he does to most people who want to join his lab.

00:09:28.700 So I wrote to him pretty soon after, maybe six months, I was finishing up. Can I come to your

00:09:32.980 lab? And he wrote back like he does to everybody. Sure, you can come. But then a millisecond later,

00:09:38.660 I was disappointed because he said, you have to bring your own funding. So that was no small task.

00:09:43.040 And that's a story in itself. Just briefly, though, this is a lesson for anyone who's listening,

00:09:47.400 who thinks that getting to somewhere like this is easy. You have to be massively determined. You

00:09:54.500 have to have grit. And I just wouldn't give up because there's nothing else I wanted to do

00:09:58.640 in my life. I certainly was looking at patent law even, but I think I would have died if I had done

00:10:05.440 that as a career. I just don't have the attention span. Anyway, I actually found funding. It turns out I

00:10:11.500 applied to the Helen Hay Whitney Foundation, which is a prestigious foundation here. And they wrote to me

00:10:15.820 and said, you can't apply. You're a foreigner. And I said, well, this is the old days with early

00:10:21.500 email. I think it might even be post. And they wrote back. They said, well, you're a foreigner.

00:10:26.180 We can't afford to fly you out to Boston, Cambridge for an interview. And I said, well, I'll sell my car

00:10:32.760 and I'll pay for the ticket. As I understand it, I was the first foreigner who was allowed to interview.

00:10:37.500 And I flew here. I stayed in Nicanor Austriaco's basement. He was very kind. And my interview was

00:10:43.480 with a guy who everyone was telling me is a real tough guy, super smart. I'd never heard of him.

00:10:49.780 Of course, now everybody in science knows of Doug Melton. He's king of, well, endocrinology and stem

00:10:57.080 cells at Harvard. And I was just this kid showing up for an interview. And there was a line of people

00:11:01.440 outside his door waiting. And I was fifth in line. And I went in and Professor Melton said to me,

00:11:06.920 David, tell me what you want to do. And I had literally five minutes to impress this guy,

00:11:15.000 one of the smartest people you'll ever meet.

00:11:16.380 So you've sold your car, flown 22 hours for a five minute interview.

00:11:20.540 Yeah, that was basically it. And so I thought about it most of my adult life, what was aging about.

00:11:26.540 And a lot of people in those days, back in the late 80s, early 90s, were talking about

00:11:31.120 the evolution of aging genes, death genes. And I studied evolutionary biology myself. And that

00:11:38.020 didn't make any sense. You don't evolve death genes. And I never subscribed to the group theory

00:11:42.060 of selection. So every person for themselves, selfish gene, love dork and stuff. And so my thought was

00:11:48.260 the only genes that I could understand could evolve that have relevance to aging are longevity genes.

00:11:53.780 And right about that time, there was the discovery of, in C. elegans, the nematode worm of the DAF2

00:11:59.780 mutation from... Yeah, I was about to say, this must have corresponded with Cynthia's work, right?

00:12:03.380 Around the same time. It's just happening. And Lenny, at the same time, had just discovered a mutation

00:12:09.060 that they weren't sure what it was doing. But it turns out it led to the Sirtuin story. And so I said to

00:12:14.700 Doug, I want to come to Lenny's lab and discover life genes, genes that give life and longevity.

00:12:23.780 And I guess he liked the idea of what I was saying. I was certainly very passionate.

00:12:27.680 It probably didn't hurt that I brought a bottle of red wine as a present. I just thought that's

00:12:31.780 what you do when you come to people's place. Later on, I learned that that's equivalent to

00:12:35.920 bribing somebody, but I was just a young kid. But yeah, that's what happened. I got the prize.

00:12:40.860 No foreshadowing the resveratrol there.

00:12:42.780 Yeah, definitely. It was auspicious kind of a thing. But being able to come to Lenny's lab,

00:12:48.720 I would have worked in Lenny's lab for free. I would have lived in the basement and done it.

00:12:52.040 That's just how much I wanted to do this. So I came over. It was late 1994, early 95 when

00:12:57.820 things were just starting to take off, trying to understand what these mutations were that

00:13:01.780 Brian had found.

00:13:03.000 Now, was Matt Cabell in there as well? Matt's also a close friend. He was not there yet. So

00:13:06.360 the lab has produced just a ridiculous amount of sort of prolific individuals in this anti-aging space.

00:13:14.860 It was a golden age. You could definitely feel that something special was going on in those days.

00:13:19.100 But I arrived, I was the first postdoc to join to study aging specifically.

00:13:22.960 Was Brian a PhD student?

00:13:24.100 Yeah. So Brian, I was this new guy on the block. Brian teach me how to do yeast aging and he taught

00:13:29.240 me. But all the other postdocs, there are probably 18 to 20 postdocs there, big lab, all working on

00:13:34.600 transcription regulation. And that was the sexy thing. And I was told by, and I don't think I've

00:13:40.400 told anybody publicly this, that the postdocs were saying, you're crazy to work on this aging

00:13:45.800 project. Lenny's lost his mind. It's a house of cards. It's going to fall down. You can't study

00:13:50.080 aging and yeast, all of these things. And within the first few weeks, I thought, maybe I've made

00:13:54.940 a mistake. Maybe I was just fooled. Maybe Lenny isn't that smart as I thought. But I stuck with

00:14:00.720 it. But I do remember at one point on the phone, Nellie crying to my mother saying, I think I made a

00:14:05.980 really big mistake. And that stands out as a point where I could have easily just quit. But I stuck with

00:14:12.060 it. And thank goodness I did. Because Lenny was right. And Lenny is really the smart visionary

00:14:17.200 that saw that this was the right way to go. So you sort of alluded to it earlier. Lenny was

00:14:22.900 sort of onto something, right? There was basically a new pathway. Now, if we go back in time to 94,

00:14:29.980 what did we know? Well, we barely knew about Tor. I mean, it was just being basically figured out that

00:14:37.420 this thing that Michael Hall had figured out a year earlier, Saul is figuring out, David is figuring

00:14:43.400 out. I mean, there's still this early triangulation of what's going on with rapamycin. At the time,

00:14:48.640 they didn't even, if I recall, I don't think we knew that there was mTorq1, mTorq2, and they were

00:14:52.680 doing totally different things. AMPK is pretty well understood. Metformin's been around. But I don't

00:14:59.400 think people really had a sense at the time that it was anything other than an anti-diabetic drug.

00:15:03.820 So talk me through this whole Sirtuin thing. That's a pretty broad question. Let me narrow

00:15:12.740 it down a little bit. Talk me through what you were just about to allude to that. What was Lenny

00:15:16.640 onto when you showed up? Well, genetics is a fabulous tool because you don't have to go in

00:15:21.500 with any hypothesis that biology will tell you the answer. And the gene that had just been cloned by

00:15:26.540 Brian turned out to be what's called SIR4. Now, SIR4 didn't turn out to be a mammalian

00:15:33.080 conserved gene. So SIR4 has not been as exciting, but there was this partner of the SIR4 gene.

00:15:39.460 It was called SIR2. And SIR2 and SIR3 and SIR4 form this complex of proteins stick together and

00:15:45.520 control, of all things, gene silencing. That's what SIR stands for, silent information regulator,

00:15:51.820 in this case, number two. And that was very unexpected. In those days, if you think back,

00:15:57.380 the cause of aging was thought to be DNA damage, mutations, free radicals. So we were all expecting

00:16:02.800 to find genes that controlled DNA repair or antioxidants. At that time, because I go back

00:16:09.000 and I think, God, at that time I was still in college studying math and engineering. I didn't

00:16:12.440 know. I hadn't taken a biology course. So I can't think about it through the context of my own

00:16:16.420 education. How well was it understood that there were introns and extrons and that much of the genome

00:16:21.980 wasn't even coding and stuff? Like, was that well understood at that point in time? It was. In yeast,

00:16:26.780 actually, they were ahead of anybody else in eukaryotes. We knew that there were introns and

00:16:31.900 not many introns in yeast anyway. But we hadn't seen the full genome. It was still bits and pieces,

00:16:37.260 maybe 5-10% was known. My PhD was sequencing three genes. That's all it took. So things were

00:16:45.020 changing rapidly. This new thing with PCR, you could move tubes into hot tubs and amplified genes.

00:16:50.360 It was all very exciting. But what we didn't have any clue was that why a silencing gene that

00:16:56.520 controlled, negatively controlled genes, other genes, why that would have anything to do with

00:17:01.880 aging. It was totally bizarre. It led to a string of cell papers. And one after another, every few

00:17:08.400 months, we were actually publishing something new and we had a science paper. And that was the gold

00:17:13.280 rush of this discovery because it really turned on the lights in this cave of a whole new area of

00:17:18.800 biology. And we're still trying to understand actually why those silencing proteins are relevant

00:17:24.100 to aging. But what we do know for sure is that these same genes, these sirtuins in all life forms,

00:17:30.000 whether they're from plants all the way to us, do play a protective role in responding to energy

00:17:34.740 and nutrients, just like the MP kinase in the mTOR pathway do.

00:17:38.140 So you alluded to SIRT2. Was that first found in yeast?

00:17:43.440 Yes, it was. It was known already, actually. Lenny and we didn't discover SIRT2. It was already known

00:17:49.980 as a silencing protein that controlled the mating type. In other words, the sex of a yeast cell.

00:17:55.680 And if you don't have the silencing, what happens is that the yeast cells get confused because they're

00:18:00.580 now turning on genes for A and alpha, which means male and female. And a yeast cell that doesn't know if

00:18:05.640 it's male or female will not mate and it's become sterile. And it turns out that's a hallmark of

00:18:10.840 yeast aging is sterility. So if you, you know, the way you can tell whether a yeast cell is truly old

00:18:17.000 is, is it sterile or is it just sick? And that's how we used to tell. But now we actually understand

00:18:23.500 the cause of that sterility. It's the actual, the movement of SIRT2 protein away from those genes

00:18:29.780 that it should be at to go deal with other problems in the cell.

00:18:32.600 I see. So it's not that SIRT2 becomes deactivated. It just, for lack of a better description,

00:18:39.420 shifts its attention elsewhere.

00:18:40.800 Right. It becomes distracted by other things going on in the cell. And, and we, we had a

00:18:44.560 cell paper in 1999 with Kevin Mills and Lenny, where we discovered, and a couple of other groups

00:18:49.700 should also get credit for co-discovering this, is that the sirtuins are also involved in DNA repair.

00:18:54.160 When you get a broken chromosome, it's the SIRT2 complex that goes along, helps unwrap the DNA,

00:19:00.020 we think, and put it back together and repair that. And while the SIRT2 complex is doing that,

00:19:05.380 it cannot be also silencing. There's not enough of it to go around. And you might ask, well,

00:19:09.520 why would the cell do that? Why don't you just make more SIRT2? What we think is that this is a

00:19:13.160 very ancient system that coordinates controlling mating and DNA repair. You don't want to be mating

00:19:20.760 and dividing if you've got a broken chromosome. So this is a way of coordinating those two events.

00:19:25.540 And it's very ancient. It's a very active system. You need DNA checkpoint signaling. So it's not just

00:19:31.400 random. But what we also have come to realize is that this, let's call it this distraction of the

00:19:37.800 sirtuins, it's conserved. We find this happens in our own aging process as well.

00:19:43.300 So there's really two roles. There's gene silencing and DNA repair. Now, sirtuins are HDACs. Is that

00:19:53.080 correct? Are they all HDACs? So HDAC, histone deacetylases, this is the old name for protein

00:19:59.360 deacetylases now. Because what we've all come to realize is histones are just one of the things

00:20:04.000 that sirtuins and these other HDACs do. They can target what are called non-histone proteins.

00:20:09.240 And they remove not just acetyl groups, but also other types of what are called generally acyl groups.

00:20:16.100 And so that's a whole new world. That means that sirtuins, the family, there are seven of them in

00:20:20.620 mammals, five of them in yeast, target other proteins, proteins that are in cytoplasm in the

00:20:26.160 nucleus, even in the mitochondria. And that's their role. It's not so much only about controlling the

00:20:32.320 chromatin and histone, but also about controlling signaling and metabolism as well. And they can do

00:20:38.820 that by targeting any protein theoretically in the cell. So what are the, you know, again, thinking back

00:20:44.940 to DAF2, DAF16 as the parallels with FOXO and IGF, were there elegant experiments in the yeast that

00:20:52.000 could show you extreme conditions of lots of sirt, no sirt, and what that phenotype is?

00:20:58.640 Oh yeah. These were the first experiments. So I'll try to take you through them correctly in sequence.

