204 - Centenarians, metformin, and longevity | Nir Barzilai, M.D.

1. 0:00 – 0:08

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. [upbeat music]

2. 0:08 – 11:13

   Insights from genetic studies of centenarians and twins

   1. PAPeter Attia0:09

      Hey, Nir. It's great to have you back. I was thinking about this when I was sort of preparing for the podcast today. There's so much I want to cover today that I don't think it's actually going to be possible. I'm pretty sure that we're gonna talk as much as we talk today, and I'm gonna be saying to the team, "All right. Let's talk about when we're gonna have Nir back," because there's really just too many things I want to go through. So anyway, thank you for making time, and, uh, let's just, uh, get right into it.

   2. NBNir Barzilai0:35

      So, thanks Peter. It's, uh, uh, I'm, I'm happy to come back, but it's you who's coming to me every week, and I'm so grateful for what you're doing for this field and for helping all of us catching this field of longevity that's going to come true, [chuckles] very rapidly, I hope.

   3. PAPeter Attia0:53

      I was thinking about the first place I wanted to start, and there's really no good one place to start 'cause we're-- there's just so much I want to talk about. But let's start with centenarians. Uh, you know, you along with, uh, Dr. Perls are probably two of the people who have spent the most time studying this very, very unique subset of the population. So I think everybody knows what a centenarian is, uh, someone who lives to be 100 or more. Um, but there's so much nuance about what it is about these special people. And then, you know, there's sort of the pop culture view of this, which is people love to talk about all of the bad behaviors that centenarians engage in, how much more they smoke, how much less they exercise, all how much whiskey they drink, and all of those things, which are, which are really cute. But when you study them scientifically, and when you study their offspring scientifically, as you've both done, we learn a lot of things, and if my interpretation of the literature is, is at least partially correct, it appears that genes play a significant role. So genes don't seem to play a big role in people living to 70 versus 80, but boy, when you start to talk about living to 90 versus 100, [lips smack] you know, relative to 70 or 80, genes play a pretty big role. So tell me a little bit about what we understand about the role that the parents play in determining the lifespan of offsprings, right? How, how fortunate were these people to pick their parents?

   4. NBNir Barzilai2:22

      Let me just, uh, tackle one of the things you said, that there's no much genetic impact in people between 70 and 80, and, and it, it's true if you compare the lifespan of fathers and sons, okay? Or, or, or mothers and daughters or sons. And, and, and let me tell you why it's problematic. My grandfather got a heart attack when he was 68, and he died. That's my grandfather. My father got a heart attack at 68, and he had triple bypass, and he died at 84. So the correlation between age of death in different cohorts is not much revealing. But let me say it now differently. Let's say it's 20%, okay? Let's say it's 20%. If we understand this 20%, understand it really, we can use that in order to prevent the 80% of the environment.

   5. PAPeter Attia3:25

      Well, maybe another way to think about it, Nir, because that example's a great example, which makes it very difficult over discrete generations to make a comparison. Do we have twin data? Because it seems to me that if you had monozygotic twin data, that would be the gold standard for looking at the discordance and concordance between the role of genes in separate environments, right?

   6. NBNir Barzilai3:48

      So let me tell you the problems with twins. Uh, twins are usually born small for their gestational age. In fact, it's more true that one of the twins is small for their gestational age. Now, I've been s- I've been doing studies with rats from before. When you, uh, ligate the uterine artery and make them small, they get diabetes, which they never get at three months.

   7. PAPeter Attia4:21

      Hmm.

   8. NBNir Barzilai4:21

      We know that twins or that, that people that, that babies that are born small for age develop age-related disease very rapidly. It's called the Barker hypothesis, right? It's observation from Holland in World War II. So, and, and we actually de- determined some of the epigenetic manifestation of what happens epigenetically when you do that. So I don't think twins are the right model unless you understand that and account for that.

   9. PAPeter Attia4:53

      Nir, this is super interesting. Can you tell me a little bit more about that? I actually was not aware of the relationship between low birth weight and the epigenetic imprint of that on reduced lifespan. Uh, and I assume healthspan, or is it just lifespan?

   10. NBNir Barzilai5:08

       It, it's mainly healthspan in humans that we know. You know, we know, uh, you know, first thing that's obvious when, when, uh, when, when you have a, um, a, a small for ges- gestational age twin, okay? There's a catch-up growth of the small baby, and those twins born in the, [chuckles] the same day, in few years, one of them is an obese child, and one is a normal child. And as you know, obesity drives aging very rapidly. So that's one, uh, mechanism. Uh, the imprinting, the changes in imprinting of epigenetic, I would say for now that it's more of a description than a mechanism. There are many genes that are involved, and I'm not aware of a recent paper that says, you know, "This is what happens."

   11. PAPeter Attia6:04

       So let's get back to the broader question, which is- When an individual or when a cohort of individuals lives to 100, and we compare them with a cohort of individuals that lives to 80, what are the types of genes that seem to be offering protection to that group that lives to 100? What is it that the centenarians have in a sort of polygenic sense that the rest of us schmucks don't have?

   12. NBNir Barzilai6:38

       When we went to the centenarians, we had three hypotheses that we had to take care of. One is that it's all the environment. Okay? It happens that they did exactly the right thing, what the doctors tell us to do now. The second-- And it's not true, as you mentioned. It's not true. 60% of the men are smoking and 30% of the women, 50% of them are overweight and obese and all that, and not exercising, and not vegetarians. The second hypothesis is that they have perfect genome. You know, we, we know that we have a lot of genotypes that are putting us at risk for a variety of age-related disease. So maybe one out of 10,000, you know, doesn't have that, and that's why they're flying in so gracefully.

   13. PAPeter Attia7:25

       So to be clear, Nir, uh, part of that hypothesis is the absence of bad genes-

   14. NBNir Barzilai7:31

       Exactly

   15. PAPeter Attia7:31

       ... not necessarily the presence of good genes.

   16. NBNir Barzilai7:33

       Exactly.

   17. PAPeter Attia7:34

       Okay.

   18. NBNir Barzilai7:34

       That only the absence of s- of, uh, of bad genes will allow them just to get without diseases.

   19. PAPeter Attia7:40

       Yes.

   20. NBNir Barzilai7:40

       I'll describe a very simple study that we've done. It was-

   21. PAPeter Attia7:44

       And sorry, what-- I, I took you off your track, but what was the third hypothesis?

   22. NBNir Barzilai7:48

       The third hy- hypothesis is that there are genes that slows their aging.

   23. PAPeter Attia7:52

       Ah, so, so good genes. So it's-

   24. NBNir Barzilai7:53

       Or longevity genes-

   25. PAPeter Attia7:54

       Basically

   26. NBNir Barzilai7:54

       ... we call them.

   27. PAPeter Attia7:55

       Yeah, yeah, yeah. So it's-

   28. NBNir Barzilai7:56

       Right.

   29. PAPeter Attia7:56

       Yep. Okay. Fair enough.

   30. NBNir Barzilai7:57

       So a- as for the second hypothesis that they have what we call the perfect genome, we took our first 44 centenarians and did whole genome sequencing at the time. Huge expense. But we only had those centenarians, okay? We don't have, had a control. But we had a great instrument, we thought. Um, it's called ClinVar. It's an accumulation of all the genes that have shown to be causing diseases. The cl- if you had a ClinVar, Var variant, you're very likely to have a, a disease. So we simply asked, "Do our centenarians have any of those, those variants?"
3. 11:13 – 22:23

   Genes with protective variants that aid longevity

   1. NBNir Barzilai11:13

      but really the majority of the study shows that it's not that. It's not the perfect genome.

   2. PAPeter Attia11:20

      Mm-hmm.

   3. NBNir Barzilai11:20

      It's something else.

   4. PAPeter Attia11:21

      We've very easily eliminated hypothesis one, which is centenarians live to 100 because of what they do, their behaviors, their environment. You now make a very compelling case that it's not number two either. It's not that they lack any disease-driving genes. So it is in fact this third hypothesis. When did you actually demonstrate that? That's, that's obviously a much harder one to demonstrate because you probably have a far smaller library of disease-sparing variants as opposed to disease-causing variants. So when did you start to arrive on what some of those variants were?

   5. NBNir Barzilai12:02

      The story was interesting because remember, we started the study in 1998, and, uh, there were other parts of the studies that I, I, I didn't talk with you about, but one of the things we had is we start to establish the phenotype. And one of the phenotype that came up is high level of HDL cholesterol. Actually very high level of HDL cholesterol that was more obvious in the offspring of our centenarians even than our centenarians. So we have offsprings that have HDL cholesterol 130, 140, you know, f- folds higher than it should be. And, and what we could do when we were, when the methods were poor and we were poor, we were going about genes that are involved in those phenotype. And we actually got a very compelling data on two genotypes that seems to be functional important that are controlling lipid metabolism. One of them was a CETP genotype, and one it was an APOC3 genotypes. And those genotypes increased from about 8 to 9% of the homozygosity in control to, uh, almost 20% in centenarians. And it's not, not only that. Look, when you have people of all ages unrelated, you can look at the trend of the genotypes. If the genotype is killing you, then as, as you go closer to 80, 90 and above, those genotypes will decrease. And if they're, if they are, uh, going up ... And, and by the way, the slope that's going up is a very important statistical tool, then they are very likely to be longevity genotypes. And this is what, what we found, and [laughs] it's so interesting. It's, it was our initial discovery, and drug companies were, uh, at our doorsteps immediately because ... Not because they're interested in aging, but they said, "Just a minute. If we have, if we make a good drug, okay? If the drug is really good, it targets exactly that without side effects, then we have already safety. [laughs] We have safety because those guys for 100 years had, uh, in, in tho- in both cases by the way, the suppression of the expression of those genes, it must be safe, so let's develop the drug."

   6. PAPeter Attia14:42

      And isn't it amazing how big the graveyard is of CETP inhibitors?

   7. NBNir Barzilai14:47

      Yes. And, and [laughs] , and I don't totally understand it. And, uh, I, I listened to one of your podcasts-

   8. PAPeter Attia14:56

      Yeah. Tom, Tom, Tom Dayspring and I have discussed this in great detail. Um, I think a lot of it comes down to not understanding the biology of HDL. I mean, the biology of LDL is relatively straightforward. The biology of HDL, I think it's safe to say we don't understand at all. I mean, that would be putting it mildly. And I think the challenge with the CETP inhibitors is they raised HDL cholesterol. So in one, in one sense they reproduced the phenotype in its most crude sense. But you can think of it very simplistically, I think, which is how do you raise HDL cholesterol? Do you raise it by putting more cholesterol into HDL? Do you raise it by impairing HDL from conducting reverse cholesterol transport and getting rid of cholesterol?

   9. NBNir Barzilai15:41

      Right.

   10. PAPeter Attia15:41

       You could ... Those are two very different approaches to raising HDL. And when you look at the centenarians and examine their phenotype, you don't really know what it is. You would speculate that they have better HDL function. But the reality of it is we have other phenotypes that exist in nature. I'm not sure if you're aware of this, but I've seen a number of, uh, papers that examine people with HDL cholesterol that's very elevated who have very advanced atherosclerosis. And in fact, the elevated level of HDL cholesterol they have suggests impaired HDL function and, uh, impaired reverse cholesterol transport. And so I think that's, that's probably the issue around why a lot of these drugs have failed, and it obviously speaks to the humility with which all of us need to be able to examine these phenotypes. And it's a clever way to go about doing it, right? A, a cl- very clever thing is look for phenotypes that are different and work backwards to find genotypes.

   11. NBNir Barzilai16:41

       R- right. So let, let, let me add, uh, two points to th- this. Absolutely the trade-offs of this pathway are amazing. On one hand, you don't clear cholesterol. On the other hand, you have high HDL. But, uh, it, it ... For me, it's not about the HDL because all the particle size are significantly bigger. So you could say it's all about high dense LDL, [laughs] right? That's the phenotype that we're depicting. Uh, so, so I, I, I think the, the ... I think this part is important. The other thing that was really striking, I, I told you about those, uh, two centenarians with APOE4 genotypes. They both had very high HDL cholesterol, and they were homozygous for CETP. Um, and so it is possible, in fact, the major phenotype for us of the HDL wasn't cardiovascular, it was cognitive function. And so when I'm saying cognitive function, maybe we're talking about physiology, you know, we are thinking of this physiology from a heart perspective, and maybe there's a physiology of that from a brain perspective that we don't totally understand.

   12. PAPeter Attia17:56

       Nir-

   13. NBNir Barzilai17:56

       And by the way, I, I did ask Merck. I said to Merck-

   14. PAPeter Attia18:00

       Yeah

   15. NBNir Barzilai18:00

       ... "Do, do cognitive function, okay?" [laughs] And, and they did, but, but the people they got to the study were between 50 and 70 years old.

   16. PAPeter Attia18:11

       Too young.

   17. NBNir Barzilai18:11

       So there's no results for that.

   18. PAPeter Attia18:13

       Yeah. Nir, did you hap- uh, you might not know this off the top of your head, but even offline I'd love to hear what you learned about the variants of Klotho that those people had, especially the ones who were homozygous for APOE4. Uh, you're probably aware, but there are variants of Klotho that seem to completely abrogate the effect of E4. Meaning you take people with APOE4, either hetero or hetero or homozygous, and if they have this particular variant of Klotho, they, they behave as though they are E3.

   19. NBNir Barzilai18:49

       This is so interesting. So we, we published on Klotho, and, and Klotho was the example of what we call a V-shape or a U-shaped genotype. Klotho basically killed, seemed to kill 50% of our subjects by age 85. [laughs] Okay? The genotype has disappeared by-

   20. PAPeter Attia19:11

       Yes

   21. NBNir Barzilai19:11

       ... age 85. And all of a sudden, after that-

   22. PAPeter Attia19:15

       [laughs] It does the opposite

   23. NBNir Barzilai19:17

       ... at age 100, it was the same, okay? It was the same. Um, and our interpretation was that, you know, those centenarians were born with Klotho, but they were also born with longevity genes, which made the b- the Klotho not significant, okay? But another hypothesis is that the actual Klotho that they had is a Klotho that was protective in another mechanism.

   24. PAPeter Attia19:42

       So what about some of these other genes that have now come to light? So FOXO, for example.

   25. NBNir Barzilai19:49

       Yes.

   26. PAPeter Attia19:49

       Tell us a little bit about FOXO. How did you arrive at that? What was the phenotype that tipped you in that direction, or did you arrive at, uh, FOXO through a pure genetic ex- analysis?

   27. NBNir Barzilai20:00

       Well, well, I didn't come up with FOXO. FOXO came out from Japan and Okinawa. And, and-

   28. PAPeter Attia20:06

       I, I'm using you in the very liberal sense, Nir.

   29. NBNir Barzilai20:09

       Yeah.

   30. PAPeter Attia20:09

       I'm, I'm giving you and the field credit, yes.
4. 22:23 – 35:37

   The relationship between growth hormone and IGF-1

   1. NBNir Barzilai22:23

      very common.

   2. PAPeter Attia22:24

      And sorry, just to double-click on that a little bit, Nir, I think it's worth maybe giving people a little bit of a primer on the relationship between growth hormone and IGF-1. And if you want, we can talk about IGFBP-3.

   3. NBNir Barzilai22:38

      Right. Well, we- okay. So the growth hormone IGF, I, I was trying to slide over that. [laughs]

   4. PAPeter Attia22:43

      No, no, no, no. I, I think this is important to the story, so please expand.

   5. NBNir Barzilai22:47

      I, so I, I, I said, uh, uh, I said growth hormone IGF, and, and, and I'll stand by picking those two, but for growth, there are actually hundreds of genes, okay? [laughs] There are hundreds of genes. Uh, i- if you only, if you only look at, uh, what determines height, there's hundreds of genes-

   6. PAPeter Attia23:06

      Right

   7. NBNir Barzilai23:06

      ... that are determining heights. Um, but, uh, the growth hormone is the growth hormone pathway or the growth hormone signaling pathway that really comes from the pituitary, uh, controlled by the hypothalamus, but comes from the pituitary and makes you grow when you need to grow. [laughs] And it has its own actions, but also it has a specific action of binding to its receptor in liver and releasing the second important growth hormone, which is called IGF-1. It stands for insulin growth factor one. And, and so those are the hormones that we're talking about. The advantage of IGF-1 is that it's measurable. Growth hormone is measurable in provocation and in young people and not much in old people. So IGF is kind of the biomarker for this action. IGF itself is really complicated because there are five, actually, I hear that there are seven binding proteins, and there's a lot of regulation in between. But it's true to say that high I- that, uh, levels of IGF are really, uh, very good biomarkers, even if you don't agree that they're causative for variety of, of health outcomes. Uh, so, so, and, and, and I, and I, and I want to say another thing. You know that in nature, uh- the, the, the dwarfs are doing better as far as longevity. The, the little dogs are doing better. The ponies are looting, are living longer. And in animals, everyone, everyone that no matter how you interfere, you're getting better, uh, longevity. Even the Laron dwarfs that have deletion of the growth hormone receptor, we, we don't know if they live longer, but at least they have less, um, um, age-related diseases like cancer or diabetes.

   8. PAPeter Attia25:09

      But they have more alcoholism and suicide, and as you said, it's not clear that they live any longer. They just seem to be spared of some of the chronic diseases in exchange for others, correct?

   9. NBNir Barzilai25:21

      I'm always describing it that they're still unhappy to be short. They drink, they, they cross the road, and nobody sees them [laughs] when they're drunk, and they're being run over, right? It's not, it's not natural. But let me tell you a, a much more optimistic story about that. We discovered, and when I say we, it's Gil Atzmon, who was a, a fellow and then a faculty with us. He's still involved, he's now, uh, in Israel. But he, uh, we, we looked at all the pathway, and we discovered that our centenarians have deletion of exome three in the growth hormone receptor. And Gil came to me and showed also the trend, okay? And as I said, the trend is important. So the homozygosity was 3% in our population and 12% in centenarians. Okay? And I said, "Gil, what's their, what's their IGF-1 level?"

   10. PAPeter Attia26:21

       Hmm.

   11. NBNir Barzilai26:21

       And he showed me. It's significantly lower. I said, "Terrific. What was their maximal height?" And he said, "That's the problem," and he shows me. They're significantly taller than the rest of the people, two, three inches taller.

   12. PAPeter Attia26:36

       Wait. The centena- the people that had 10%, the, the people that were heteroz- uh, homozygous were taller than the controls?

   13. NBNir Barzilai26:46

       Yes. Significantly taller.

   14. PAPeter Attia26:47

       And, and gi-

   15. NBNir Barzilai26:48

       Two, three

   16. PAPeter Attia26:48

       And, and two to three inches is not subtle. What was the relative Z-score difference between them in IGF?

   17. NBNir Barzilai26:54

       I don't remember. I'll get you the reference. Eh, the... It was like a 20%-

   18. PAPeter Attia26:59

       Okay

   19. NBNir Barzilai26:59

       ... decrease.

   20. PAPeter Attia27:00

       And what about their IGF binding proteins?

   21. NBNir Barzilai27:02

       There's nothing special there.

   22. PAPeter Attia27:04

       No, no-

   23. NBNir Barzilai27:04

       There's nothing special

   24. PAPeter Attia27:05

       ... no major difference.

   25. NBNir Barzilai27:06

       No.

   26. PAPeter Attia27:06

       Okay.

   27. NBNir Barzilai27:06

       But, but you, you're, you're on the right track. So, so I said to Gil, "What do you do with genetics? First of all, you need to do validation. You know, you're not ac- the paper is not accepted without validation." [laughs] I said, "Do validation." So Gil got three other studies, eh, from all over the world, actually, and all of them were showing the same thing. The oldest old had mu- had a folds difference in their growth hormone, eh, in this deletion, which was very compelling on its own. But still, why do they have lower IGF-1? So we went to-

   28. PAPeter Attia27:47

       Sorry, just to be clear, they had lower growth hormone. They should have lower IGF-1.

   29. NBNir Barzilai27:51

       Uh, no.