00:21:03.680 So what we showed with Brian, first of all, in the 1996 cell paper, was that we were looking for

00:21:09.660 this movement. There was this so-called age locus. We didn't know what it was. We didn't know where

00:21:14.460 they were going. We just knew that they left the silent mating type locus. So what we did was we

00:21:19.560 stained it. So Brian had moved on actually to his postdoc. And Kevin Mills and I, a student at the

00:21:24.400 time, our job was to find where are the proteins going. So we stained them and we could look at

00:21:30.200 them under the microscope. And what we saw was they were going to this little place in the nucleus,

00:21:35.440 which we eventually figured out was the nucleolus, which is what makes the rRNA, which makes the

00:21:41.900 ribosomes. It's a really important part. And the DNA that's within the nucleus is called the

00:21:47.500 ribosomal DNA or the rRNA. And that's where they were going, not just during normal aging, but also

00:21:53.660 during an accelerated form of aging. So there's a whole story that was lost in history, actually,

00:21:59.140 that maybe I'll just quickly touch on. One of the first things I did when I got to Lenny's lab was to

00:22:03.740 work on Werners syndrome, which is premature aging disease.

00:22:07.180 And these are kids that die in their teens or twenties, aren't they?

00:22:10.320 No, that's a different Hutchinson-Gilford syndrome. This one, Werners, they lived till

00:22:14.140 their forties. Yeah. But the gene was just cloned by George Martin and his team out there.

00:22:19.980 And the homologue in yeast is called SGS1. And I picked up the paper, it was in science,

00:22:25.220 I recall, went into Lenny's office and I said, I've just been scooped, but there's a yeast homologue.

00:22:31.620 I'm going to work on that. Is that okay? And he said, yeah, go for it.

00:22:33.880 And so we worked on SGS1 for a little bit. And what we found was that they were going through

00:22:39.200 accelerated aging as well. So we had a science paper on that. And what was exciting about that

00:22:43.260 was that they were also becoming sterile and the two complex was moving as well, just like the

00:22:49.240 normal aging. So we had this model, rapid aging model. And you might say, well, so what's the big

00:22:54.920 deal? You've got a rapid aging model. But A, that told us that there was some universal process that

00:23:00.260 results in premature aging in humans, probably in yeast, the same thing. And we could also study

00:23:05.640 this much more easily than an old yeast cell. Consider that to find a single old yeast cell,

00:23:11.680 it's really hard, especially if you're just studying replicative aging, which is the number

00:23:16.860 of times they divide. Each mother cell produces on average 10 to the power of 25 offspring.

00:23:23.500 Wow.

00:23:24.660 Okay. So that's, by my calculations, about 30 million offspring. And you have to pull out

00:23:29.860 that one cell and study it biochemically.

00:23:31.960 Wait, you said 10 to the 25.

00:23:33.620 Yeah.

00:23:34.300 Oh, sorry. Two to the 25.

00:23:35.780 Oh, okay. Okay.

00:23:37.000 Yeah. But in any case, that's way more. So what we used to do is to sort out the old cells. We'd label

00:23:43.560 them with a chemical and pull them out with magnetic beads. But it was a real, we couldn't get many of

00:23:48.780 them. You'd just get a handful. But with these SGS-Werner's proteins-

00:23:51.800 You could get a bunch of them.

00:23:52.980 The mutants. We could get a lot more. And so we'd made a lot of progress using that.

00:23:56.560 But every time we made a discovery with the SGS protein mutants, we went back to the normal yeast

00:24:01.680 cells and verified. But we were actually able to figure out with that mutant what the distracting

00:24:07.100 problem was for the circomplex. And that was actually DNA breaks and DNA recombination that was

00:24:13.640 occurring at the most repetitive regions, the most unstable region of the genome, which is the

00:24:18.320 our DNA, which is in the nucleolus. And that was what was distracting those proteins.

00:24:22.620 Interesting. When you knock out SIR2, is it easy to knock it out?

00:24:26.620 Yeah. So that was the next experiment.

00:24:28.100 Okay.

00:24:28.480 So then we wanted to know, the prediction is if you knock out SIR2, you should get a lot more of

00:24:32.740 this instability at the RNA.

00:24:34.140 Yes. And the question is, does it translate to accelerated aging or not necessarily accelerated

00:24:38.640 aging, but more cancer or some other phenotype, right?

00:24:41.260 Well, in yeast, it led to accelerated aging through the process I was telling you about.

00:24:44.480 Genomic instability, DNA repair went down. And also that happens in animals, although it's

00:24:51.140 a little more complex because it's embryonic lethal in a lot of mice. So you can't easily

00:24:56.840 do that experiment. But what you can do is the opposite. You can turn on or overexpress the

00:25:01.860 SIR2 gene in a yeast cell. And if we're right, you should get a few things that are going to

00:25:06.140 happen. You'll have more genomic stability at this, particularly at this RDNA locus in the

00:25:11.660 nucleus. And the yeast cells should live longer. And that experiment was done by an incoming graduate

00:25:16.700 student, Matt Cabellon. And what a fantastic project to get when you walk in. He did it.

00:25:22.800 And the day that he got lifespan extension with extra SIR2 was a very good one for him and the lab.

00:25:27.900 So what's the next step from there? The most obvious thing is how do you develop a compound

00:25:33.180 that would do this without the genetic mutation that empowered it?

00:25:37.200 Yeah, that was the issue because you can't easily genetically manipulate humans. So the

00:25:41.020 question was, how do you turn on these genes? Now, we spent about three, four years working

00:25:46.420 on caloric restriction in yeast and then in mammals. And my lab and some others were leading

00:25:52.160 the charge in showing that SIR2ins, both in yeast and mammals, were not only necessary but

00:25:58.380 were sufficient when you overexpress them to mimic calorie restriction. Put another way, if you

00:26:03.120 knock out SIR2, you don't get the benefits of calorie restriction.

00:26:06.020 You don't get the benefits of CR.

00:26:07.660 Right. And that's also now been shown by others to be true in mice as well. So that led to the

00:26:13.040 idea that- Is that true in all mice?

00:26:15.120 I couldn't say. Even in yeast, you can get around the need for SIR2ins if you stress the yeast really

00:26:21.060 intensely with very little amount of calories. But there are aspects of calorie restriction benefits,

00:26:28.360 such as a lifespan extension, that are ameliorated, lessened by a SIR2 knockout. But it's still

00:26:35.220 complexified by the fact that it's lethal in embryos. And you have to knock it out in the adult

00:26:40.520 to do a real experiment.

00:26:41.180 Yeah, it's the same sort of issue that Cynthia had with the DAFs, which was if you do too early,

00:26:45.740 the C elegans doesn't make it into an intermediate stage.

00:26:48.840 You know what? Somebody hasn't even done the proper experiment, which is to take a mouse that you

00:26:54.320 can knock out SIR1 in an adult, whole body, and then calorie restrict. Something that we probably

00:27:00.380 should have done years ago. We didn't. But the technology is there to do that. But what we did

00:27:06.040 learn actually was, both in yeast and in mammals, was that it's not just one of these genes that's

00:27:10.920 important. It's the whole family. And that if you knock out- Take yeast, for example. If you knock

00:27:15.260 out SIR2 in yeast, you lose the ability to respond to some mild calorie restriction. But if you

00:27:20.060 really calorie restrict them, they'll still live longer. And there was a big debate actually between

00:27:24.560 Brian, Matt, myself about that. And where we settled on was that these other SIR2-related genes

00:27:32.860 were also helping, and they work as a family. And if you knock one out, the others can compensate-

00:27:37.900 The yeast only have one?

00:27:38.920 Yeast have five.

00:27:39.700 Yeast have five. And humans have a whole family, like eight or something, right?

00:27:42.500 Just seven.

00:27:42.880 Oh, okay. So only two more. It's interesting.

00:27:46.000 Little known fact, most people ignore the other yeast SIR2ans, but they're just as

00:27:49.920 interesting. And what we've found is they also can extend lifespan as well.

00:27:54.400 So when you, actually, it's funny. I was going to go back to something else you said a second ago,

00:27:58.260 but what's the teleologic explanation for why caloric restriction and SIR2ans would move hand

00:28:05.160 in hand? I'm just like, you talked earlier about your appreciation for sort of evolutionary biology.

00:28:10.300 So an organism is, you know, in a nutrient deprived environment, it still has to be able to do a bunch

00:28:17.700 of things if it's going to be fit. Do we believe that that's an environment where we need to see

00:28:22.920 more stabilization of the genome or repair or silencing? Or what do we think is the biggest

00:28:27.440 insult during that period of time?

00:28:29.100 Yeah. So the biggest insult to any life form is a broken chromosome. That's lethal if you don't

00:28:33.200 fix it.

00:28:33.920 And do we see that more likely happening during nutrient deprivation?

00:28:38.040 I would see that as, I would have assumed, to be honest with you, I would have assumed that

00:28:40.100 was independent of nutrient exposure, or at least if anything, inversely correlated.

00:28:45.100 Well, if you don't have enough nucleotides to complete replication, you're going to break

00:28:48.720 a lot of times.

00:28:49.280 I see.

00:28:49.520 So they do go hand in hand. But the bigger picture is that the SIR2ans evolved, we believe,

00:28:55.380 what are we talking about, three and a half billion years ago in the first life forms,

00:28:59.140 early life forms. Maybe just after the first, one of the first proteins to actually evolve,

00:29:04.540 we think would be a SIR2an. And its job is to sense stress, biological stress in the environment,

00:29:10.260 whether it's DNA damage, or it's a burst of cosmic rays, change in temperature, or a lack

00:29:18.020 of nutrients. And their job is to allow that organism to hunker down and survive. Stop

00:29:23.980 mating, stop breeding. We can do that in another day. If we don't survive this, our offspring

00:29:28.780 are going to die anyway. So we think they control which genes to turn on and off in response

00:29:35.520 to adversity. And they allow those organisms to survive. But they're also talking to other

00:29:41.460 pathways. So they're going to talk to mTOR, they're going to talk to Cynthia's DAF pathway.

00:29:46.140 And collectively, these are the genes that we've settled on as the longevity pathways.

00:29:51.440 But they didn't evolve for longevity, they evolved for survival during adversity.

00:29:55.300 How conserved are these across, let's use the big four models of eukaryotes from yeast,

00:30:02.460 worms, flies, you know, larger mammals like mice and rodents. Is this relatively well conserved

00:30:08.100 the way the TOR pathway is conserved? Or does it have more bends in the road?

00:30:12.420 Well, they're surprisingly conserved that you can just manipulate one gene in each of these

00:30:18.100 organisms and get lifespan extension or one drug works in all of these organisms. I would challenge

00:30:22.860 anyone to use a chemotherapy to help a yeast cell. So this is quite a magical discovery that the same

00:30:29.080 pathways are that well conserved and that ancient. And that's actually one of the advantages we have.

00:30:34.820 Aging is actually not that difficult to be able to control. And that's because our models are very

00:30:40.580 good. I truly believe that if we can extend the lifespan of a yeast, a worm, and a mouse, humans are so

00:30:48.980 close. Right. If you can do it across a billion years, you should be able to make that leap to a few

00:30:54.620 other hundred million years. Exactly. It's really just the regulatory agencies and making sure that

00:30:58.540 we don't do any harm and it's safe. But the biology is all still there going way back three and a half

00:31:04.040 billion years ago. So it was 2006, 2007. When did resveratrol emerge as an early sirtuin

00:31:11.980 activator? 2003. Okay. And yeah, the story behind that was that we were looking for an activator.

00:31:19.020 We're hoping for an activator. Now, were you in your own lab at this point? Yeah. You finished your

00:31:22.240 postdoc, I'm guessing? Yeah. I managed to move to Harvard in 1999. So that was the year when a lot

00:31:31.160 of things happened. While I was moving, we published this DNA repair connection.

00:31:36.060 But just going back to the silly sort of social question, did you at some point think,

00:31:39.660 I want to go back to Australia and set up a lab here? Like, was it a difficult decision for you to

00:31:43.300 stay in Boston as opposed to... Because you came from Sydney, if I recall.

00:31:46.560 Right. Well, the goal was to...

00:31:47.860 Because like, those are pretty different climates. I've been to Sydney once. I spent two weeks there.

00:31:53.160 I could stay there. Yeah. I miss that. But I also like adversity. I thrive on adversity. And so I've

00:31:59.240 come to it like living here. The intention was to come here for two years. I had a job to go back to.

00:32:04.700 But the first week of being here in Boston was like a city I could only dream about. This is the

00:32:10.940 Athens of ancient Greece, Rome of ancient Rome. For biology, this is it. And so I was in heaven.

00:32:17.220 And I'd never experienced a city where you're on the train and people around you are reading

00:32:21.920 science magazine and nature. That's my dream. So it was a very easy decision not to go back to

00:32:29.200 Australia for reasons that if you really want to change the world, you got to do it from here.

00:32:34.580 So now you're in the process of kickstarting your own lab, which comes with its own stresses,

00:32:38.900 right? You've got to secure funding and all those other things. And then what's happening

00:32:43.080 on the front of this stuff? Yeah. So 1999, a few major things happened. One was this

00:32:49.980 DNA repair connection. The second one was Lenny's lab published that NAD was a requirement for

00:32:56.260 sirtuin activity. And Shinemai, who's at WashU now, was the postdoc who made that somewhat serendipitous,

00:33:02.320 but brilliant discovery. And then the third thing was the connection to calorie restriction was happening

00:33:07.980 around that time too. Going back to the second thing, we talk about it now today, like it's in

00:33:12.380 textbooks. It's so obvious, right? That sirtuins are NAD dependent deacetylase. Okay. NAD is so

00:33:19.300 ubiquitous in cells that if the quantity you could have in a cell varies on a scale from one to 10,

00:33:27.640 what is sufficient to produce this deacetylase activity? Is it anywhere from two to 10 or does it

00:33:33.840 have to be quite a high concentration? It can be two to 10. You can actually get very low levels in

00:33:38.540 some disease conditions and the animal is still alive. So it's basically only saying that NAD is

00:33:45.060 necessary for sirtuins to work. Right. Well, without NAD, we'd be dead in 30 seconds.

00:33:51.760 By other reasons as well. I mean, wouldn't we be dead just from not being able to do electron

00:33:55.960 transports? We would. And there's more than 500 reactions that we need just to survive. But what we

00:34:02.760 didn't know in the 2000s, and it was actually quite a crazy thing to think that NAD was regulating

00:34:08.080 anything. And that was actually what we first worked on in my lab was the control of sirtuins

00:34:12.600 with NAD levels. The reason it's crazy is you read textbooks and NAD is the most ubiquitous,

00:34:18.680 important molecule in the cell. How could it possibly be varied during aging, let alone during

00:34:25.540 the day when you eat something or your circadian rhythm? Now it's obvious. We know NAD goes up and

00:34:30.540 down, it changes with age. But in those days, people thought if you changed NAD levels, you'd

00:34:35.300 probably die. That's not true. Was it known at the time that doesn't complex one of the mitochondria

00:34:41.140 basically convert NADH to NAD? So you would at least know that in the mitochondria, the concentration

00:34:49.060 of NAD must go up and down or else you couldn't actually respire. Well, locally it goes up and down,

00:34:55.340 but the steady state level is pretty constant. And when you say going up and down, are you talking

00:35:00.620 cytoplasmic, nuclear, plasma? Where are we talking about? You know, we had a paper, I think it was

00:35:06.100 2007, where we had quite a surprising result, which told us that it's not just the cytoplasm that it

00:35:12.640 goes up and down. It was also the mitochondria going up and down. And we didn't know that. We

00:35:18.720 actually, we stumbled upon it. We found that if we kept cells with high amounts of NAD,

00:35:24.460 they would survive better. DNA damage, others, insults. And we could deplete NAD in the cytoplasm,

00:35:30.480 but they still, the cells still lived. And we didn't understand that.

00:35:33.560 How did you do that, by the way? How do you deplete NAD?

00:35:35.620 Actually, come to think of it, we could either overexpress NAD depleting enzymes, but actually

00:35:39.960 the way we found it was that when you damage cells with the DNA damaging agents, say chemotherapy

00:35:45.140 drug, the cells themselves deplete NAD naturally with this enzyme called PARP1, which is an NAD

00:35:52.340 consuming enzyme. And actually that's very well known that if you hit a cell with a DNA damaging

00:35:58.060 agent, the reason that it dies is NAD depletion. So we were measuring the NAD depletion in the

00:36:04.040 context of- And that's because the cell is trying to utilize that NAD to repair the damage you've just

00:36:08.680 caused? Right, right. Or you didn't know that at the time? No, that was well known. So PARP1 is a

00:36:12.960 known DNA repair protein. And that's, if you block PARP, you also protect cells. But what was

00:36:18.340 interesting was that we could overexpress, give more copies of a gene that made NAD. And this is

00:36:26.220 called NAMPT, which is the equivalent of the PNC1 gene in yeast, which we found was important for

00:36:31.760 lifespan in those organisms. So we were overexpressing this NAMPT. Cells had more NAD. We hit them with the

00:36:38.400 toxin. They'd survive better than the regular cells, but the NAD was still being almost completely

00:36:44.140 depleted from the cytoplasm. I'm sorry, just because this is sort of at the crux of it.

00:36:48.180 Did they survive because they were unable to deplete their NAD? No, we saw the NAD just disappeared from

00:36:54.920 the cell, but they survived. But they still survived. But there was a place we weren't looking at the

00:36:58.780 time. And we tracked it down to the mitochondria. So this begs the term, the mitochondrial oasis hypothesis.

00:37:05.140 So myself and Anthony Sauve from Cornell coined this term. Because what we found was that as long

00:37:10.500 as the mitochondria stayed active with their NAD, it didn't matter. The cell could survive and recover

00:37:15.400 from that stress. And actually it turns out that the levels in mitochondria NAD levels are even more

00:37:21.420 important than cytoplasmic NAD levels for survival. That makes sense. And of course, that's a hard thing

00:37:26.640 to measure, isn't it? It was extremely hard. That's where Anthony came in. Anthony is a chemist and a

00:37:31.560 biochemist at heart. And it was extremely hard to isolate these mitochondria, preserve the NAD in

00:37:36.480 them. We had to use new technologies to be able to do that. Well, how was that done? We were using

00:37:41.420 mass spectrometry for the first time to measure NAD. And what Anthony did brilliantly was to make

00:37:45.980 labeled versions of NAD in its precursors. And he could spike those in and use those as references

00:37:52.580 to measure NAD levels in these compartments. And NAD, if I recall from just biochemistry,

00:37:58.460 you don't get to move that in and out of plasma into cells. It's made de novo in the cell. You have

00:38:04.500 what you have. You can make more, you can bring in precursors, but you don't get to shuttle

00:38:07.760 NAD between cells, correct? As far as we know, right. Okay. Yeah. I mean, it's sort of like an ATP

00:38:13.920 problem. Like it's really hard to quantify ATP in a cell. By the way, does NADP do any of this as well?

00:38:20.800 Well, it's important, no doubt. It's part of this whole problem that we're working on. But if you add

00:38:27.880 NADP or even NADH, which is only different by 100, those don't work to activate sirtuins,

00:38:34.940 only NAD plus will do that. And I mean, not to get too nerdy on this, but it's obviously more

00:38:41.160 than just the charge, but the charge must play a role if NADH can't work, right? So it's probably

00:38:45.780 a combination of the charge and some other size. Yeah. Okay. So now you've made these three

00:38:53.460 discoveries, the second of which we just went into in a little bit more detail. How does the story

00:38:58.580 unfold now? You've got your spanking new lab. Well, you worked for a little while on the SGS1

00:39:04.000 bonus protein and telomeres, put out a paper on that. And we didn't work on sirtuins for about a

00:39:09.280 year because Lenny said, I don't want you working on sirtuins when I left the lab, which was a bit

00:39:13.900 of a shock. Why? He doesn't want, didn't want the competition, I suppose. But I thought a year

00:39:19.160 was enough to give him a headstart, but we quickly started working back on that. Is that a common

00:39:23.640 request of people when postdocs leave their labs? No, of course not. But what am I going to do? I

00:39:28.560 mean, the guy, the guy trained me. I go in my career, but in those days it was very competitive.

00:39:33.320 And so, you know, the Lenny of today is not the Lenny of previous years. And he's a wonderful friend

00:39:38.260 and mentor to me, but that's how it was in those days. It was very cutthroat. I see. But if it were

00:39:42.560 up to you, you would have continued to work on sirtuins. Right. So then now we're basically back

00:39:47.220 to 2001, 2002. The moratorium is up. You're now back to working on it. And nobody at this point in

00:39:52.820 time has yet figured out a way to exogenously manipulate sirtuins more than the stuff that

00:39:59.520 we've already talked about, which is nutrients, stress, and things like that. Yeah. We were trying

00:40:04.260 to feed yeast, NAD, and we gave them nicotinamide, which is a precursor to NAD, vitamin B3. And

00:40:10.400 actually Kevin Bitterman, who's now a very successful venture capitalist, my first student,

00:40:15.120 he put nicotinamide on yeast and we could measure the sirtu activity by the color. And if sirtu was

00:40:19.840 more active, they'd turn red. And he walked into my office, one of his first experiments when we

00:40:24.580 worked on sirtuins, and he said, David, something's weird. We didn't get activation. We got inhibition.

00:40:30.840 So the yeast had gone red. And I said, Kevin, it doesn't matter what happens. If it's unexpected,

00:40:35.500 that's even better. So that led to a paper that said that vitamin B3 high doses is inhibitory

00:40:40.780 of sirtuins. And now the labs around the world use nicotinamide as an inhibitor for sirtuins. And

00:40:46.580 I wouldn't recommend taking really high doses of nicotinamide.

00:40:49.540 Why is that?

00:40:50.420 There's a few answers. Biochemical answer is that there's an evolved pocket in the sirtuin

00:40:55.500 structure that measures nicotinamide levels, and it's a feedback loop. So nicotinamide is,

00:41:00.760 to get nerdy, is the product of the reaction. It takes NAD, cleaves it.

00:41:06.720 Oh, I got it. So it's just a negative feedback loop.

00:41:08.460 It's negative feedback loop.

00:41:08.840 It's seeing too much B3, and it's saying, I have too much of my output.

00:41:13.200 Slow down.

00:41:13.620 Turn it down.

00:41:14.160 Exactly. So we struggled with that. We couldn't get NAD to go into cells. It's too big.

00:41:18.280 Even with mammalian cells, it's difficult. So we were looking at ways to make more NAD in the

00:41:23.080 cell. That was our original thesis before asveratrol was on the radar. And we were turning on and

00:41:28.980 discovering the genes that made NAD in yeast. And we cloned some of the genes in that pathway.

00:41:34.360 And there was one particular one that is called PNC1. And it had been studied in the context of

00:41:40.260 tuberculosis. And what we found was that when we calorically restricted yeast cells, this was one

00:41:47.020 of the most highly upregulated genes in the whole yeast cell, which was very unusual. People had

00:41:53.080 discovered this before in their own lab, but they were wondering, what the heck is this NAD

00:41:57.600 synthesis pathway? Got to do with calorie restriction, got to do with stress. But we knew

00:42:03.360 exactly what was happening. This is a stress response that was turning on NAD production and

00:42:08.560 activating sirtuins. So we had our first nature paper actually on that 2002, I think, 2003. And we

00:42:16.560 found that PNC1 could mimic caloric restriction and raise NAD availability. And then if we knocked

00:42:22.140 out the PNC1 gene, yeast cells didn't live longer when we calorie restricted them. And what's really

00:42:27.600 interesting about that, I think, is that PNC1 doesn't just get turned on by caloric restriction.

00:42:32.860 It's turned on by heat, low amino acids, salt, high salt. And so this is a gene that senses the

00:42:40.920 environment and turns on the sirtuins. Exactly what I was explaining earlier about those early life

00:42:46.000 forms on the planet, sense their environment, and through NAD and other ways, they can turn on

00:42:50.620 these pathways for defense. So where did you go from PNC1 to resveratrol?

00:42:56.300 Well, we teamed up with a company at the time, they were called Biomol, and they were making

00:43:01.840 reagents for HDAC assays, this kind of thing. And Conrad Howitz was a scientist there, and he had

00:43:07.920 invented, wasn't even available yet, an assay for sirtuin activity in vitro. I forget why he reached

00:43:15.120 out to me, but he said, hey, well, maybe I wrote to him, but whatever happened, he sent me some kits

00:43:19.760 to test. And they worked, and it looked great. And what was the gold standard prior to these kits?

00:43:25.920 Oh, gosh. A measure to an activity required Western blotting, which is detecting the cell

00:43:31.300 groups. It was horribly hard, still is. And this was a very quick way to look for molecules. And what

00:43:36.560 Conrad did was to take that assay and look through his collection of molecules at Biomol. They had

00:43:42.500 libraries of these things. And two of the first molecules that were discovered by him

00:43:47.960 to change the activity of SIRT1, human SIRT1, were a couple of plant molecules. Now,

00:43:54.000 he found plenty of inhibitors. That was-

00:43:56.720 Inhibiting wasn't the hard part.