   30. PAPeter Attia27:51

       You're saying, but they were taller.
5. 35:37 – 44:29

   Use of growth hormone as a longevity tool

   1. PAPeter Attia35:37

      I want to ask you another question about growth hormone. It's a, it's a hormone that, that I've prescribed to patients when they're healing from injuries. So I've seen pretty good literature, um, that says, you know, you're having ... You know, you tear a bicep, you have surgery to repair it, growth hormone for eight weeks fosters rehabilitation, uh, better than if you did nothing. So, so that's the very narrow window in which I've prescribed growth hormone, is typically around the healing from orthopedic injuries. A couple things I'll say. Um, every patient I've prescribed it to, and there hasn't been many, maybe half a dozen over the last 10 years, they all say, "I've never felt better." Which then helps me understand why this cottage industry of doctors out there exists who run longevity clinics prescribing growth hormone. Um, I've drawn a hard line in the sand with my patients that I don't believe in the literature that would suggest that prescribing growth hormone is a pro-longevity tool. But if I'm being brutally honest, and I tell them this as well I can't tell you that it's killing you either, right? Like I, I, I can come up with, uh, theoretical arguments why prescribing growth hormone is going to make you feel better but is going to shorten your life. But I don't really see any data one way or the other. And even when you look at extreme cases, which are basically athletes who use... You know, growth hormone is the most abused drug in all of sports because we don't have a test for it. Um, you'd think that the, the mortu- the, the morgue of athletes would be much bigger. So, uh, what, what is your view on exogenous growth hormone, uh, as, as a, as a not necessarily a pro-longevity tool, but as an agent that clearly helps healthspan but might be not as destructive to lifespan as I believe it could be?

   2. NBNir Barzilai37:50

      I think you're absolutely right. Look, we're talking about chronic, you know, chronic environment, okay? And that has nothing to do with the fact that there could be indication for growth hormone. You mentioned one. Uh, there is a paper about growth hormone after strokes, okay?

   3. PAPeter Attia38:11

      Mm.

   4. NBNir Barzilai38:11

      We were actually interested in growth hormone in the brain. Uh, there are more examples like that, so I don't think those are mutually exclusive.

   5. PAPeter Attia38:20

      Right. And, and, and I've of- I've often wondered, by the way, I haven't seen the literature. If you know of it, I'd love to see it. Would growth hormone be protective in stages of early cognitive decline? Um, but anyway, l- putting that aside for a moment, what about this idea of the 50-year-old who goes to the longevity clinic and they're being given low doses of growth hormone every single day? Typically, it's somewhere between .4 and 1 milligram daily.

   6. NBNir Barzilai38:50

      I'm not going to answer you about the dose, but I'm, I'm going to make the, the thing that I think is very important, and it's getting us back to this antagonistic pleiotropy, and it's relevant to TAME and metformin. It is possible that things that you're doing are good for you when you're young-

   7. PAPeter Attia39:08

      Mm

   8. NBNir Barzilai39:08

      ... and against you when you're old, right? So when people are asking me on any of those, uh, geroprotectors, gerotherapeutics, vitamins, um, w- what, what, when do we start them, okay? The answer is, I really, I really don't know. I think, I think you shouldn't get senolytics before you're 70 [laughs] or 80 years old. I think probably metformin, although we start the study at 65, most of the studies so far that showed really large effect of metformin are people who were recruited above the age of 50. So I think it's 50. So I, I don't know to tell you for a singular patient who chronologically, chronological age is 50, and biological age [laughs] I don't know what it is. You can determine it better. What, what do I tell them? I don't, I don't really know based on literature, based on clinical trials.

   9. PAPeter Attia40:07

      So last question on this, Nir. Based on the number of people that are taking growth hormone out there, and I, I don't know how you would quantify this, but, uh, um, presumably it's not rocket science to figure it out. But let's just say that there are hundreds of thousands of people in the United States alone who are taking growth hormone daily as part of a geroprotective regimen. Um, why aren't they all dying prematurely?

   10. NBNir Barzilai40:35

       Well, we don't know that.

   11. PAPeter Attia40:36

       Uh, assuming that they're older. Well, well, but, but wouldn't we-

   12. NBNir Barzilai40:38

       Yeah. We don't know that

   13. PAPeter Attia40:39

       ... w- well, that's true we don't know it, but wouldn't we see a signal of it?

   14. NBNir Barzilai40:43

       I think not, because the people who are taking growth hormone are probably taking also metformin and exercising and doing other things.

   15. PAPeter Attia40:50

       Yeah. So fair, fair point. There's too many confounders.

   16. NBNir Barzilai40:53

       Yeah.

   17. PAPeter Attia40:54

       Yeah. It... I mean, again, I, my view is still, and probably will remain for the foreseeable future, that it is not a great geroprotective agent, um, because I do have these concerns. But I re- this is an example of something where I really wish we had data.

   18. NBNir Barzilai41:10

       I want to tell you another thing that also is, is a gray zone for me. Most of the negative effect of growth hormone IGF in humans we see in females, not in males. A- actually-

   19. PAPeter Attia41:24

       Mm

   20. NBNir Barzilai41:24

       ... in, in animals too, in animals too. So I'll, I'll describe two things. Um, when we look at our centenarians, that, that's done by Sophia Milman, who's running the longevity studies now, and she measured IGF-1, uh, in, in all our, our, our patients. And she looked at our centenarian, um, uh, and our centenarian... So they're already 100 years old, okay?

   21. PAPeter Attia41:50

       Yeah. Hmm.

   22. NBNir Barzilai41:51

       Um, its IGF-1 level predicts their longevity. And remember, centenarians are likely to die, 30% of them are going to die each year. [laughs] So, uh, so those with the lowest half of IGF-1 lived twice as long as those with the highest level of IGF-1.

   23. PAPeter Attia42:13

       And that's females only or both sexes?

   24. NBNir Barzilai42:16

       That's females only.

   25. PAPeter Attia42:18

       Okay.

   26. NBNir Barzilai42:19

       Males, we don't have... You know, the ratio of female/male centenarians around the world is there are 85 females for every 15 men. We have better results because most, a lot of the female centenarians have never got married. You know, nuns [laughs] and other things.

   27. PAPeter Attia42:38

       Yeah.

   28. NBNir Barzilai42:38

       Going back to your problem with your kids, right?

   29. PAPeter Attia42:40

       [laughs]

   30. NBNir Barzilai42:41

       Um, but we need people with offspring. Our study's based on, on-
6. 44:29 – 50:04

   Longevity genotypes: the role of APOE e2, Lp(a), Klotho, and CETP

   1. PAPeter Attia44:29

      So, uh, let's continue down this path of double-clicking on the centenarians and their bucket three genes. That is to say, their good genes rather than their absence of bad genes. Are centenarians more likely to have APOE e2 than non-centenarians, which is the protective variant of that gene?

   2. NBNir Barzilai44:49

      That's the most common general longevity genotypes that we have. And APOE e2, either an allele frequency or the homozygosity of APOE e2 is the most validated longevity genotype that we have.

   3. PAPeter Attia45:07

      Okay.

   4. NBNir Barzilai45:08

      First of all, it's the truth if you measure, [laughs] if you measure genotype. It was hard for me to accept it, and it's only recently that I convinced myself. And the reason is that APOE e2, uh, genotype is also associated with diseases too. It's not so simple. Uh, and, and I thought for a long time that, uh, what, what, what we have actually, we have a problem. It, it is, it's ascertain- ascertainment bias, that to our study, we don't get people with APOE e4 because they're demented and they're not getting to our study or to any study, so that we increase [laughs] the proportion of other genotypes. But what convinced me is that it should have been equally distributed between APOE e2 and APOE e3, and it's not. It's really an APOE e2, uh, phenomenon. And so I'm, um, although I don't understand totally the mechanism, I, I'm convinced myself that there is something true in, in this, and that APOE e2 by mechanism that I don't totally get is a longevity genotype.

   5. PAPeter Attia46:32

      Presumably, this is backtracking a little bit on something you said, I'm guessing centenarians have less Lp (a) genotype?

   6. NBNir Barzilai46:40

      Lp (a) genotype is really interesting. It... Remember we talked about how we are losing Klotho with age.

   7. PAPeter Attia46:47

      Yes. Until we regain it. Yeah.

   8. NBNir Barzilai46:49

      Right. We are losing LP- l- Lp- a- Lp (a) and regaining that. Now, what, what we've done is, uh, with compu- computational biologies, assistant biologies, we interacted every one of those bad genotypes with a longevity genotype. And actually, the people with high, uh, the centenarians with high Lp (a) all have CTP. They are homozygous for the CTP genotype.

   9. PAPeter Attia47:20

      So they have some protection to counter it. And by the way, they might be getting some benefit from Lp (a) . There may be something that Lp (a) ... 'Cause you have to think, Lp (a) is common, right? It's about 10% of the population. So 10% of the population overexpresses this thing. 10% of the population has an elevated phenotype for Lp (a) . And it's true that evolution wasn't selecting against atherosclerosis, but there are arguments to be made that Lp (a) could have played a role in managing infections, for example, that this could have been a manner in which we fought oxidative stress. So it, it begs to, you know, at least question the idea, do the centenarians who have it get some benefit from it while having genes that offset some of its negatives?

   10. NBNir Barzilai48:14

       Yeah. But, but you have to explain on, on a population base how all of a sudden at age 85, you switch and this genotype becomes protective, [laughs] you know? Yes, you're selecting a lot-

   11. PAPeter Attia48:30

       Yeah. Is it... Do you... Is that, is that really necessary, or is it just a denominator problem, where at 85 you've really eliminated so much of the population that you're now concentrating the people who were never harmed from it? So in those people, they've never been harmed by the gene, and now they are disproportionately rising to the surface because the population around them has, has withered away so quickly.

   12. NBNir Barzilai48:55

       Right. So those are the two explanations, either what you just said or that, uh, they're protected by other longevity gene, and it makes it irrelevant what this Lp (a) gene does.

   13. PAPeter Attia49:06

       Although I don't think those are mutually exclusive. I think the former is an explanation... Or pardon me, I think that the latter is an explanation for the former. It's the amplifier of it, right? It's what lets them get there in the first place, is that, like using CETP as an example, they happen to have a CETP, uh, you know, mutation or a CETP variant that offers remarkable protection against atherosclerosis, of which an interesting but kind of irrelevant phenotype is high HDL cholesterol, and that's offsetting the damage of their Lp (a) . And then eventually at some point when everybody else has died because of their Lp (a) , they're still standing, and they might even be getting some benefit from Lp (a) that everybody gets, but it's ... in other people's cases, it's so dwarfed by the damage of Lp (a) . Again, total hypothesis or speculation, but that ... It's a, it's a, it's a, it's plausible, right?

7. 50:04 – 56:30

   The correlation between high TSH and longevity

   1. NBNir Barzilai50:04

      It is.

   2. PAPeter Attia50:04

      Okay. Tell me about TSHr. I've never found... I've never understood that one fully.