00:43:58.240 Exactly. But he called me up and he said, David, something's weird. We've got these

00:44:02.940 molecules that seem to activate the enzyme. And I said, that's great. That's what we need. And he

00:44:08.840 goes, well, I don't know if it's real, but let's work on this. So we worked on it together

00:44:13.260 for about six months, trying to prove this wrong. Because in the history of pharmaceuticals,

00:44:19.120 there's only been a handful of molecules ever that have been true allosteric activators,

00:44:22.780 as these apparently were. But we thought it could be fake. It could be messing with the

00:44:27.800 assay. It could be an antioxidant activity. But what really clinched it for me at first was,

00:44:33.740 we put these molecules onto cells. And they lived longer, but only when the SIRT1 gene was present.

00:44:41.260 And the chance of that happening and us being wrong about this idea were pretty low. So that

00:44:46.860 was a good sign. But the other thing that's not well known in history is that those first two

00:44:50.700 molecules that Conrad Howitz discovered, they were not resveratrol. They were actually,

00:44:56.260 I think, pisciotanol and quercetin. Quercetin's found in fruits and onions, I think.

00:45:01.040 But there was a brilliant CEO, Rob Zipkin. And Rob was a chemist. And Conrad showed him these

00:45:08.700 structures that were quite similar, these two molecules. They look like two rings connected

00:45:12.840 by a bridge. And Rob said, hey, you know what these two molecules look like? Resveratrol.

00:45:19.320 And so Conrad and I are like, oh, what's resveratrol? Anyway, I certainly was. I didn't know much

00:45:25.380 about resveratrol. But I Googled it. And it comes up with, I'll suspect an ingredient for red wine.

00:45:31.220 And I could just see the next 10 years of media, which actually happened. But it was an interesting

00:45:38.320 time because we were, it was the first molecule that I can recall was clearly lifespan extending

00:45:44.580 in an organism that you had a defined genetic pathway that wasn't just found off the shelf.

00:45:50.180 We really knew the pathway and we figured out. And it's still, as far as I know, the only drug

00:45:55.000 program that, that has come out of the aging field where it was by design that we find these

00:46:02.020 molecules. So, you know, full credit to Dave and to others who have their molecules that have come

00:46:07.700 out of drug development. So when they first started to make resveratrol for the purpose of

00:46:11.440 these experiments, they weren't extracting it out of naturally occurring sources. It was just being

00:46:14.800 synthesized straight away, even though it was acknowledged that, hey, this thing also exists in nature.

00:46:19.400 Well, no, I think that probably was an extract, but I'm not being very articulate. But the point

00:46:24.380 I want to make is we did it in a different order. So rapamycin and metformin were already

00:46:30.500 on the shelf doing other things discovered by others for doing things. And then you can trace

00:46:35.580 them back to the pathway and you get lifespan extension. We didn't do it that way. We said,

00:46:39.940 here's the pathway.

00:46:40.800 This was the direct target.

00:46:42.240 We went genetics first and then found a molecule and then tested it on the organism, which is,

00:46:46.560 you can do it both ways, but this was more rational science. But anyway, that's the reason. But we

00:46:52.860 also had this very interesting result that we found a yeast mutant that, and actually a certain one

00:46:59.860 mammalian mutant that was blocked that couldn't respond to resveratrol. So we already knew that

00:47:06.480 there was an amino acid that was required for this activation by resveratrol in the test tube,

00:47:11.860 which told me this isn't just some random thing. This is a highly conserved mechanism because we

00:47:18.160 could also show this amino acid was found in other organisms as well.

00:47:22.540 And which amino acid was that?

00:47:23.800 In SIRT1, it's called E230 and the mutation made a lysine. So it went from a negative charge to a

00:47:28.400 positive charge at that location. We didn't know why it blocked it. Now we do, but that was one of the

00:47:34.660 early things that we had in our knowledge base to be able to go forward.

00:47:39.940 Now, when you put resveratrol in cell culture, like you had with the previous two compounds,

00:47:45.440 you mentioned with the previous compounds, if they lacked SIRT2 and they did not get the longevity

00:47:49.840 phenotype. Did you see the same thing with resveratrol?

00:47:52.640 We did in yeast and then in worms and then in flies. And so the fly work, a couple of Brown

00:47:57.580 University scientists, Mark Tater and Stephen Helfand did the fly work. We did the worm work

00:48:01.800 predominantly. And that went into another science paper, I think 2005, 2004. And what was exciting

00:48:08.780 about those days was that here we had things as distant as a yeast cell and a fly separated

00:48:14.620 probably by 500 million years or more. And we had a SIRT2 dependent drug lifespan extension,

00:48:22.400 molecule lifespan extension, which to me said that we're onto something interesting here.

00:48:26.520 Yep. Remind me, what was the phenotype of the non-SIRT bearing organism?

00:48:33.320 Oh, now you're stretching my memory. In flies, I don't recall there being a strong phenotype. If

00:48:39.420 you're asking, were they really short-lived?

00:48:41.120 Yeah, yeah, yeah. That's what I'm basically trying to get at is when you demonstrate the

00:48:45.180 first proof of concept, which is this drug won't work on you if you don't have SIRT. In other words,

00:48:50.940 I think where I'm really going with this is, are there other plausible explanations for how these

00:48:56.400 compounds could have extended life outside of SIRT2?

00:48:59.960 Yeah, yeah, sure. There's plenty of possibilities. I mean, it could have just been that the SIRT2s

00:49:04.420 were making them so sick that they weren't. But one of the reasons that we thought that it was real

00:49:09.260 was that we tried to rule out every other possibility. We fed flies, antioxidants, even if you

00:49:14.420 got life-saving extension, it wasn't through the SIRT2s. You know, you can only make hypotheses and test

00:49:19.500 them as best you can with the tools you have in those days. That's what we did. But now we can

00:49:23.400 actually go back and replace the SIRT2 and mutant with this point mutation that only knocks out,

00:49:30.020 changes one amino acid, which is real. That's real microsurgery. And when we do that and we go back

00:49:36.820 now, we can still see a requirement for SIRT2 for these effects.

00:49:41.440 So it was the mouse paper in 05, 06, that was the one that kind of brought this to everybody's

00:49:49.940 attention, even outside of the aging community, correct?

00:49:52.300 Right. Well, so the resveratural story in yeast was one thing, but when the mouse paper came out

00:49:57.340 in Nature in 2006, it went global and it caught the attention of probably most people on the planet,

00:50:05.180 certainly those who drank wine paid attention. The wine industry sales, I'm told, went up 30%

00:50:10.080 and have stayed up. But yeah, that was 2006, very interesting time. And what's not well known

00:50:17.480 in history is that we didn't know if this was going to work. I mean, it was a real Hail Mary pass.

00:50:22.840 Going back to that experiment, those were not wild type mice. Those were overfed mice, correct?

00:50:28.180 They were metabolically ill?

00:50:30.140 We had both experiments running in parallel, but we got the results earlier for the fat mice.

00:50:34.740 And that was what? So you had the control mice and you had the treatment mice, the control mice,

00:50:39.820 but both mice were fed the same, which was a sort of high fat, high sugar, metabolically disruptive

00:50:44.380 diet, presumably the usual.

00:50:46.520 Yeah. The so-called Western diet.

00:50:48.360 Yeah. Yeah. And in that, so what was the outcome of that experiment? How much longer did the

00:50:54.080 resveratrol treated animals live approximately?

00:50:56.520 I think it was 20%, something like that, 25%.

00:50:59.060 And that was initiated at what age?

00:51:01.400 A year.

00:51:02.360 So those are pretty mature mice. They're middle-aged mice almost, right? They're what,

00:51:05.800 30, 40 years old equivalent?

00:51:07.280 Exactly.

00:51:08.380 What dose? Do you remember?

00:51:09.760 I'm going to guess, I think it was 200 milligrams per kilogram.

00:51:14.540 Per day?

00:51:15.260 Per day. But we also had a group on feeding every other day as well. And those turned out to be

00:51:21.260 pretty interesting as well.

00:51:22.280 That's a pretty high dose relative to, did the ITPs that came out that following used doses that high?

00:51:28.020 So we've done it now in two different doses. We've done 210 times less.

00:51:33.940 Okay.

00:51:34.020 And it actually, it works in both. And what we find actually is that the higher dose

00:51:39.620 is acting on other pathways, including the AMP kinase metformin related pathway.

00:51:45.540 Activating it? So it's synergistic with metformin?

00:51:47.860 We don't know that. But part of the debate about resveratrol is that

00:51:52.160 if you give cells in culture or mice too much resveratrol, then it kicks in other pathways.

00:52:00.620 And in this case, it was activating AMP kinase as well. We published that in our first paper in

00:52:05.020 2006 in the supplemental that most people haven't read. But we knew it was activating AMP kinase at

00:52:10.280 that high dose. And what that means is that when you're activating multiple pathways, it's very hard

00:52:15.160 to dissect that. So we, these days, both in cell culture and in mice, we're very careful to use

00:52:21.800 the minimum dose to get an effect, not overdose, because it just makes things much more complicated.

00:52:27.520 So that you mentioned that you had a parallel experiment that was done in presumably mice

00:52:32.040 that were not overfed. What did that experiment show?

00:52:35.560 So the fat mice, they were healthier. That goes without saying, I think most people know that.

00:52:39.780 In the thin mice, they also were healthier. They had better cardiovascular system, less cancer,

00:52:44.820 a whole variety of things that were exciting. It didn't reach statistical significance when they

00:52:49.000 ate resveratrol every day. But if we gave it to them in their diet every other day,

00:52:54.200 we saw a lifespan extension that tells me a couple of things. One is that it could be that

00:52:59.440 being fed every other day kicks in some other pathways that are helpful. We don't know that for

00:53:04.080 sure.

00:53:04.180 Wait, we'll be kicking in pathways that aren't helpful, wouldn't it? If I understood you correctly,

00:53:08.040 didn't you say that the mice, the non, so the lean, we're going back to the lean experiment. If you

00:53:12.440 fed the treatment animals resveratrol every day, they did not have a statistically significant

00:53:16.620 survival advantage. If you fed them resveratrol every other day, they did. Is that what you said?

00:53:20.920 Yeah. Every, so if you only give them food with resveratrol every second day, we had mice that

00:53:26.540 were living far longer than just that, just the diet alone.

00:53:30.160 Were they being fed non-resveratrol food on the alternate days?

00:53:34.220 No, they were hungry.

00:53:34.660 Oh, so they were calorically restricted.

00:53:36.060 Correct.

00:53:36.460 Okay. So there's now two very, so they could have been the caloric restriction that was

00:53:39.800 extending their life.

00:53:40.620 No, because the resveratrol added on to that as well.

00:53:43.400 So there was another control of just being fed every other day.

00:53:45.940 Exactly. Right. Right. And that came out in a cell metabolism paper in 2008.

00:53:50.080 So from that experiment, one might conclude that resveratrol enhanced caloric restriction,

00:53:55.800 the response to CR.

00:53:56.780 It did. Yeah.

00:53:57.720 So if you had a control group, a CR group fed every other day, and then a CR plus resveratrol

00:54:04.460 group, you would see a dose response.

00:54:06.500 And we did that. And one of the things that might have been happening is that now resveratrol is not

00:54:11.660 a very potent molecule. We've got things that are a thousand times more potent now. But the other

00:54:15.800 problem with resveratrol is that it's not very soluble. And the blood levels, both in mice and in

00:54:19.840 humans, doesn't get up very high unless you eat some fat. So that Western diet, we had much better

00:54:25.880 absorption than this low dose lean diet. And so it may have just been getting the drug on board,

00:54:32.940 quote unquote, the drug, or it may just be that resveratrol isn't potent enough or that we're

00:54:38.320 wrong about this. But the reason I don't think we're wrong about the sirtuins is when you

00:54:42.160 overexpress the gene in the brain, for example, it will extend lifespan and other sirtuins do that as

00:54:48.680 well. Just going back to that, that's a very interesting idea about the fat solubility.

00:54:52.600 Was the experiment ever done where you took mice and you fed them with and without the

00:54:58.160 resveratrol? Because presumably it's not the solubility of the fat that they're eating.

00:55:02.440 It's the bile acids that enable the emulsification of the molecule and the, you know, whatever,

00:55:07.960 the jejunal absorption. So that would be a quick way to show, even without a hard outcome,

00:55:13.380 if you were just getting more into the cells, right? If the resveratrol had greater absorption

00:55:17.100 with and without a fatty food that's resulted in bile acids secretion.

00:55:21.340 Yeah. Well, we didn't measure bile acids, but we could definitely see by measuring

00:55:24.800 blood levels that resveratrol was getting on board when we gave some fat in the food.

00:55:29.940 And that's true in humans. That's why if I take resveratrol, I do it with something that's

00:55:36.160 fatty. So some oil, a yogurt, it works really well.

00:55:40.020 Got it. Okay. Well, that's, so that's elegant. Okay. So then three studies come out thereafter.

00:55:45.560 Two of them were ITPs through NIA. One was not, you were on two of those papers, I believe. And one

00:55:52.860 of them, actually two of them were sort of looking at multiple molecules in testing, correct? And I

00:55:59.000 think one of them, I thought it was odd because it looked at rapamycin, which made sense. And then

00:56:03.280 simvastatin and then resveratrol. I never understood the simvastatin part. Even like, I wouldn't expect

00:56:08.120 that a short-term treatment with simvastatin would have much of an outcome. What did those studies find,

00:56:14.020 the ITPs? They just showed what we already published, which is that if you give resveratrol

00:56:18.800 in regular food, it doesn't extend lifespan. And why did they, why couldn't that have been

00:56:22.540 overcome? I mean, that seems like they should have given that you'd already put, cause you

00:56:26.160 published yours in 06. These were like 08 and 11 or 11, 12, something like these were several

00:56:31.420 years later. Well, yeah, those scientists didn't consult me at all. They just put in the food

00:56:37.180 and went for it. I see. So in parallel to this now, something really interesting happens,

00:56:42.760 which is all of a sudden a pharma company takes notice of something, which is resveratrol. Was

00:56:48.640 there an IND that gets filed on that or was this a pure grass application and meaning an FDA sort of

00:56:54.220 generally regarded as safe pathway? How was resveratrol taken into a clinical trial with

00:56:59.580 humans? Well, what was going on in the commercial side was screening of more molecules. So there was

00:57:05.080 a whole bunch of synthetic molecules that we can talk about. Resveratrol itself was considered a

00:57:10.160 proof of concept molecule largely. If it ended up in the clinic, it would have, I mean, as a drug,

00:57:14.500 it would have been great. But what we were trying to do- And your intuition was, it might be, it might

00:57:18.800 not be. Well, we knew it was a terrible molecule. Because of the solubility alone. Yeah, right.

00:57:23.260 But we- Was it millimolar? Like what kind of concentrations were needed once it was in the

00:57:27.240 plasma to reach its, is it a, is it a micromolar or millimolar drug? Yeah, it's a micromolar,

00:57:30.920 which is, it really, that's not a drug you'd want to go ahead with, but it allowed us to,

00:57:36.080 to get into humans and see what would happen. Do we see the same kinds of things? Or could we deliver

00:57:41.120 it on the skin or in the eye? So that was our goal. And there was some very good formulation

00:57:45.700 chemists who were trying to, and succeeded in working out ways to make resveratrol absorbable

00:57:51.760 in the body. And there were some clinical trials that were initiated under an IND. And

00:57:57.920 there was one that was looking at blood sugar levels. And that one I think is published now.

00:58:05.000 And what kind of doses were they using in the phase one? Do you remember?

00:58:08.160 It was massive levels because the scientists that were running the studies, they were worried that

00:58:14.360 there wasn't enough bioavailability. So they were giving, I think, 10 grams a day, which is-

00:58:19.540 Was there any toxicity at 10 grams?

00:58:21.700 Unclear. Unclear. There was some, in regular people, there was nothing. There was a couple of

00:58:28.000 patients in a cancer study that had renal failure, which happens anyway in these late stage patients.

00:58:34.400 So that, but that was enough to say, this is not worth it because this isn't a blockbuster drug

00:58:39.580 anyway. It's a probe at best, at least according to the company that was running the trials.

00:58:45.320 So they, you know, exercised an abundance of caution and stopped that trial in the cancer

00:58:51.240 patients.

00:58:51.740 That's odd. Why was it being done in cancer patients?

00:58:54.140 Well, part of it was that, trying to remember, but the person who was running the trials had a lot

00:58:58.260 of experience in it. But I recall that there was some animal data or at least some in vitro data

00:59:04.980 that resveratrol could help there.

00:59:06.600 I see. So I didn't, I didn't actually realize that at all. I didn't, so you're saying it was

00:59:11.120 in a phase one that they had this questionable outcome and thought, well, maybe it's not worth

00:59:15.840 pursuing this and we'll move on to the second and third generation variants of these?

00:59:19.620 Well, right. So the company was, was bought by a large pharmaceutical company and a large

00:59:25.180 pharmaceutical company looks at resveratrol and they say, this is not a drug. This is not

00:59:30.820 something that we want to continue with. And so that was certainly part of the decision I'm

00:59:35.500 imagining. But what was, they really were excited about whether the new chemical entities,

00:59:40.580 there were hundreds of them made that were very potent drug-alike molecules that they wanted

00:59:45.680 to take further. And they did take those into humans as well. And I should mention that those

00:59:50.060 molecules have been in mice and Rafa de Cabo deserves a lot of credit for doing that. And so

00:59:56.440 he's taken the same molecule that went into humans, put them into mice, these same one-year-old mice

01:00:02.180 and found that those do live longer, even on a regular diet. So that's why I think maybe it's

01:00:08.780 just resveratrol wasn't as potent as we needed it. And these other molecules succeeded.

01:00:12.260 Now you mentioned, and I want to come back to this at the end, because it's, it's interesting.

01:00:15.960 You're one of the few people in this space who speaks openly about, you know, look in the presence

01:00:20.420 of incomplete information, I still take compound XY. You alluded to a moment ago, you still take

01:00:24.300 resveratrol without having any certainty. Is it your hypothesis that you might not be taking enough,

01:00:30.900 but it's unlikely that there's any harm. And you said you take how much about a gram?

01:00:34.420 Well, so my calculation is this, first of all, I like experimenting. That's, you know,

01:00:38.740 I'm not afraid of death. That's for sure. But I want to be the first person to know if there's

01:00:42.480 a problem. So I'm also keenly aware that what's going to happen to all of us if we don't do

01:00:48.580 anything is not pretty either. And so what have I got to lose? It's cheap. I've got buckets of it

01:00:53.500 in my, in my basement. There's been never any sign of toxicity. It's been in humans for,

01:00:58.440 for a long time now. So that there's no downside.

01:01:01.160 Bigger risk, it would seem, is what if you're not taking enough?

01:01:03.680 Sure. But, you know, one gram, I think if it's not, if it's not working at a gram,

01:01:07.780 then it's not working. I don't think it's worth going higher. But, you know, what's important

01:01:13.240 is that we've made advances since then. We're talking about discoveries from a decade ago.

01:01:18.320 We've got much better things now. So I still take my resveratrol because I've seen enough data

01:01:23.500 in humans as well that it can protect the heart. You know, is it going to make me live 10 years

01:01:29.120 longer? Probably not, not even five, but will it potentially delay cardiovascular disease?

01:01:35.180 Absolutely. So why not?

01:01:36.400 You mentioned in a talk that you, I think you mentioned this in the talk, but you take

01:01:39.880 metformin as well.

01:01:40.960 Yeah, quite recently, probably at least half my colleagues that I talked to.

01:01:44.300 Yeah. Now you're only taking a pretty low dose, if I recall from at least what you said in that

01:01:48.800 talk. Is that because of the additive effects potentially of resveratrol also activating AMPK?

01:01:54.840 Yeah, you're exactly right. If you're starting to take combinations of molecules like I do,

01:01:59.120 you want to ramp it up. We're going into unknown territory. So I mean-

01:02:03.000 Especially if there's overlap in these pathways, right? As you've alluded to.

01:02:06.280 There absolutely is overlap. Anyone who says there isn't is myopic or lying. These are pathways

01:02:13.160 that are additive. So it could be that taking two grams of metformin plus I'm taking two other

01:02:18.840 molecules would be overdosing it. And I don't want to do that. So what I do is I start on a reasonable

01:02:24.840 low dose based on all the data that I've read. And then I make sure that I'm okay. I feel okay.

01:02:31.140 My blood tests are okay. And then, you know, I talk to the experts. They're all my friends. And I

01:02:36.320 say, what do you think about going up to one gram, one and a half grams? So actually recently I have

01:02:41.560 gone up to one and a half grams given advice from people who shall remain nameless.

01:02:45.540 Yes. We'll keep everybody nameless. So let's fast forward to some of these other molecules because

01:02:50.660 this story is just so interesting and feel free to go back and patch pieces of history if it makes

01:02:57.160 things to where we are today. But today we are in a place where there's a company,

01:03:02.080 there are two companies out there that are selling NR, precursor to NAD. They're packaging it with,

01:03:08.620 is it a terastilbene?

01:03:10.480 Right.

01:03:11.060 Tell me what that molecule does specifically and why it would make sense to include that with NR.

01:03:16.420 Yeah. So terastilbene is essentially just resveratrol with some methyl groups on it. It's a

01:03:20.880 more novel, sexier version of resveratrol, but that's the-

01:03:24.560 But is it any more active in your opinion?

01:03:26.440 So Lenny has told me that it is, but I don't know enough to be able to give a sensible answer.

01:03:31.460 Okay. So you now have a SIRT activator with an NAD precursor that are both basically over the

01:03:39.820 counter, right?

01:03:40.580 That's right.

01:03:41.200 So tell me about the excitement in that space. I don't want to get too much into the politics

01:03:45.440 of the companies because they're, at the time of this recording, they are in World War III.

01:03:50.140 So let's just talk about the science and not sort of all the other stuff.

01:03:54.100 Yeah. Well, if you take the 40,000 foot view of this, so Lenny is in his 60s now and I'm in my 40s,

01:04:01.980 very late 40s. And you've got to do a calculation. How many years do you have left to not only see

01:04:08.340 what happens, but potentially even be vindicated? And I'm sure that's part of Lenny's thinking.

01:04:13.200 What would Lenny be vindicated for?

01:04:15.020 For finding that the sirtuins are important for health, longevity in humans.

01:04:20.720 Oh, I see. Meaning that following this discovery, some of the air left the balloon and now there's

01:04:27.520 a resurgence of, hey, no, it really did matter. Is that what you mean by being vindicated?

01:04:32.400 Well, I think there's a race to see whose pathway is more important.

01:04:36.420 Got it.

01:04:37.120 And the sirtuins and mTOR and ambikinase and some others are in this race. You know,

01:04:43.800 I think it's a silly argument because they're all important and they talk to each other.

01:04:46.920 But, you know, ego is involved and people want a legacy. And Lenny's legacy, as I understand it,

01:04:52.720 can't speak for him directly, but is that he wants to have made a major contribution to human health.

01:04:58.780 And this is a way of showing that within a timeframe that's reasonable, who wants to wait

01:05:03.520 another decade? If I was him, I wouldn't want to. And so I think that that was a good way of

01:05:09.140 being able to quickly test the hypothesis in an area that, you know, going through the supplement

01:05:14.940 route. I, on the other hand, I think because I'd had the good experience with pharmaceuticals and I

01:05:21.160 also have more time to wait, I took that route. And so the two of us are heading in parallel.

01:05:27.040 You know, we're very good friends. We talk all the time about this, but it's an interesting from an

01:05:31.100 historical perspective that we've got these two guys who are taking very different routes

01:05:36.580 to what we hope is achieve the same thing, which is to help people in the end.

01:05:41.720 And Elysium, obviously they've talked very publicly about their goal is to sort of provide

01:05:48.040 a supplement, but at a much higher quality, obviously in the United States. I can't speak

01:05:51.960 to this in the, in other countries, but the regulatory environment here is quite unique in that

01:05:56.060 basically these supplements are quite unregulated. So you're sort of at the mercy of the person who's

01:06:01.100 making the supplement. And obviously having a number of Nobel laureates involved with a company

01:06:06.060 like Elysium and a commitment, a public commitment to use the highest quality stuff,

01:06:10.460 at least a person can buy this and say, look, I'm not getting crushed bird feathers, which I'm

01:06:14.360 pretty much guaranteed to be getting with half the stuff I buy online. Look, I bring this up because

01:06:19.280 I think half my patients are either taking Elysium's basis or the fact I can't remember the name of the

01:06:24.780 other company, Chromadex is the other. Yeah. Half my patients are probably taking NR. They always ask me,

01:06:30.520 what do you think? To which I say, I have no earthly clue. I'm pretty sure it's safe. So that it passes the

01:06:35.740 first test, which is, I don't think it's hurting you. One of the issues I've always struggled with

01:06:39.680 is if it worked half as well as it works in the mice, it shouldn't be subtle. You know, you showed

01:06:47.500 in one of your talks and exercise, a contrast between two mice running on a treadmill. And that

01:06:52.660 was actually one of the milder successes. That was like, you know, a 50% improvement in exercise

01:06:57.260 tolerance. I've seen other studies that talk about an 80% improvement in exercise tolerance.