   3. NBNir Barzilai50:09

      So the thyroid story is interesting because we found a correlation between high TSH and longevity. And wh- when I say correlation-

   4. PAPeter Attia50:23

      A- as an endocrinologist, Nir, maybe give people the, the two-minute story on what TSH-

   5. NBNir Barzilai50:28

      Sure

   6. PAPeter Attia50:28

      ... is and how it functions.

   7. NBNir Barzilai50:30

      You know, I, I promise to some of my, you know, my, my sisters are listening to, and I promise I'm going to be so simple you won't need to call me again and ask me, "What did you mean?" And now I'm falling into-

   8. PAPeter Attia50:43

      I know. I, I-

   9. NBNir Barzilai50:43

      ... into [laughs]

   10. PAPeter Attia50:44

       ... it's ... I'm doing a bad job of this. I'm sorry.

   11. NBNir Barzilai50:47

       You're, you're absolutely right. So, uh, T- TSH is really the c- the, your control of thyroid function in the sense that if you become hypothyroid, then this TSH, this hormone from the pituitary, will increase in order to get those thyroid hormones to be normal again. And they might fail, and then you'll be hypothyroid, but there's a, an, an effort to get those thyroid out of your glands. Okay, so that's TSH.

   12. PAPeter Attia51:19

       So when we see a high TSH in a normal person, we s- ask the first question: Is their thyroid gland not making enough T4 and/or converting enough of that T4 to the active hormone T3? Which is the feedback loop that tells the pituitary how much TSH to make. So, so what you're saying is we see a higher amount of TSH in long-lived people, suggesting either a s-

   13. NBNir Barzilai51:46

       And their children. And their children.

   14. PAPeter Attia51:49

       Yeah. So s- so- so maybe suggesting a subclinical or potentially a clinical degree of low thyroid function or hypothyroidism. Is that a f- a safe summary?

   15. NBNir Barzilai51:59

       Correct. And, and I'll tell you, our discovery has, uh, led to several papers and to change in the thyroid, uh, association recommendation of what to do with old people. You know, the endocrinologists or the thyroidologists are looking for business. So, uh, once TSH was above 10, and then they said, "You know, it might be subclinical at seven," and we went to five, and now if you're three and, and symptomatic [laughs] , which all we ... we are always because we're tired. [laughs] Eh, eh, you know? So that's where the science came. And we pointed out to the fact w- we did it in our study, then we, uh, did it in a, in a national study, and we said, "You know, you have to leave those older people because maybe this is a physiological, uh, way for them, uh, to be well [laughs] and we don't need to increase their-"

   16. PAPeter Attia52:56

       And tell, tell me how high you're seeing the TSH. What is the difference when you age match them between centenarians and-

   17. NBNir Barzilai53:04

       It's like five to eight. Okay?

   18. PAPeter Attia53:05

       Wow.

   19. NBNir Barzilai53:05

       So normal is, like, until 5:00.

   20. PAPeter Attia53:08

       Yeah.

   21. NBNir Barzilai53:08

       Okay? And there's-

   22. PAPeter Attia53:08

       Or even 4.2 on s- on our lab.

   23. NBNir Barzilai53:11

       Well-

   24. PAPeter Attia53:11

       Yeah

   25. NBNir Barzilai53:11

       ... oh, yeah. And ch- and changing baseline. So-

   26. PAPeter Attia53:15

       Yeah, yeah

   27. NBNir Barzilai53:15

       ... there... And, and look, their, their thyroid hormones themself are normal, okay? It's really only the TSH.

   28. PAPeter Attia53:23

       Yeah. So normal free T4, normal free T3, but they walk around with a TSH of five to eight.

   29. NBNir Barzilai53:29

       Right.

   30. PAPeter Attia53:30

       Now, here's the kicker, and this is where I'm hoping the offspring can help us. Do you know what their TSH would've been in their 30s and 40s? Would they have also had a TSH of five, six, or seven?
8. 56:30 – 1:04:38

   Important pathways for longevity

   1. NBNir Barzilai56:30

      straight away.

   2. PAPeter Attia56:31

      Has anyone done Mendelian randomization on any of these clusters of genes and looked for... 'Cause we haven't really established a causal relationship here, have we, in, in, in these genes?

   3. NBNir Barzilai56:45

      No. Eh, we... So we're do- we're trying to develop... You, you know, by the way, Peter, you j- you just said another word that nobody knows, right? Mendelian randomization. [laughs]

   4. PAPeter Attia56:57

      Okay. Sorry. Do you want to, do you want to, do you want to explain a Mendelian randomization?

   5. NBNir Barzilai57:01

      W- well, well, I, I would just... I, I don't want to go long into that, but because we have so much genetic data, and by the way, genetic data d- is disappointing because, because they're not so predictive most of them. You can find lots of genes for, for obesity, and you'll be lean, for lipids, and you'll have normal lipids, right? But we have lots of genotype, and we try to integrate those genotypes in order to assess how much they are increasing the risk of us of getting a disease, and usually it's not by much. [laughs] Eh, what we're trying to do, we're trying to have an instrument that will do Mendelian randomization to longevity, okay? So we can see what's your genotype that fits longevity more than anything else. That's in, uh, evolution now. Uh, but otherwise, look, I, I have to tell you, um, uh, y- the reason, the reason this is not good is very simple. We're doing something so stupid in genetics. We do lots of genotypes, and we take each one of these genotype, and we ask, "Is this associated with obesity or, or diabetes or not?" And we found many things, and in order to, by the way, to make them statistic significance without increasing their power much, we just need to get 100,000 more people in the study, okay? But we're not built with one genotype at a time. We're built with numerous genotypes. And what we've started doing lately, and that's our latest Nature paper, was to say, "Just a minute. We're looking at the difference between centenarians and, and people without longevity, and we're going to take all those rare genotypes, less than 1%," okay? Because, because to be centenarians, one out of 10,000, so we need to find rare genotypes. And, and by the way, there are 80,000 rare genotypes just in our population. And then we take those genotype and put them in pathways, and look at the enrichment of the pathways rather with a specific genotype. And then we get really important information. And by the way, the important information that we got in the study in, in a summary statement is that the genetics of longevity in humans is exactly what we learn from animals. It the insulin signaling pathway, it's the mTOR signaling pathway, it's the MAP kinase si- si- uh, pathway. It's exactly the same genotype that distinct centenarians and other people. And I think this is really very important for us because people have blamed us that our animal models are not, you know, animals models are not good. Yeah, they're not good for diabetes. They're not good for Alzheimer. [laughs] They're not good for other thing. But for aging, actually, our models are really good because it's so conserving evolution. All our animals, their skin, their hair, their skeletal, their, they get cancers, they get diseases. So this is the same, but it's really the same pathways, and the, the first that comes out is the IGF insulin signaling pathway.

   6. PAPeter Attia1:00:33

      Yeah, which as you said, goes all the way back to C. elegans, right? One of the simplest organisms we can study. Um, all of this really points towards the importance of polygenic risk scores. And, you know, when I talk to someone like Richard Isaacson, who is so focused on understanding Alzheimer's disease, um, and, and Richard and I work so closely on this 'cause it's obviously one of the most important things we think about in our practice. I think of the evolution that we have had in our thinking over the past five years. In fact, we're working on a paper now that's looking at this polygenic assessment of, of risk in dementia. You brought up earlier APOE4. Obviously, any listener to this podcast is no stranger to it. We've spent so much time talking about it. One of the things that I would say is- 10 years ago, we thought that being homozygous for E4, so being in that roughly 1% of the population that has two copies of the E4 gene, that was a death sentence. As you noted earlier, that's, that's a person who's going to have Alzheimer's disease by 60, and they're going to be dead by 70. Uh, it's -- there's no way out of that. Their, their risk is deemed at about 20-fold that of the general population. And then five years ago, we, we looked at the data again and said, "You know, it's still awful, but it's not 20 times the risk of the E3, E3. It's 12 times the risk." And then we look at the data again two years ago, and, you know, it's still bad, but it's, it's -- maybe it's five times the risk. And now we are looking at patients who have E4, E4, and they don't have ... Not only do they not have Alzheimer's disease, more importantly, they don't have any of the early signs of it based on really, really advanced cognitive testing, that, that, that shows very subtle signs decades before. And we're starting to look at other genes that are abrogating some of the effects of this. And so now the focus has been less at looking at APOE4 and making a determination, and it's looking at E4 plus TOMM40 plus mitochondrial haplotype plus Klotho plus a whole bunch of genes and taking a polygenic approach to risk. Um, it seems to me that this would be the most logical way to do the same thing with respect to longevity, right? And, I mean, I think this is true with cardiovascular disease. Lp (a) is part of the story, but, you know, it's not the whole story, right?

   7. NBNir Barzilai1:03:23

      Absolutely. No, uh, absolutely you're right. I really, I really don't have ... Uh, you, you described the problem and the, the solution absolutely right. I, I would just tell you that in, um, in, in looking for those l- longevity genes that we just published, 12 of them are associated -- We're funded [chuckles] for that, but they're associated with resiliency, uh, to Alzheimer's. And I think that, um, not enough of the genetics is explaining not only the genetics but the resiliency, uh, or, or looking at the genetics of resiliency-

   8. PAPeter Attia1:04:03

      Mm

   9. NBNir Barzilai1:04:03

      ... which is what we're calling longevity in this case, but the resiliency to diseases, which happens to diseases that you get in young age, too. Not every genotype causes this disease. So I, I think you're right.

   10. PAPeter Attia1:04:15

       Would you put FOXO in that category as kind of a general resilience gene that is less disease specific and more broadly protective?

   11. NBNir Barzilai1:04:25

       Uh, yeah. I, I actually count the FOXO3A as, uh, in the insulin signaling pathway-

   12. PAPeter Attia1:04:31

       You do. Okay

   13. NBNir Barzilai1:04:31

       ... in the insulin IGF signaling pathway. Uh, w- we, we, we [chuckles] , we can argue about it, but that's, that's

9. 1:04:38 – 1:14:56

   Insights from centenarian studies, nature vs. nurture, and more

   1. NBNir Barzilai1:04:38

      my bucket.

   2. PAPeter Attia1:04:39

      What, what are the genes that you would put in the general resilience pathway, not necessarily disease specific or, uh, or, or system specific as in the endocrine system?

   3. NBNir Barzilai1:04:51

      We have 750 centenarians in our study. Now, they're all Ashkenazi Jews, and they're Ashkenazi Jews not because re-

   4. PAPeter Attia1:04:59

      Why is that?