01:07:01.640 If people were experiencing a 20% improvement in exercise tolerance, I'd believe we'd know about

01:07:07.040 it. Do you feel that that's happening and we're missing it? Or do you feel it's just not going to

01:07:11.880 be possible to elucidate that without a clinical trial, even though it's a supplement?

01:07:16.180 I get a lot of emails every day.

01:07:18.440 You might be the single most emailed person on this topic, I'm guessing, right?

01:07:21.580 Oh, yeah.

01:07:22.200 Wait till your book comes out.

01:07:23.280 Probably a thousand of them this week, actually. And I'm not exaggerating. And to any of you who've

01:07:29.260 written to me, I'm sorry, I just can't answer them all. I will try. One of the main questions

01:07:33.400 is-

01:07:33.860 Well, hopefully by having this discussion, let's go as deep as you want into it so that you can say,

01:07:38.220 go listen to that discussion and you'll get all your nuanced points across.

01:07:43.720 Yeah. Or go buy my book.

01:07:45.280 Even better.

01:07:45.840 That's coming out next year in 2019.

01:07:47.820 Do you have a title for it yet, by the way?

01:07:49.320 It's a tentative title.

01:07:50.860 Okay. So at the time of this recording, for people listening, we don't yet know the title,

01:07:54.820 but David's book will probably be out in the late summer, early fall of 2019.

01:07:58.820 That's right.

01:07:59.200 Okay.

01:07:59.620 Yeah. So I have some insights into this NAD world as it's developed. It's extremely hot. They're

01:08:07.320 selling tons of the material, which is great. It helps people. Now, I get a lot of emails from

01:08:14.300 people who claim and they show me data that they used to do races when they were 40 and then now

01:08:22.560 they're 60. They can't win races. They can't cycle, but they've gone on this or that in our

01:08:27.700 product or even NMN and now they're winning races again. So these are stories I hear constantly every

01:08:33.640 few days, but I can't judge those because these are people I don't know. There's no placebo,

01:08:37.640 but I think that some of this, if it were true, that's what we would expect. If these molecules could

01:08:45.640 help people, you would hear these anecdotes, which I hear, but I can't declare that I know anything

01:08:51.280 more than you do, Peter, about this because they're all anecdotes. So that's why we're doing

01:08:55.920 a human clinical trial.

01:08:57.420 Now you mentioned NMN a moment ago. Can you tell us listening to this, the difference between NR,

01:09:04.000 nicotinic riboside, which is a one step precursor to NAD and NMN?

01:09:07.960 Well, it's very simple. So NR is converted by the body into NMN and then NMN is immediately

01:09:13.480 converted to NAD. So those are the steps.

01:09:16.220 So I misspoke. I actually thought it was NR that was one step away from NAD and NMN went to NR,

01:09:22.280 but it's the other way around.

01:09:23.220 Correct.

01:09:23.780 Okay. Both of these can be, we know definitively both of these can be brought into cells to be used

01:09:30.920 as cellular building blocks for NAD. Is there any dispute about the ability to get from high plasma

01:09:36.300 levels into the cell?

01:09:37.420 Yeah. There's a debate. It's not earth shattering. It's very academic, but yeah, we're debating in the

01:09:42.420 field about which molecule gets transported and which one doesn't. And NR definitely gets

01:09:49.160 transported. The question is, does any NMN get in transported?

01:09:52.460 And I believe you've written in, I think I read in one of your review articles perhaps,

01:09:56.320 but it could have been somebody else's, that NMN might be slightly more stable than NR.

01:09:59.660 Well, we find that in a lab that if we put them in solution on the bench or leave them on the shelf,

01:10:05.900 that NMN is more stable than NR, that's why I keep my molecules and lab's molecules in the freezer

01:10:13.760 just to give them some extra shelf life.

01:10:16.360 And did you imply by what you said a moment ago that there is no dispute that NR at least gets,

01:10:21.640 if you have a high plasma level of NR, it is brought into the cell. Is that diffusion mediated?

01:10:26.500 Is that transported?

01:10:27.360 There's a transporter for NR. There's evidence that there's an NR transporter,

01:10:30.980 but either way, they both raise NAD levels quite effectively in the body, in humans as well.

01:10:37.100 And I'm sorry, I know I asked this already, but when you say they raise NAD levels,

01:10:41.320 you mean mitochondrial NAD levels or cytoplasmic NAD levels?

01:10:45.300 Oh, gee. So most of these studies have been done on whole cells from blood or tissue.

01:10:50.900 So they're just like PBMCs or something like that?

01:10:52.700 Exactly. The problem with that is that it's a very dynamic system. This isn't a regular drug that

01:10:57.760 just hangs around and you can measure it. This is actively utilized by the body. So even if it

01:11:02.360 disappears into some pathway, it's still probably being recycled. So we have to be very careful

01:11:07.880 not to jump to conclusions. If you don't see it in the blood, maybe it was taken up by the muscle

01:11:12.040 or the brain. So these are the studies that are ongoing now.

01:11:15.500 And if you see it in the PBMC, it doesn't mean it made it into the hepatocyte.

01:11:18.840 Right. This is all just in an animal, you can do that. We're starting to do those experiments in

01:11:23.380 humans right now using NMR to be able to measure NAD levels in the living tissue.

01:11:28.120 And when you say NMR, do you mean like MRS or like-

01:11:32.940 Yes.

01:11:33.360 Okay.

01:11:33.800 I do. So phosphorus, MRS.

01:11:35.580 Yeah.

01:11:36.320 And you can measure ATP and AD.

01:11:38.360 Right, right.

01:11:38.900 So those are really powerful and you can actually now do it with seven tesla magnets with people

01:11:43.020 in the machine while they're exercising. So that's where we're headed with this in our next

01:11:46.680 clinical trial, hopefully.

01:11:48.760 In your intuition, David, if you could cherry pick the hierarchy with where you'd want to see

01:11:55.580 the upregulation of NAD most, which cells would you preferentially be directing it into?

01:12:00.160 Well, it depends on the, if we want to treat a disease, obviously we've got to target that

01:12:04.500 particular tissue. So if we're treating a mitochondrial disorder or the muscle,

01:12:08.420 obviously the muscle. For longevity, I would want it to definitely get into all tissues if possible.

01:12:15.420 I think it would help if it could get into the hypothalamus where there's some central

01:12:20.380 regulation. But what the field has discovered is that all these tissues, not all, but many of

01:12:26.960 these major tissues are secreting proteins that can induce longevity. So I wouldn't want to

01:12:32.060 prioritize unless we're talking about a particular disease like liver disease or muscle wasting.

01:12:36.320 One of the things David Sabatini and I talk a lot about, I'm actually going to see David for

01:12:39.960 dinner tonight. And I'm sure this will come up is if you could wave a magic wand and make rapamycin,

01:12:45.920 for example, tissue specific, let alone complex specific, but you get into this. And the same

01:12:51.700 thing with metformin, it probably does have some tissue specificity, probably working more in the

01:12:55.860 liver than it is working in other cells. It seems unlikely that a molecule would have uniform and

01:13:02.440 ubiquitous take up of all cells, right?

01:13:04.340 Well, of course. Yeah. So with NAD, we don't know.

01:13:07.400 So we're still at the, we're basically still in the infancy of knowing where the NR or NMN would

01:13:12.160 be preferentially taken up, but it sounds like the MRS studies would help us understand that.

01:13:16.300 So that's going to help. And the reason I qualified that statement was that, you know,

01:13:19.680 we're still getting approval for these studies, but that's the plan. But also there are labs that I'm

01:13:24.860 aware of. I think she'll remain nameless as well for, to protect their own confidentiality,

01:13:29.560 but they are working on tracer studies to be able to give NR, NMN and see where it goes in the body

01:13:35.480 and be able to measure each tissue. That we'll know probably within the next six months to a year.

01:13:40.020 So you mentioned that what Elysium or Chromadex are doing is using, they're just basically in a

01:13:46.640 different regulatory paradigm, which is they're using molecules that are generally regarded as safe.

01:13:51.280 They're outside of these IND pathways. You're interested in the same sort of targets,

01:13:56.120 but you're going to go down. I don't want to say more rigorous because that, but it is more

01:14:00.180 rigorous. Let's call this made a spade. You're going down a much more rigorous pathway.

01:14:03.040 It's more expensive. That's for sure.

01:14:04.620 Yeah. I mean, literally two logs more expensive, if not three logs more expensive. So I want to be

01:14:11.240 sensitive to any confidentiality because that's the nature of the work that you're doing now. But

01:14:15.700 what can you tell us about the molecules you're working on directly and indirectly in that space?

01:14:20.640 Sure. In the NAD space, there's a couple of companies. One is, I can do it. It's called

01:14:25.660 Metro Biotech, which is here in Massachusetts. And they've been working for five years on making

01:14:30.840 NAD precursor molecules that are better than these two that are available publicly. And there

01:14:36.300 are ways to improve them, better bioavailability, better stability, better efficacy. And those are

01:14:42.620 moving into the clinic as well. And then there's another company called Jumpstart Fertility, which is

01:14:47.860 both here in Massachusetts and down in Australia. And we're finding really great effects of these

01:14:53.500 molecules on female infertility or low fertility. And that's something we're going to be publishing

01:14:58.600 shortly. And is there a type of infertility that this seems most amenable to? Because going back

01:15:03.160 to your evolutionary argument, under periods of stress, we see fertility as one of the first things

01:15:08.160 to go for obvious reasons. But infertility comes in so many flavors, right? There could be an inability

01:15:13.800 to release an egg. There can be aneuploidy. Even when the eggs are secreted, there can be uterine

01:15:20.260 hostility. There's so many things that can result in infertility. What does this particular thing

01:15:24.840 target?

01:15:25.780 Well, so what we find in the, so the biochemical pathway we've figured out, we've published a

01:15:29.920 little bit on this, is that there's a protein called BUB-R1, which is a kinase that regulates

01:15:34.800 spindle quality. And one of the problems with old eggs is that they don't have nice spindles and they

01:15:39.800 rip their chromosomes apart when they-

01:15:41.620 Hence the aneuploidy.

01:15:42.640 Exactly. So Down syndrome, et cetera, abortion, aborted fetuses. But what we found is that this

01:15:48.680 BUB-R1 is regulated by the SIRT2 protein, which requires NAD. And what we think is going on after

01:15:56.060 chemotherapy or during aging is that the levels of NAD in the ovary and in the egg are low and

01:16:02.680 it's getting this aneuploidy. And that explains why when we give NAD to, or NAD precursors to

01:16:08.840 eggs in vivo, the eggs come out healthier, more numerous, and are much better at allowing for

01:16:16.120 fertilization and healthy offspring.

01:16:17.800 I don't know much about fertility as this next question will illustrate, but presumably you can

01:16:22.820 still see aneuploidy on the male side. So is there a male fertility opportunity here as well? I realize

01:16:28.540 it's not as probably as common a problem, but presumably you still have to have a perfect split

01:16:34.860 of the chromosome in the sperm. Yeah. Possibly. It's an area that we're looking into. I don't

01:16:40.600 have anything solid enough to be able to say if it works or not, but in theory, yeah.

01:16:46.060 And you're just going back to something earlier. Is NMN available over the counter?

01:16:49.700 It is. More recently, I can see it on the internet.

01:16:53.340 Okay.

01:16:54.120 But one of the things that I want to bring up is you can find my name all over these products.

01:16:59.520 Not basis, they're reputable, but there are others that use my name all over the place.

01:17:03.340 Meaning without your permission.

01:17:05.180 Correct. And Harvard's permission. And so I've sent more cease and desist letters than you can

01:17:09.860 imagine. And they keep popping up.

01:17:11.660 So that's an important point. So if a listener after this talk is saying, hey,

01:17:15.720 David Sinclair sounds like a smart, reputable guy. If his name's on something, I should take it.

01:17:19.840 What can your name be associated with right now that is with your permission?

01:17:24.340 Nothing.

01:17:24.900 Okay. So basically anything that's out there that's over the counter that has your name on

01:17:29.080 it is not endorsed by you.

01:17:30.240 Correct.

01:17:30.480 Okay. Thank you for clarifying that. That would be frustrating.

01:17:34.800 Yeah, it is. But I try to stay above the fray.

01:17:37.740 It's nice when you can stand on Harvard's shoulders and let their lawyers send those

01:17:41.080 cease and desist letters.

01:17:42.100 It would be nice if that were true, but I spend a portion of my salary every year on this.