   5. NBNir Barzilai1:05:00

      Not because religious is important, but because Ashkenazi Jews are, A, genetically homogeneous. They went through a bottleneck-

   6. PAPeter Attia1:05:10

      Oh

   7. NBNir Barzilai1:05:11

      ... uh, a, an expansion and then a bottleneck, and, and very few survived, and they lived in, uh, isolation and intermarriage, and their genetic pool is much more homogeneous. In fact, we can measure it. It's gene- it's, it's, um, it's genotype specific, but we need between 20 and 50 less times, between 20 and 50 times less people in order to get the same data. So-

   8. PAPeter Attia1:05:42

      Yeah

   9. NBNir Barzilai1:05:42

      ... think abo- about it at not 750, but few thousands. But it's still not enough to find all longevity genes. And one of the things that we realized is that there are 50 ways to live your life, or there are 50 ways probably to get to longevity. Uh, it's possible there's only one person who's 150 years old somewhere, and if we knew his genotype [chuckles] , he will solve the problem for anyone. And the genotypes we are discovering are things like that. We, we have 20 genotypes in centenarians and one in control, okay? But those for geneticists who are dealing with 400,000 people in study, they say, "Well, in 750 centenarians, this can change any minute." Okay? So what can we do? Well, what we can do is look at the function of those genotypes. And you know our friend Yuxin Su. That's-

   10. PAPeter Attia1:06:41

       Yes

   11. NBNir Barzilai1:06:41

       ... that's what she's doing with our studies. She takes those discoveries and either takes the lymphoblast of our patient, or she does construct and express those genes in cells and see how resilient they are to, to injury. So there are a lot of genes, and the -- I think the biggest news for me now is that, uh, American Federation of Aging Research has, has gotten contribution from, uh, a single guy, $2.8 million, uh, to recruit 10,000 centenarians across the United States and their offspring and control. And I think that this will give us such an acceleration of understanding longevity and such an acceleration of getting drugs that have, uh, probably are likely, uh, to work, and also things that we don't know yet. Like, who knows? S- some of the things that we discovered are in pathways that we're not They're, they're not, uh, i- i- in our longevity lexicons

   12. PAPeter Attia1:07:53

       Nir, that's interesting. Only $2.8 million is required to recruit 10,000 centenarians plus their offsprings plus appropriate controls?

   13. NBNir Barzilai1:08:03

       Well, well, let's see. [laughs] Let's see where we get.

   14. PAPeter Attia1:08:06

       That seems like a very high ROI for that donor.

   15. NBNir Barzilai1:08:10

       We hired two, uh, companies who have approaches, and actually there's a preliminary data, a preliminary study to see what's the best way to approach these people, because it's all going to be basically web-based, so we need their children and grandchildren, and we're going to send them a swab so that they can do it with help, and we'll get the swab at least as the first-

   16. PAPeter Attia1:08:38

       Yeah

   17. NBNir Barzilai1:08:38

       ... uh, on the first pass, and be able to rapidly, uh, do the, the genetics and post it, by the way, just immediately post it so people can start looking at it and making sense of the data.

   18. PAPeter Attia1:08:53

       And you're gonna do whole genome sequence or exome?

   19. NBNir Barzilai1:08:56

       Both. We're going to do mainly exome sequencing, and maybe switch as the whole genome sequencing price comes down, which it does rapidly.

   20. PAPeter Attia1:09:06

       What's the current price of whole exome?

   21. NBNir Barzilai1:09:10

       Eh, I don't re- I don't totally remember that. The, the reason I don't remember is that our... We were, uh... O- Our genotypes was done by, eh, Regeneron [laughs] and they paid for that. [laughs]

   22. PAPeter Attia1:09:23

       Yeah.

   23. NBNir Barzilai1:09:23

       So I don't, I don't remember how much it is now.

   24. PAPeter Attia1:09:26

       So let's talk about a thought experiment. You, you mentioned something earlier, which is what made me think of this, right? So you said there's somebody out there maybe who's gonna be 150 years old, one person that will concentrate all of these genes in perfection, and they'll get to be 150, and if we could look at that person's genes, we might have an answer. I would push back and say, "Or not," right? It might be that we're discounting the stochastic nature of this, and even if you found that 150-year-old person, and even if you identified which genes played a role, the likelihood that you'll identify which environmental factors turned on those genes or amplified some and attenuated others seems very low. So this... it begs this thought experiment, right? If you took 10,000 identical people with whatever program you have of the perfect genotype. So this is 10,000 people that have as many of the good genes as possible and as... and have none of the bad genes. We put them in a time capsule, and we let them live their lives. But now we randomize them to, I'm making this up, but three groups, right? One group is the base case. Go and live a normal life. One group is the do everything bad that you possibly can. So I want you to start smoking when you're 15. I want you drinking three drinks a day. Never exercise. Uh, you're only allowed to eat at McDonald's. Away you go. And then the, the third group becomes the do everything right. You know, we're gonna exercise, we're gonna... We, we, you know, we do the opposite. Give me your prediction of how long each of those three groups lives.

   25. NBNir Barzilai1:11:16

       [laughs] So Peter, I was trying to do things simple, and you complicate me again.

   26. PAPeter Attia1:11:22

       [laughs]

   27. NBNir Barzilai1:11:22

       And I'm taking back. First of all, when I said 150, human... I, I, I think the maximal of, uh, of human lifespan as a specie for us is about 115 years, even if we argue, even if there's one 122 somewhere, [laughs] okay? And, and so, so, uh... And, and, and so I'm, I'm not sure. So this... And, and we die before the age of 80. So we're t- we're talking about 35 years that we can realize. It's a lot of years. We should realize that. But I think aging will improve by other methods and mechanism that can break eventually this-

   28. PAPeter Attia1:12:02

       Yep

   29. NBNir Barzilai1:12:02

       ... 115 years and maybe get us to 150. The experiment, the experiment [laughs] that the, the, the... You know, when people are asking me, "When will we live 150?" I, I said, "Oh, in 150 years," because even if we start the experiment now, it'll take, [laughs] take 150 years to get there, right? We wouldn't know. Eh, so, so of course this experiment, I, I, I don't know what, what, what-

   30. PAPeter Attia1:12:30

       Uh, I'll tell you what I'm getting at in the experiment. I wanna understand how in the perfect genetic, uh, makeup, how much can environment hurt or better what is already a genetic lottery?
10. 1:14:56 – 1:20:56

    The contraction of morbidity that comes with improved healthspan

    1. PAPeter Attia1:14:56

       So Thomas Perls has written quite a bit about this idea of dividing centenarians into buckets. Uh, I think we have the escapers, the delayers, and the survivors. Are, are you familiar with that terminology?

    2. NBNir Barzilai1:15:09

       Yeah. Yeah. Of, of course. But you know, uh, I, I'll tell you two things about it. First of all, Tom Perls and Paola Sebastiani are, uh-- did terrific job, and we're collaborating a lot, and, and, uh, and, and they've been great. And I, I don't hear, uh, Tom talking about it because this is the point. Uh, some people -- a-average life expectancy is 80, right? [chuckles] Some people are going to be 81, 82, 83. It's not that 100 years old is any special. You're picking at one time people who actually aged before or will age later. And what we've done together to kind of overcome that is -- and, and that's very important thing. We looked at our data in both studies and harmonized them, and asked what is the healthspan of, of centenarians versus, by the way, cohort that lives now. It's not their cohort. Their cohort died [chuckles] before.

    3. PAPeter Attia1:16:13

       Yes. That's right.

    4. NBNir Barzilai1:16:13

       And the answer is that it's not only that they live long, they get variety of age-related disease 20, 30 years later. Um, the, the people, the peop- their, our control group by age between 60 and 80 accumulate lots of diseases. At 80, only 10% of them don't have a disease. In our centenarians, at after the age of 100, 30% don't have a disease and are not treated with anything. But, but there's a 20, 30 years of healthspan. This is not really the important part. The important part that it -- the end of their life, they get sick and die. Some of them don't wake up in the morning, okay? But they have such a compression of morbidity, they are sick for months at the end of their life, unlike us that are sick for years at the end of our lives. And I think this is, uh, this is really the boundaries and, and -- so first of all, there is an example, uh, there's example of humans that can live healthy and long and have contraction of morbidity, and for me, it really says it's not that they didn't get older. Of course they got older, but at some point, uh, they had great life, they have great health, and at some point they're checking out much quicker [chuckles] without diseases at the end of their lives. And this is what we're trying to imitate.

    5. PAPeter Attia1:17:42

       I completely agree, although I'll throw a wrinkle into it, Nir, which is could it be that, um, you know, the average person has their first heart attack at 70, languishes with congestive heart failure for five years, and dies at 75. The centenarian has their first heart attack at 101 and, you know, they die six months later. Could it be that the reason that the first guy languished for five years is he really technically had more resilience given that he was 25 years younger? And, um, if so, you can now do a very grim thought experiment, which is we could easily replicate the healthspan -- uh, we could easily replicate the contraction of morbidity in non-centenarians with a rule that says the moment you get a disease, you get a pillow over the head, right? The moment you get your first heart attack, we're not gonna cath you, we're gonna kill you, right? [chuckles] I mean, again, thought experiment, please, let's be clear.

    6. NBNir Barzilai1:18:42

       [laughs]

    7. PAPeter Attia1:18:42

       But you would, you would immediately square everybody's longevity curve for the most part. You would contract that period of morbidity to replicate that of the centenarians, but you would dramatically truncate lifespan as well now. And now you would even widen the gap between the non-centenarian and the centenarian. So in my mind, it's been -- it's very difficult to disentangle the, the, the objective for someone like me, [lips smack] which is I do want to lengthen lifespan. I do want to delay the onset of chronic disease, and I want to compress the period of morbidity, not by having you die quicker, but by having you live better longer, if that makes sense.

    8. NBNir Barzilai1:19:28

       Absolutely, uh, uh, makes sense, Peter. And, uh, y- of course, your, your point is very important, but it's like, it's like the, uh, podcast last week on the, on the COVID. You had, uh, scientists and the advocates, right? That's how you call them?

    9. PAPeter Attia1:19:46

       Yes.

    10. NBNir Barzilai1:19:46

        The scientists and advocates.

    11. PAPeter Attia1:19:47

        Which by the way, our, our mutual friend, David Allison, that's -- I-- he was really the one who I think made me first realize we need to s- talk about these two things totally separately, right?

    12. NBNir Barzilai1:19:57

        Absolutely true. And, and, and what you did, you really stopped me from being advocate because you're absolutely right. I think that the reason that centenarians are dying so fast is because they're already frail. They are aging, and so they are less resilient. But on the other hand, without diseases, I mean, some of them are working as hedge fund managers until 107.