01:17:45.840 Really? That's a shame. I'm sorry to hear that. So fertility is a super interesting angle. I would

01:17:53.260 have never thought about that. That strikes me as highly testable as well, which one of the

01:17:59.140 challenges of longevity research, as you know better than I do, is if you want to make claims

01:18:04.700 in humans, you better buckle up because it's almost untestable. So when you look at what other

01:18:12.560 companies are doing, like Restore Bio going down the mTOR pathway, they're not going after longevity,

01:18:17.860 right? They're going after very, very specific indications that are testable in shorter periods

01:18:21.900 of time, respiratory failure, things like that. What are the other disease states that you think

01:18:26.680 would be most exciting if you don't already have plans to go down that from your pharmacologic

01:18:31.480 standpoint?

01:18:32.200 Well, we've been targeting diseases that are rare and have a high unmet need. So I can't

01:18:38.240 divulge all of those because that's company stuff. But the fertility part, that's very

01:18:43.540 clear. I'm able to tell you that those trials will begin next year in IVF clinics. And that

01:18:49.440 will be the first time a doctor looks at those eggs from a woman. She'll probably know that

01:18:55.460 it's working or not. So that's a very clear outcome.

01:18:58.060 And when you say company, so we're sitting right now in a headquarters that is the name

01:19:02.320 of, what's it called? Is it Life Bioscience?

01:19:04.860 Yes.

01:19:05.540 And that's a parent company or sort of, tell me how that fits into a number of the scientific

01:19:11.380 entities that you're involved in.

01:19:12.820 So Life Bioscience is a family of companies that uses shared resources and knowledge. There

01:19:18.160 are eight of us right now that work on different aspects of aging, not just NAD biology, but the

01:19:24.560 usual suspects, all the major hallmarks of aging that we could list off. Each one of these

01:19:29.100 companies has world leaders and drug development programs in that so that we think we can, quote

01:19:35.260 unquote, conquer aging from different aspects. But together, we're stronger as one unified company,

01:19:41.540 Life Biosciences.

01:19:42.220 Earlier, you spoke about sort of eight or nine central tenants of aging. We've covered some

01:19:49.560 of them, but I know, and I'm guessing that your book is going to go into this in greater

01:19:53.460 detail, but can you rehash what you, or at least as many of those as you're going to recall on

01:19:59.260 the spot? Not to put you on the spot, that's a long list.

01:20:02.260 Yeah, sure. There's epigenetic change of cells of cell communication and inflammation. There's,

01:20:07.100 let me count this, senolytics, so senescent cells build up. There's protein misfolding. There's

01:20:13.200 telomere loss and genomic instability. There's metabolic changes. So NP kinase and metformin

01:20:19.520 would address that. And then there's responses to what you call amino acids and other nutrient

01:20:26.500 inputs. And those collectively go awry during aging. But what causes all of those to happen?

01:20:33.460 That's something that we've been working on for quite a while.

01:20:35.340 And you think those are more coupled than they are uncoupled, those pathways? Or do you think

01:20:40.120 that, I mean, there are clearly situations in which external stressors can perturb more than one of

01:20:45.920 those, but like senescence seems somewhat uncoupled from nutrient sensing, doesn't it?

01:20:50.960 It may, but I-

01:20:52.540 And I'm not asking that rhetorically, like I just don't know.

01:20:55.080 Well, no, the answer is we think that we've found an explanation for all of these things to happen.

01:21:01.120 A unifying theory?

01:21:01.980 Right. So I've kept it close to my vest for a number of years, but it actually goes all the

01:21:07.160 way back to the sirtuin story in yeast. And hopefully the listeners who've stuck with this

01:21:12.860 podcast are still with us because this is the punchline.

01:21:15.760 Yeah. I promise you they are with us.

01:21:17.680 So the punchline is that, so this is all off the top of my head here. We haven't published this yet,

01:21:24.080 but I'm going to tell you my thoughts and your listeners. So the genome is digital information.

01:21:31.600 It's very easy to preserve. It's the reason we went from analog to digital in the 2000s.

01:21:36.700 DNA is four letters. It's digital. It's easy to replicate. It's easy to store. You can boil it.

01:21:41.280 It's very robust. And so what we've actually come to discover is that the genome is fairly

01:21:45.960 intact in old people and old animals. We've sequenced the genomes of lots of old mice and

01:21:51.180 all the genes are still largely intact. So what's going wrong? Well, the other part of information

01:21:56.600 that you inherit from your parents is the epigenetic information. Okay. And I use that

01:22:02.840 term loosely, but basically it means what's the pattern of gene expression, which genes are

01:22:07.560 turn on and off at which time. And that is analog information. Okay. That has to be analog because

01:22:13.800 instead of just being a single code, it has to operate in three dimensions, actually four if you

01:22:18.540 count time. And so that's an analog system. And it's constantly adapting to what we eat, what we

01:22:24.200 drink, if we run, when we sleep. And you have to turn genes on and off all the time. But that pattern

01:22:30.960 of gene expression that's set down when we're young, because it's analog, analog information doesn't last

01:22:36.380 very long. Anyone who's had a record player or magnetic tape knows that these things don't last.

01:22:43.160 And that's the problem I think with aging is that we don't lose the digital information. So the compact

01:22:48.640 disk of our lives is still intact when we're old, but it's as if we've got a scratched CD and the cells

01:22:54.780 don't read the right genes at the right time anymore and they lose their identity. In fact, if we, there's

01:22:59.660 an analogy which is called Waddington's landscape, where in the 1950s, Waddington drew a picture.

01:23:04.680 It's a beautiful picture of some hills. It's a mountainscape. And cells actually roll down the

01:23:10.500 mountainscape and land in different valleys down below. And that's to, before he had access to the

01:23:16.780 genome, that was his way of saying, this is how cells know what they are. They land in these valleys

01:23:21.220 and they stay there. But what I think is happening during aging is due to the vibration of noise over

01:23:26.740 time. We lose that pattern of gene expression. We lose that information, epigenetic information.

01:23:32.560 And those cells or those marbles in Waddington's landscape, they jump over into different valleys

01:23:37.980 and lose their identity. So your neurons are not functional like neurons anymore. Your liver cells

01:23:42.640 are more like neurons. And we see that in our lab. We're just writing up a couple of papers right

01:23:48.840 now for this. And we're able to actually manipulate the epigenome in cells and in mice and have a look

01:23:56.680 what happens to those animals. And the prediction is that you get all the hallmarks of aging.

01:24:01.080 You know, the challenge with this entire space is you think back to the time in the 1950s when he

01:24:05.780 made, when he created that analogy. And it's, in some ways, it's amazing that it could still be

01:24:11.200 relevant 75, 80 years later, whatever it is. On the other hand, it, it humbles you to realize how much

01:24:18.300 more has been learned about that process in that time. And sometimes I think about it because you

01:24:24.320 and I are interested in the same problem that I'm worried. I just don't know anything. You know,

01:24:29.300 I'm worried that in 10 years, I'll look back at my hypotheses and my, or not even my hypothesis,

01:24:34.720 just my understanding of the current state of the art today and think, you know what, that was

01:24:39.260 directionally right, but it was so oversimplified. And oh my goodness, like, you know, so it's sort of

01:24:47.140 like, we're back in this problem of time. Like we're going to run out of time. And I mean,

01:24:51.220 how confident are you that, because you and I are almost the same age, like how confident are you

01:24:55.280 that in our lifetime, we will see step function changes in human longevity. And to put this in

01:25:01.500 context, there really hasn't been a step function change in human longevity, probably since the

01:25:08.080 introduction of sanitation. I mean, everything has been quite incremental, maybe antibiotics,

01:25:13.160 vaccinations, antibiotics have probably been the last step function change.

01:25:17.240 Will we see one in our lifetime? How confident are you?

01:25:19.960 I'm getting more and more confident. Honestly, when I started in this field,

01:25:23.680 I thought we'd probably not see the type of technologies that I'm seeing now.

01:25:27.560 It's making my head spin, not just in the technologies, but also the investment and the

01:25:32.960 number of people working on this now. This was the back order of biology when we started.

01:25:37.360 And there's been some new results, which I'll just hint upon because we haven't published and it's

01:25:41.580 very early, but I've seen, it sounds like a scene out of Blade Runner, but I've seen things you

01:25:48.060 wouldn't believe. It's maybe not that dramatic, but let me go back to the compact disc analogy.

01:25:54.100 You've got the scratched CD. How do you find the polish? What is that? Let's go back to the yeast

01:25:59.420 analogy. What causes those scratches? Why do you get loss of gene regulation? Anyone who was paying

01:26:04.400 attention earlier on in this conversation will remember that these DNA breaks in the chromosome,

01:26:09.960 broken chromosomes, distract the serocomplex and they move away and you get the expression of

01:26:16.500 genes that have no right being on. Because the sirtuins have lost, they're distracted from the

01:26:22.360 deactivation function and they're dealing with the repair function. Exactly. So using that, what we've

01:26:28.240 got a lot of evidence for now is that something very similar, if not essentially identical in

01:26:32.940 principle happens in mammals as we age. What that means is that insults to the genome, and one of the

01:26:40.260 major insults is a double strand break, but there are probably others, cause these proteins, sirtuins

01:26:45.340 and other factors. I'm not saying only sirtuins, but factors that control gene expression, silencing and

01:26:50.980 other things, have a dual role, we know, in DNA repair and other things, such as responding to stresses,

01:26:57.900 heat, whatever. But this is the cell's way of coordinating gene expression changes, hunkering

01:27:03.900 down during times of adversity and going off to repair the system, which in this case we study DNA

01:27:09.100 breaks. And that's a beautiful system when you're young. It works great. You get exposed to cosmic

01:27:14.820 rays or you go out in the sun, you've got lots of DNA breaks. Eventually these proteins will go repair

01:27:19.600 those breaks and then go back to where they came from to settle down the response, to turn off the

01:27:25.440 inflammation, to turn off the DNA repair when it's not needed. But the problem we think is it's

01:27:30.180 antagonistic pleiotropy. Okay, so Peter Medawar and the other brilliant scientists in the 50s

01:27:35.960 speculated, I think correctly, is that things that are really good for you when you're young

01:27:40.420 come back to bite you in the ass when you're older. And I think that's what's happening here is that

01:27:44.060 this response to these stresses, like a break, end up not just distracting these proteins, but end up

01:27:48.880 disrupting the actual structure of our chromatin. And these proteins don't always go back to where they

01:27:54.320 came from 100%. Do that for 70 or 80 years. And it's not surprising that the genes that were once

01:28:01.320 perfectly programmed and turned on at the right time lose their ability to do that. And we've got

01:28:06.540 remnants of that program when we're 70 and 80. But what's exciting is that information is still there

01:28:13.240 to be accessed. The question is, how do you get the cells to remember to access at the right time?

01:28:17.560 What's that polish? And I think we're pretty close to finding that.

01:28:20.640 If you had unlimited resources, and not just financial resources, but sort of metaphysical

01:28:26.900 resources, like any experiment would be ethical, you could do something that today no IRB would

01:28:32.840 approve. Is there an experiment that you would wish to see done that could accelerate our knowledge

01:28:38.760 in this space log fold?

01:28:40.640 You mean staying within ethical boundaries?

01:28:43.640 Yeah. But, but, but, you know, for example, like, you know, to do a human experiment in longevity

01:28:47.940 would be ethical, but impractical because of the duration of time. But if you, if I gave you like

01:28:52.680 a time machine and an infinite amount of resources, tell me what the most elegant experiment you can

01:28:56.960 think of that would, again, just leapfrog our knowledge.

01:29:00.080 Okay. So the experiment that needs to be done, whether it's with metformin or other drugs in

01:29:05.740 development, including these wrapper logs, um, and the NMN and NAD precursors is to take a group

01:29:12.360 of 5,000 people that would be sufficient and just give them the medicine and wait three,

01:29:18.460 four years. And you'd know from that number of people that you're changing the hazard ratio,

01:29:24.820 the mortality rate. You'd have to start with people probably in their seventies. I think that

01:29:28.700 was the calculation that I did, but you don't need to wait a whole lifetime to know that these

01:29:32.900 things work. So this is basically Nir's argument. Yeah, exactly. But Nir's not doing mortality

01:29:37.080 as much as he's doing health span, but it's exactly right. You do enough people. I mean,

01:29:41.800 it's going to cost tens of millions of dollars, but think of the trillions of dollars that would

01:29:45.940 be saved if we can prove this. But, but if I'm going to play devil's advocate for a moment,

01:29:49.500 what if by doing that experiment, we are missing the opportunity, the window of opportunity for these

01:29:56.720 drugs to act. In other words, you know, we know that caloric restriction is less and less effective

01:30:01.920 the longer you wait in the organism, at least within mice. And that's what made rapamycin so

01:30:06.080 interesting as you could, it blew everybody away that you could start this drug on mice that were

01:30:10.440 600 days old and they still had, you know, 9%, 14% increase in law and lifespan. If you had more time,

01:30:19.440 do you think we could get a more clear answer starting earlier, acknowledging that you'd have to

01:30:25.600 wait longer if you wanted to use a hard outcome? Like, do you worry that we would risk doing this in

01:30:29.900 people in their eighth decade that it might not work, but that just tells us that it doesn't

01:30:34.260 work late, not that it doesn't work period? I don't worry about that. We could, with enough

01:30:39.080 capital and money invested, we could do multiple different experiments. We could do people in their

01:30:45.180 50s, 60s, 70s, and 80s. So, you know, dream with me. The other thing that makes me optimistic is

01:30:50.780 it's not just rapamycin that works late in life. We've got results in my lab now that we'll be publishing

01:30:56.060 that if we start even later than 600 days in a mouse, which is what, closer to a 75-80-year-old,

01:31:02.880 we can still extend lifespan. Using what, I know you won't.