    13. PAPeter Attia1:20:25

        Yeah.

    14. NBNir Barzilai1:20:25

        Some of them are painting. As long as they have no pain and mobility, their life is good. Not like when they were 20, but their life is good. So I, I totally agree, but a- as an advocate, I wanted to hide that, uh, Peter. I didn't want to. [laughs] But, but, but you're right. Why, why they're dying. Uh, but you know what? I think it's still important for people, and I think this concept is probably true. If you prevent aging and age-related disease, you're going to compress morbidity

11. 1:20:56 – 1:26:14

    Defining healthspan

    1. NBNir Barzilai1:20:56

       too.

    2. PAPeter Attia1:20:57

       One of the biggest challenges I have with healthspan is I don't think that, that we have great ways of describing this in medicine. I, I think there's several issues with it. The first is, um, our definitions, I think, are not wonderful, right? We talk about freedom from disability and disease, but that doesn't really capture it. I, I can tell you a lot of people who don't qualify for having disability or disease, but their healthspan is still poor. And by the way, this gets... This completely excludes a very important element of healthspan, which I think is emotional health. So let's put that aside because it's not particularly age dependent, and it's, it's outside of the purview of what we're talking about today. But if you just limit it to physical and cognitive, in fact, if you just limit it to physical, right? You can, you can have people who can still carry on activities of daily living, but one of them has a VO2 max of 50 mils per minute per kg, and the other is 30 mils per minute per kg. By the way, neither of those people would ever qualify as disabled, because whether you're at 30 or 50 in VO2 max, you can still do any activity of daily living. But one of those people can clearly get more out of life, right? You can take someone who can, you know, uh, has the grip strength to hang onto a bar for 30 seconds versus hang onto a bar for two minutes. Both of those people will see no immediate difference in their day-to-day activities, but one person can do far more should they choose to. Y- you know, one person can sit on the floor for half an hour and play with kids and feel nothing. Another person, their back will ache for the rest of the day. Neither of those people are debilitated or disabled, and therefore health... by healthspan, you know, by traditional healthspan metrics, they're both equal. But they're nowhere near equal. And so that's problem one that I have with the way we as a community talk about healthspan. The second thing is nothing that you or I learned in our medical training even remotely prepares us for how to help people be truly stronger late in life. I... It just, it just wasn't part of our training, right? Like, th- there's nothing about that. So, um, it, it, uh, I guess my point here is it's hard for me to really interpret the data and get at something I'm very interested in, which is do centenarians truly have better healthspan, or are they just dying later? And, you know, for the most part, they have this period of compressed morbidity, so it looks like they have better healthspan. But do we really know that... I mean, I think they do, uh, based on the literature. Like, I think a 90-year-old who will become a centenarian is functioning more like a 70-year-old who will not. Um, but it's still very difficult to quantify. I don't think we have great metrics here. Do, do you disagree with me?

    3. NBNir Barzilai1:24:02

       No. I, I don't think that healthspan is well defined. Um, definitely. But there... So there, so there are two comments that I will make. Um, for the NIH, right? Back to TAME. Uh, for them, what is aging is if we can prevent diseases.

    4. PAPeter Attia1:24:26

       Mm.

    5. NBNir Barzilai1:24:26

       That's their measurements, right? Uh, wh- which, which, uh, which, which, which is not satisfying, not to geriatrician and not to physician, okay? But that's how you get drug approved. For the economist, there are two issues. One is, uh, w- what we're counting as the, the cost of medical co- the medical cost of the last two years of life.

    6. PAPeter Attia1:24:53

       Yeah.

    7. NBNir Barzilai1:24:53

       By the way, in centenarians, the CDC has data. In centenarians, the, the last two years life are third the cost in 100 years old than in when you die in 70, okay?

    8. PAPeter Attia1:25:05

       Oh, that is fascinating.

    9. NBNir Barzilai1:25:06

       Yeah.

    10. PAPeter Attia1:25:06

        I mean, to me, that is something that speaks to what we're really aspiring to. And, and, and actually, that statistic capture, captures much more about the quality of a person's life.

    11. NBNir Barzilai1:25:16

        Right. But, but the... David, uh, uh, sorry, Andrew Scott had-

    12. PAPeter Attia1:25:23

        Yeah

    13. NBNir Barzilai1:25:23

        ... a paper in Nature. I think I sent you guys.

    14. PAPeter Attia1:25:25

        I, I read it. Yes.

    15. NBNir Barzilai1:25:26

        Right?

    16. PAPeter Attia1:25:26

        You sent it to me, yep.

    17. NBNir Barzilai1:25:27

        And he describes an economical term that's called the value. And by the way, it's very hard. If you want to know more about this paper, we should talk. It's, it... I had to sit with him in order to understand what he was saying. But basically saying, "Hey, if you increase the healthspan of someone, it's not only medical cost, because this guy is going to travel, and spend money traveling, and buy gadgets, and buy houses for his kids, you know?"

    18. PAPeter Attia1:25:57

        Yeah.

    19. NBNir Barzilai1:25:57

        It's going to be the value of the person life is going to be increased, and all of a sudden-

    20. PAPeter Attia1:26:02

        And some of those people, by the way, are going to still work.

    21. NBNir Barzilai1:26:04

        Oh, exact- ri- right.

    22. PAPeter Attia1:26:06

        Yeah.

    23. NBNir Barzilai1:26:06

        And so-

    24. PAPeter Attia1:26:06

        They're not just playing golf.

    25. NBNir Barzilai1:26:08

        Right.

    26. PAPeter Attia1:26:08

        Yeah.

    27. NBNir Barzilai1:26:08

        So the, the economical value is, is, is, is huge. So you can, uh, do it economically.

12. 1:26:14 – 1:33:32

    Unique perspectives and positive attitudes of centenarians

    1. NBNir Barzilai1:26:14

       And the third thing [laughs] I wanted to tell you is this story About the, the real story about this 102-year-old guy that I met, and I'm sitting and talking with him, and he's the nicest guy I've ever met. Okay? He's so considerate. He's so ... He's thinking about life in such a nice way. Um, uh, nothing bad about his daughter-in-law, [laughs] right?

    2. PAPeter Attia1:26:40

       Mm-hmm.

    3. NBNir Barzilai1:26:41

       And, and so I'm spending time with him. I'm going out of the room, and I'm bumping into his son, who's 80 years old, right? [laughs]

    4. PAPeter Attia1:26:48

       Yeah.

    5. NBNir Barzilai1:26:49

       And I'm telling this 80 years old what I'm telling you. [laughs] "You know, your father is just the nicest guy I've ever met." So he looks in my eyes and says, "You should have be- seen this son of a bitch when he was my age."

    6. PAPeter Attia1:27:01

       [laughs]

    7. NBNir Barzilai1:27:01

       "He was a terrible, terrible person." [laughs]

    8. PAPeter Attia1:27:04

       [laughs]

    9. NBNir Barzilai1:27:04

       Okay? So then I realize, and, and you'll see why it's connected to what you just told me. Then I realized that because we wrote paper about the personality of centenarians, and you have to be positive and stuff like that, but apparently he became positive only when he was 100 years old-

    10. PAPeter Attia1:27:21

        [laughs]

    11. NBNir Barzilai1:27:22

        ... not when he was 80 years old.

    12. PAPeter Attia1:27:23

        [laughs]

    13. NBNir Barzilai1:27:24

        And, and then, then you see papers, like in University of Pennsylvania, they took two groups of people, young and old people, and show them bad slides, you know, cockroaches in pizza, and good slides, like islands in the Caribbean, and they ask them to repeat what they've seen. And the young people knew, remembered a lot from both bad and good. The old people remember less, but mainly the good things, okay? So I'm waiting for this part in my physiology-

    14. PAPeter Attia1:27:57

        Yeah

    15. NBNir Barzilai1:27:57

        ... [laughs] that I remember-

    16. PAPeter Attia1:27:58

        [laughs]

    17. NBNir Barzilai1:27:59

        ... only the good thing. But what I'm, what I'm telling you is that think of the complexity now, right? Because your brain age, you also retired, you lost your spouse, you move from independence or you move to somewhere else. You moved several times. [laughs] You get to 100 years old. So, uh, so apparently there's changes not only in your environment, but in your physiology, where life can still s- look good to you. [laughs] Is this wrong?

    18. PAPeter Attia1:28:29

        Actually, that's such an interesting point, Nir. I know you mentioned already that a number of the centenarians in your cohort were not married. Um, what fraction were married?

    19. NBNir Barzilai1:28:39

        No. My, my centenarians have to have offspring.

    20. PAPeter Attia1:28:43

        Oh, okay. So all of them were at least had a, at least had a partner.

    21. NBNir Barzilai1:28:46

        At least married for a while. [laughs]

    22. PAPeter Attia1:28:48

        Okay. And then what fraction of them have lost their spouse?

    23. NBNir Barzilai1:28:52

        A lot of them. Uh, a, a lot of them. M- most of them. Most of them. We do have-

    24. PAPeter Attia1:28:57

        And, and, sorry, one other question, Nir. What fraction of them have also lost children?

    25. NBNir Barzilai1:29:01

        Uh, also a lot of them. [laughs]

    26. PAPeter Attia1:29:04

        Y- you know, this gets to something very interesting. Um, someone asked me once at a dinner party, uh, "If you could wave a magic wand, how long would you want to live?" And I said, "Not that long, truthfully, because unless I could wave that magic wand for the people around me, [clicks tongue] I think it would be an awful life." Like, could you imagine if I waved a wand and said, "Nir, you have immortality. And not just immortality. I'm gonna let you preserve your quality of life today. So as smart and healthy and able as you are now, I'm gonna let you do this for the next 500 years"? I would view that as an awful curse.

    27. NBNir Barzilai1:29:41

        [laughs]

    28. PAPeter Attia1:29:41

        Think of, you know, you'd have to watch your wife die. You'd have to watch your children die, your grandchildren die. Sure, you could remarry and do it all over again, but then they're going to die. So, so, you know, that's a, that's a silly thought experiment, but I also think it gets to something I've never really considered with respect to actual centenarians, which is the price of being a centenarian is giving up and losing most of your friends.

    29. NBNir Barzilai1:30:08

        Right. And, and-

    30. PAPeter Attia1:30:09

        And how many funerals do you go to?
13. 1:33:32 – 1:38:48

    Lessons to take away from centenarians

    1. PAPeter Attia1:33:32

       So the flip side of everything I just said is I've never really met somebody who's dying at the age of 75, and that's a phenotype I've seen an awful lot in my training, who didn't wish to have another year of life, it could-- if it could be had at a higher quality. Which now brings this whole discussion full circle. 9,999 out of 10,000 of us will not live to 100, directionally speaking. But if we want to live an extra year or five years, what is the most important lesson we can take away from the centenarian that we can actually do something about?

    2. NBNir Barzilai1:34:15

       I want to start with, uh, what you mentioned before, w- one of my darkest day in research when Jay Leno in The Tonight Show said, "You know, there's those people at Einstein, and they said the secret for lo- longevity is don't exercise, don't, uh, [chuckles] you know, be obese, don't do." And you know what he said? "If you die, you don't care anyhow," right? And, and that was the wrong lesson from the centenarian study. If you, [chuckles] if you're going to be centenarian, maybe it's not important. By the way, it could be important for centenarians, right? I mean, this woman-

    3. PAPeter Attia1:34:52

       Yep

    4. NBNir Barzilai1:34:52

       ... that I have that smoked for 90 years and died at 110, I just wonder, wouldn't she be the next Madame Calment [chuckles] without smoking? Um, so the, the lesson for most of us is still, right, e- exercise and nutrition, whatever it means to everyone, and everything else that you give, right? That's, that's the lesson, and it's not the lesson from centenarians. The lesson from centenarians is that there are, uh, longevity genes that could be translated into drugs, and I believe that they could afford, uh, years of healthspan, however we want to define that. Um, and, and, and, and, and that's really what I'm trying to, to say that is, uh, not an emotional part, but a, but a, a clinical part.

    5. PAPeter Attia1:35:45

       Would you agree with my takeaway from this cohort, which is the s- 'cause the single most important lesson I glean from everything we've said, and, and in addition to lots that we haven't said that you and I have talked about elsewhere or that my own work has, you know, pointed me to based on my study of this problem, their superpower is simply delaying the onset of bad things. Like, bad things just happen to them 20 to 25 years later. So it's not that they don't get heart attacks. They just don't get them when they're 65. It's not that they don't get cancer. They just don't get it when they're 60. It's not that they don't even get dementia. They just don't get it when they're 75. And when-- The last time I looked at the distribution of death for centenarians, it was shockingly similar to that of non-centenarians with a couple of differences. They tended to have a little more atherosclerosis, a little more heart attacks, a little less Alzheimer's disease, and I think a little bit more pneumonia. But directionally, they had the same actuarial table of death as people dying in their 80s. It was just a time shift.

    6. NBNir Barzilai1:37:00

       In fact, I, [chuckles] I reviewed the paper from Germany where they looked at pathology, okay? It's a pathological.

    7. PAPeter Attia1:37:09

       Yeah.

    8. NBNir Barzilai1:37:09

       They looked at, uh, thousand centenarians that over the years died in their homes.

    9. PAPeter Attia1:37:15

       Hmm.

    10. NBNir Barzilai1:37:16

        And they're right, because in the hospitals, we kill them in other ways, [chuckles] right?

    11. PAPeter Attia1:37:20

        Yeah.

    12. NBNir Barzilai1:37:20

        So died in their homes versus thousand, uh, I'm not sure about the numbers, of, of other people that died at their homes. And basically, the paper was funny because the, the title was like, "There's nothing special about the centenarians. They're dying for the same thing." But [laughs] 30 years later, okay, they missed the point. It was like a negative study. But you're right. You're right. They're kind of dying from the same thing much later, much later on. So it's... You, you can look at it about what you said, the resiliency that got them there, the resiliency for anything that detect them to get them there, or the fact that their aging was slow. [chuckles]

    13. PAPeter Attia1:38:07

        And so what's the takeaway for us? To me, the takeaway for us as physicians or people who want to have an extra five years of life or 10 years of life, even if we can't have an extra 20, is nothing matters more than prevention of chronic disease And by the way, you don't get to prevent it once you have your heart attack. Secondary prevention is not prevention.

    14. NBNir Barzilai1:38:29

        Right.

    15. PAPeter Attia1:38:29

        We're, we're talking ultra, ultra, ultra primary prevention. And if healthspan is something that the medical system hasn't been poised to teach, ultra primary prevention is also something that we haven't really been prepared to teach. So,

14. 1:38:48 – 1:50:07

    Metformin overview: history, studies, and potential for gero-protection

    1. PAPeter Attia1:38:48

       um, okay. Let's pivot to another topic that we visited last time, but I think so much has happened in the interim, which is metformin. I probably get an equal number of questions, Nir, about the following three things. So, uh, the frequency of this would be several times a week. A patient or a friend is asking me about metformin, rapamycin, or some combination of NR, NAD, or NMN. Somehow those three things seem to rise to the level of everybody's curiosity when it comes to gero-protection. Um, let's talk a little bit about all of them, but let's focus on metformin. So for folks coming to this who have heard of metformin, because I think at this point many people have, but don't know much more than that, can you give a brief background of what metformin is, how long it's been around, what it's historically been used for, and, and then of course we'll talk a little bit more about why we're gonna talk about it.

    2. NBNir Barzilai1:39:58

       Oh, so boring. I, I also get those questions. [laughs]

    3. PAPeter Attia1:40:01

       What's the distribution, by the way? What, what, what do you mostly get asked about while we're on that subject?

    4. NBNir Barzilai1:40:06

       The most common question is, "I hear you're doing a metformin study. Can I volunteer?"

    5. PAPeter Attia1:40:12

       [laughs]

    6. NBNir Barzilai1:40:13

       "Can I be... Can you assure me I'm not on placebo?" [laughs]

    7. PAPeter Attia1:40:16

       Yeah. [laughs] I was just about to say, "Are you sure you want to volunteer?"

    8. NBNir Barzilai1:40:19

       [laughs]

    9. PAPeter Attia1:40:19

       Okay. Yeah.

    10. NBNir Barzilai1:40:20

        So, [laughs] so by the way, I'll tell you something really interesting. Um, I, I'm not... Because I'm leading this study, I, I'm not pushing metformin, okay? Again, the difference between advocate and scientist, okay? I, I'm, I'm doing this study, okay? I believe in that, [laughs] but I'm doing this study, so I cannot tell you that it's good. So I'm not going to prescribe to anyone. Even to my friends, I'm not going to prescribe. But I have a method that works 100% of the time. There are two papers that I wrote, one I think in 2016 about metformin and TAME and the clinical data, and one in 2020 about actually the mechanisms of action that was in cell... Both of them were in cell metabolism, but the mechanism of action, the fact that metformin actually hits all the hallmarks of aging, [laughs] miraculously. I'll, I'll explain it later. And I'm saying to those people, "Send it to your doctors," and say, uh, "Ask the doctor, 'What do you think about me taking metformin?'" And there are one of two things that always happen. One could be that the doctors reads the paper and said, "Oh, shit, I should be on metformin myself. Of course I'll give metformin." Or the other is the doctor said, "You know, I'm busy, but, you know, metformin is a safe drug and stuff. Let me just give them metformin," and that's the end of the... And that's 100% success. [laughs] Everybody can get metformin. Uh, now I know that I'll get emails asking for those papers. I'll put it in a [laughs] in a box.

    11. PAPeter Attia1:42:02

        We'll, we will, we will absolutely link to those papers in the show notes, yeah.

    12. NBNir Barzilai1:42:05

        But I, I think what people don't realize is that metformin is an extract of the French lilac. So some people say it's nutraceutical. It i- it is modified, and it is a drug.

    13. PAPeter Attia1:42:17

        The three best drugs in the world are nutraceuticals: rapamycin, statins, metformin. There you go.

    14. NBNir Barzilai1:42:23

        Right. But you need prescriptions.

    15. PAPeter Attia1:42:25

        Yeah.

    16. NBNir Barzilai1:42:25

        Uh, but, but, but also, look, one of the medi- mo- modification was phenformin. It's an early form of metformin that kind of was, uh-

    17. PAPeter Attia1:42:36

        A little too potent. [laughs]

    18. NBNir Barzilai1:42:38

        ... too potent on the mitochondria, and caused, caused a trouble, but we're over that for 80 years. But metformin was used initially to treat, uh, the flu and malaria and inflammatory diseases, and it's at that time that people noticed that people with type 2 diabetes have lower glucose when they take metfor- when they took metformin. So the whole metformin moved to diabetes.

    19. PAPeter Attia1:43:07

        And that was about the 1950s or '60s, right?

    20. NBNir Barzilai1:43:09

        Right.

    21. PAPeter Attia1:43:10

        Yeah.

    22. NBNir Barzilai1:43:10

        1950s and '60s. Uh, uh, interestingly, in the United States it was approved only in 1993-

    23. PAPeter Attia1:43:19

        Hmm

    24. NBNir Barzilai1:43:19

        ... or, or so. I came, uh, as a fellow to Ralph DeFronzo at Yale, and my, my mission was to describe the metfor- the mechanisms of action of metformin in, in humans. You know, I did insulin clamps, and I'm the first to describe that metformin decreased hepatic glucose production rather than increase insulin sensitivity in the periphery. It's serendipitous. I didn't think about it as aging. I came to Ralph DeFronzo, and I did aging in another way to [laughs] insulin-resistant and aging, but not, not metformin. Uh, but the point is there are billions, billions years of use. Remember, every patient takes it for years, and there are people on metformin who are 90 years old. I actually know them.

    25. PAPeter Attia1:44:09

        Yeah.

    26. NBNir Barzilai1:44:09

        Uh, so, so people, people, uh, there are billions use of year, and I cannot think of a drug with better safety record. And if there are any side effects to metformin, they happen usually in the first week of use, and, and that's even if you didn't take them the way you should, which is small doses with food. And when I say with food, after the first bite, [laughs] when your, when your stomach is full. And, and then usually there is no side effects, but 3 to 5% of people, and maybe more with elderly, have diarrhea that doesn't stop, and we basically stop metformin in those people, uh, whether, whe- whether there's... Well, uh, yeah, to stop diarrhea. [laughs] Uh, we, we don't know if it, i- if there is something. But by the way, in TAME study, we're going to follow those pa- uh, those patients that were sensitive to metformin and see if there is something unique about them. That's one of the things we hope to do.