01:31:06.020 This is, and I can tell you, we're using the NMN. Okay.

01:31:09.860 So, there are multiple ways to act later in life. And so, when you use NMN in the lab, are you also

01:31:14.200 using like a PT analog or a resveratrol analog, or are you able to just use NMN and see?

01:31:21.360 Just the natural molecule will work. We're now gearing up to do the drug substance.

01:31:25.260 And this is not in high-fat, overfed animals. This is in wild-type animals.

01:31:29.840 We just put it in their drinking water.

01:31:31.560 Oh, because NMN is more soluble.

01:31:33.160 Exactly.

01:31:34.260 Interesting.

01:31:34.940 Yeah, but we've got better molecules that we're now testing. We think that we can beat,

01:31:39.080 or again, try to beat rapamycin, and maybe the combination together.

01:31:42.440 Do you think there's overlap in those pathways?

01:31:44.340 Yeah, yeah. We're both thinking the same thing.

01:31:46.240 We don't have to do the combination.

01:31:47.500 Yeah, yeah, yeah. And I want to take the combination one day.

01:31:49.780 Well, we now actually have some early data. I don't want to scoop myself, but we're able to now

01:31:56.560 genetically modify adult mice with AAV, the virus, associated virus. And we can now genetically change

01:32:04.360 a mouse. So, we've just put in all seven SIRT1 genes into mice, in old mice.

01:32:09.960 You've put the seven human SIRT1 genes into mice?

01:32:12.560 Seven mouse genes into a mouse. But that sort of experiment would have taken a decade to do

01:32:17.660 just a few years ago. But now that we can deliver genes, we can do very quick experiments.

01:32:22.740 Not only that, we can also do it multiplexed. We can do combinations of genes and combinations

01:32:27.360 of molecules. So, even an experiment-

01:32:29.300 Yeah, you're stacking the matrix now.

01:32:30.780 Well, yeah. I mean, we should be doing this. It's just a matter of resources. But I think we're

01:32:35.180 now at a point in the aging community where these combinations need to be tested. It's the

01:32:40.320 question that's on everybody's mind. What happens if you put them in combination? Are they better

01:32:44.740 or worse, together? And so, what we've done is we've put all seven SIRT1 genes into a mouse

01:32:49.740 and fed them some NMN to give them the fuel and the genetic requirement. And interestingly,

01:32:56.500 there are additive effects when you do both of those things. And this is how we're able to see

01:33:01.860 these dramatic effects in these old mice.

01:33:03.940 So, is your optimism towards the NAD precursor space and the SIRT2 and activating space equivalent?

01:33:12.400 And do you see them as necessarily parallel paths?

01:33:16.740 They have different uses. The NAD is where I'm mostly focused on now.

01:33:21.020 And is that because of the observed age-related decline in NAD?

01:33:24.540 In part. But it's also because, in theory, all of the seven SIRT2ins should be good. And

01:33:30.420 their lack of NAD could be the main problem that's going on in older people. And so,

01:33:36.960 the idea is that instead of just activating one SIRT2in, which is what resveratrol did,

01:33:41.520 we think, you can potentially activate all seven of them and replenish what's been lost over time.

01:33:47.700 And I think seven is probably better than one.

01:33:50.200 You mentioned at the outset of this discussion that you were four years old when you became

01:33:54.360 aware of mortality. Was there something that occurred that made you aware of mortality at

01:33:58.840 such a young age?

01:33:59.780 I had an unusual grandmother who was really honest with me. She would never lie. And any question I

01:34:05.000 asked, I was...

01:34:06.020 And you were probably very precocious and curious.

01:34:08.340 I suppose I was. But yeah, she would never lie. So, my question that most kids have is,

01:34:13.500 are you always going to be around? She didn't even... I couldn't call her grandma. She wanted to use

01:34:17.240 her first name, which is Vera. So, Vera, are you always getting around? Of course not. I'm going

01:34:21.320 to die. Yeah, but what about mom and dad? Yeah, they're going to die. What about my cat? It's

01:34:26.860 going to die. And then, of course, you're thinking, if they're all going to die, what's

01:34:31.220 going to happen to me? But it turns out all kids go through this. It's been studied extensively that

01:34:35.640 between the ages of four and seven, kids understand that there's death. And at first,

01:34:41.500 they're in denial. They say, well, maybe those adults will die, but my teachers and my parents,

01:34:45.520 they're not going to die. But then by age seven, it's undeniable. All kids know that everything

01:34:49.580 around them that's living at one day will die, including themselves. But what's very interesting

01:34:53.680 that happens at age seven is it's buried deep in the subconscious. You very rarely think about it

01:35:00.040 until you have to. Because I don't think as a species we could get by if we're all running around,

01:35:04.600 oh my God, I'm going to die one day. So, seven-year-olds onward till about 50, you try not to think about

01:35:10.000 it. That's pretty common. You start looking at yourself in the mirror at 50, you notice your teeth are

01:35:14.440 wearing out, you're starting to feel a little bit of age, you see some wrinkles, you think,

01:35:17.740 oh yeah, crap, this is really happening. And you think more and more about it.

01:35:24.120 I'm unusual because I work on this every day. So, I'm always thinking about it. But I think on

01:35:28.900 average, when I talk to people, especially in their 20s and 30s, it's not something that

01:35:32.460 is on their radar because it's going to be something that happens in the distant future that

01:35:36.400 they're not even looking at. Do you have kids? I have three. How old are they? They are 15,

01:35:40.560 13, and 11. How do you explain what you do to them? I was just as brutal to them as my grandma was

01:35:46.520 to me. Yeah. And actually, I saw my oldest daughter go through this, actually all my kids,

01:35:52.220 but it was more dramatic to see it for the first time myself. And I gave a TED Talk about this.

01:35:57.160 When I told her that I was going to die, she burst out crying and for a week couldn't sleep. It was

01:36:02.520 traumatic. And maybe I'm a cruel parent, but I also try not to BS my kids either. But what I saw with

01:36:08.600 her was what even I think most kids do, including myself, was you just can't think about it. It

01:36:13.920 drives you nuts. You won't sleep. So, she forgot about it and we've never talked about it ever

01:36:18.560 again. And if I talk about death, she says, shut up. I don't want to hear about it. And she probably

01:36:23.840 won't think about it in a big way until I'm old or her grandparents are dying.

01:36:28.400 David, this has been a really interesting discussion. I want to be sensitive to your time.

01:36:32.540 I think the listeners of this podcast will be upset to know that we're only going for about,

01:36:37.000 you know, an hour and 40 minutes instead of the usual three or four hours. But

01:36:41.000 where can people find you on social media? And what, how do you like to interact with people

01:36:45.560 that have questions besides adding to the list of the thousands of emails you get a day?

01:36:49.640 Yeah. Emails. I can't reply to everyone, but, um, on social media, I'm now on social media. I find

01:36:56.040 that's a good way to communicate with people. And, uh, so I have a Twitter handle, which is, uh,

01:37:00.820 David A. Sinclair. Uh, and I'm also on LinkedIn, but we're putting together a social media

01:37:06.120 page so we can have a discussion. Uh, it's now, there's so many people interested in this

01:37:10.900 and the information that's locked in my head seems to be on demand. So that's how I want to

01:37:15.660 reach people. This book is coming out, which has me regurgitating and vomiting on the page,

01:37:20.760 everything from what we've learned in my life with my kids all the way through to

01:37:25.440 understanding why we age in this universal hypothesis that we're putting, I'm putting

01:37:31.100 forward. And then the consequences of what happens when we do this. Now it's not a question

01:37:35.820 of if anymore, it's a, when it's going to happen, what happens to planet earth? What

01:37:40.640 happens to humanity? What happens to your family as this starts to come out and some good, some

01:37:46.560 bad, what do you have to get ready for economically, socially? And it's all going to be in there.

01:37:51.120 Well, I really look forward to reading it. You know, I'm in the midst of writing a book as

01:37:53.680 well, and I'm guessing you struggled with the same thing I'm struggling with, which is not just

01:37:59.020 the writing of it. But more importantly, you almost don't want to hand the thing in because

01:38:03.700 you know that the day you hand it in, there's something new that you're going to want to,

01:38:07.940 you're going to know something more. And so as we were talking about it before we started the podcast,

01:38:12.340 like you submit these books a full year before they hit the press. And then of course it basically

01:38:18.220 is a static document until, you know, sure you could have an online updated to information or,

01:38:23.680 but did you struggle with that? Especially, I think, you know, people like us, I think have a little bit

01:38:28.620 of a humility around the half-life of facts. And that sounds like a very, you know, sort of pompous

01:38:35.020 thing for us to say, but I just think we have the luxury of knowing that basically whatever we know

01:38:40.080 today is, you know, quite likely to not be entirely true tomorrow. How did you cope with that? This is

01:38:45.640 now just a very personal question for me as I'm struggling with this phenomenon.

01:38:48.900 Well, yeah, you're a perceptive guy, Peter. So I'm also one of those guys that I'm at the podium

01:38:54.540 about to give a talk to a thousand people and I'm still changing my PowerPoint slides. I'm

01:38:58.040 just obsessed with perfection. And that's one of my downfalls. Same thing with the book. I've been

01:39:04.060 writing it for 10 years and it's needed updating, of course, even to the point that last night I was

01:39:08.840 editing it. I've already turned it into my editor three weeks ago. You're a nightmare to the editor.

01:39:14.580 And she's received probably seven updates already. And I'm going to stop, I promise. But

01:39:20.480 every time I wake up, there's something more really interesting to add that I want to put in

01:39:25.100 there. And, uh, you know, a year from now, I think it's going to be an even better book than it is

01:39:29.260 now, but I'm really happy with everything I've gotten down on the page because when I talk to

01:39:33.540 people, people write to me every day, I'm able to answer questions that I think are burning in a lot

01:39:38.120 of people's minds. Well, David, this has been great. I find it, it's sometimes hard to talk to

01:39:42.000 people you don't know until the day of the podcast, which is the case here. But, uh, I found there's a

01:39:46.280 common language, uh, that we, that we speak or maybe a common passion, not a common language.

01:39:50.320 This is a topic that's new to me, but anyway, this has been really exciting. And I, I can't

01:39:54.240 thank you enough for your time. Well, I appreciate the opportunity and I've really enjoyed it too.

01:39:57.240 Thanks. You can find all of this information and more at peteratiamd.com forward slash podcast.

01:40:04.860 There you'll find the show notes, readings, and links related to this episode. You can also find my

01:40:10.140 blog and the nerd safari at peteratiamd.com. What's a nerd safari you ask? Just click on the link at

01:40:16.220 the top of the site to learn more. Maybe the simplest thing to do is to sign up for my

01:40:19.960 subjectively non lame once a week email, where I'll update you on what I've been up to the most

01:40:24.660 interesting papers I've read and all things related to longevity, science, performance, sleep,

01:40:29.640 et cetera. On social, you can find me on Twitter, Instagram, and Facebook all with the ID peteratiamd,

01:40:36.160 but usually Twitter is the best way to reach me to share your questions and comments.

01:40:39.840 Now for the obligatory disclaimer, this podcast is for general informational purposes only and does

01:40:44.420 not constitute the practice of medicine, nursing, or other professional healthcare services,

01:40:49.260 including the giving of medical advice. And note, no doctor patient relationship is formed.

01:40:54.660 The use of this information and the materials linked to the podcast is at the user's own risk.

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01:41:09.700 condition they have and should seek the assistance of their healthcare professionals for any such

01:41:14.240 conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all

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The Peter Attia Drive - November 05, 2018

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

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