    27. PAPeter Attia1:45:11

        Hmm. Well, we'll, we're definitely gonna talk about TAME. So, so let's pick up the story 10 years ago. All of a sudden, people start to notice things. People start to notice that diabetics who take metformin when compared to diabetics who don't take metformin do better. And when I say do better, I mean they have lower mortality from all causes and lower mortality from very specific causes. And if you look at it, um, in some extremes, if you compare the patients taking metformin to the patients taking insulin, the difference could be 50, 80% difference in mortality. Um, is that a fair assessment of where curiosity began to peak, that this wasn't just a good diabetes drug, but it might have some protection a- against aging?

    28. NBNir Barzilai1:46:08

        Yes. A- absolutely. When, when one drug... We, we should just know that's, that's the base of a, of a, of, of, of gero-therapeutic. It, it has to be a drug that has effect beyond its disease, whether it's on other diseases, whether it's on overall mortality, not a, a disease-specific mortality. That's when you have to think this, this drug is a gero-therapeutics, and that's exactly where metformin fell. And I, I would just add one thing. Look, some, some of those studies are association studies, but some of the studies were clinical studies. The Diabetes Prevention Program, the DPP, is an NIH-funded study where metformin was one arm. There was also a, an arm of lifestyle changes. Uh, both of them were preventing diabetes in about 30%. Uh, and by the way, the study was stopped early because it was significant after four years, okay? Although the study was funded for five years. The UKPDS and many study-

    29. PAPeter Attia1:47:20

        Now, I do, I do wanna talk about that study, Nir, uh, and some of this, of course, you and I have already talked about, but I think it's just good for people to be able to hear our, our discussions on this. One of the challenges of these studies, and I think this is frankly true of every single study I've looked at for metformin, is when you squint your eye at the study, there's always a problem. And in the case of the DPP, the problem is the patients in the metformin arm could easily fall out of that arm and therefore not be counted. So if they're, if they progressed to a need for medication beyond metformin, or if they couldn't tolerate metformin, or if they were not compliant with metformin, they were no longer counted. And so when you compare, and this is true not just of the DPP, but of course when you compare the, um, metformin patients to the other patients who are taking other diabetes drugs, you always have this potential confounder, which is you are disproportionately selecting the healthiest people, which are the people who, A, can be compliant with medications, which might say much more about their behaviors outside of medications, whose diabetes is maybe just mild enough that it's always kept at bay with metformin, never requiring other medications, including insulin. So am I correct in saying we don't to date, and TAME we will talk about in a moment, but we don't to date have any clean example of a study that demonstrate, uh, metformin's gero-protection?

    30. NBNir Barzilai1:48:55

        Look, you're right.
15. 1:50:07 – 1:59:29

    The TAME trial (Targeting Aging with Metformin)

    1. NBNir Barzilai1:50:07

       Um, you know, in other words, it, they didn't have diabetes, so it's not that they switched to other medication. So there, there are lots of examples li- like that, but you are right. Uh, if, if this was compelling, if this was compelling on its own- Um, you could argue we wouldn't have to have TAME even, right? Uh, and really TAME is not about, it's not that we, there were not studies for each one of the diseases, but there was no studies to be agnostic of the diseases. Okay? We, we don't care. Look, we're targeting aging. We don't care what disease you have, and we don't care which disease you're going to take-

    2. PAPeter Attia1:50:56

       Yeah

    3. NBNir Barzilai1:50:56

       ... to get. If you're obese and your mother has diabetes, you're going to get diabetic next. We have to think in geroscience that aging is going to drive your next disease.

    4. PAPeter Attia1:51:07

       Yeah, yeah.

    5. NBNir Barzilai1:51:07

       And therefore, it's the cluster that is going to, to count, and we're counting the clusters. By the way, we had this discussion about mortality. Uh, mortality, you get a point for mortality [laughs] just like you get a point for a disease, and the important thing of the cluster is that we cannot do TAME study. Im- imagine we do a TAME study, and in two years cardiovascular disease comes up as, as significant, and the FDA-

    6. PAPeter Attia1:51:43

       As in significant reduction of cardiovascular-

    7. NBNir Barzilai1:51:46

       Right

    8. PAPeter Attia1:51:46

       ... mortality, yeah.

    9. NBNir Barzilai1:51:46

       And the FDA will say, "Hey, we have to stop this study because we cannot go with the study when with placebo," right? And it will ruin it for us. So the whole, the whole problem of the statistics of TAME is to make sure that we're not getting to any significant in any disease, just to trends, and that the only way to stop... By the way, the one, one way to stop the study is if mortality is significant. That will trigger a stoppage of the study. Otherwise, what will stop the study is the integral approach of-

    10. PAPeter Attia1:52:23

        Right

    11. NBNir Barzilai1:52:23

        ... the cluster disease.

    12. PAPeter Attia1:52:24

        So, so statistically you just can't... Your biggest mistake here is overpowering the study for mortality, and therefore appropriately powering the study for subs- subsets of mortality.

    13. NBNir Barzilai1:52:37

        Right.

    14. PAPeter Attia1:52:37

        Yes? Is that, is that a safe assess-

    15. NBNir Barzilai1:52:39

        Well, subs- subsets of mortality, you mean diseases.

    16. PAPeter Attia1:52:41

        Disease specific-

    17. NBNir Barzilai1:52:42

        Yeah

    18. PAPeter Attia1:52:42

        ... mortality is what I mean. Yes. Well, let, let's talk a little bit about TAME. This is something you and I spoke about, God, two years ago. Um, so this is a study that is going to look at people who do not have type 2 diabetes?

    19. NBNir Barzilai1:52:59

        Right. It's an exclusion criteria.

    20. PAPeter Attia1:53:01

        And they are over the age of 65?

    21. NBNir Barzilai1:53:04

        65 to 79.

    22. PAPeter Attia1:53:05

        Okay. So 65 to 79, no diabet- no type 2 diabetes. Any other exclusion criteria?

    23. NBNir Barzilai1:53:12

        Yes, but it's not important for our discussion. So if you have cancer in the last year, okay, things like that.

    24. PAPeter Attia1:53:19

        Yeah, yeah, yeah.

    25. NBNir Barzilai1:53:19

        You know?

    26. PAPeter Attia1:53:19

        Okay.

    27. NBNir Barzilai1:53:19

        Very specific. If you had heart attack in the last three mon- you know?

    28. PAPeter Attia1:53:23

        But again, these people are gonna be taking statins, they're gonna be taking medication for blood pressure. Some of them will be overweight, some of them will be normal weight, presumably.

    29. NBNir Barzilai1:53:32

        Right. W- the, the point, the point here, though, is that, look, we don't want to recruit a bunch of centenarians to be-

    30. PAPeter Attia1:53:39

        Yeah
16. 1:59:29 – 2:07:27

    The challenge of studying metformin in animals models

    1. NBNir Barzilai1:59:29

       [laughs]

    2. PAPeter Attia1:59:30

       Now earlier you spoke about how animal models are not really great for Alzheimer's disease, cancer, and cardiovascular disease, which, uh, I think any listener of this podcast is well aware of those limitations. But you note that, look, animal models are pretty darn good for aging given how conserved it is, and yet one of the challenges metformin has had is in animal models. Um, now Rich Miller was on this podcast a while ago. We spoke about the ITP, where metformin was successful in the ITP when combined with rapamycin, but alone was not. Um, again, I think the ITP is a very rigorous, uh, type of experiment. I know you've probably thought a lot about this. What explanation do you think exists for why metformin did not succeed in isolation in the ITP study? Which I'll just take for a moment to explain to people the ITP. If you haven't listened to that podcast with Rich Miller, you should go and do so. We'll link to the appropriate section here. But these are studies that are conducted using a particularly good model of mouse that is kind of less troubled by the usual, uh, difficulties, uh, mice studies have. It's also done independently at three separate laboratories concurrently. So I think those would be some of the, uh... A- and, and then the final thing is they look at all-cause mortality. So, um, tell us why you think that, that, the, that we could be misled by the ITP.

    3. NBNir Barzilai2:01:05

       Let me make a, a big picture, uh, statement now. It is possible that some of the drugs that had mild effect in ITP will have much bigger effect in humans-

    4. PAPeter Attia2:01:19

       And vice versa

    5. NBNir Barzilai2:01:19

       ... and the other. You know-

    6. PAPeter Attia2:01:20

       Yeah

    7. NBNir Barzilai2:01:20

       ... maybe rapamycin is going to be not as effective in humans as it is in animals, okay? We just have to accept that [laughs] we, we're all... Rich Miller can, uh, Rich Miller, if it's not in, in true in mice, it's not true. [laughs] But it's not-

    8. PAPeter Attia2:01:37

       Well, which I don't think Rich says, by the way.

    9. NBNir Barzilai2:01:39

       No, no. I know.

    10. PAPeter Attia2:01:39

        I, I, I've never heard Rich say that. I, I think, you know, Rich is-

    11. NBNir Barzilai2:01:42

        No, no, I'm-

    12. PAPeter Attia2:01:42

        ... just says, "This is what it is in this model." Yeah.

    13. NBNir Barzilai2:01:44

        I'm kidding. He, he start, he started saying that initially, and he, he took it back of course. I, I think one of the problems with animals is the dosage that they're using, okay? The dosage in animal were u- were used, uh, i- if you look back, as 0.1% in a solution to 1%. 1% is deadly, okay? Because listen, metformin, after all, is a weak cyanide, okay? [laughs] It binds to, uh, to a complex in the mitochondria. It probably affects complex one and also complex three. It's not totally clear, but if you give too much, uh, there is a trade-off. So you have to give right. And I think that the, uh, studies in animals E- e- except, by the way, mice. It's not true for, you know, nematodes, and there are several other fish. There are several other animals that live longer and healthier with metformin. But I don't think that 0.1% is really the appropriate dose, and also I don't think-

    14. PAPeter Attia2:02:53

        What do you think is the... So you think-

    15. NBNir Barzilai2:02:55

        I don't know. [laughs] I don't know. There's no dose response.

    16. PAPeter Attia2:02:57

        But you, so you're saying 1% is clearly problematic.

    17. NBNir Barzilai2:03:01

        Yeah. I think 0.2% maybe will be d- will be better if we wanna optimize that.

    18. PAPeter Attia2:03:07

        Because this is the other, the other... There's a paper that gets a lot of attention. I think it's 2013, the Rafael de Cabo paper-

    19. NBNir Barzilai2:03:13

        Right

    20. PAPeter Attia2:03:13

        ... which gets touted as, "Oh, look at metformin." I, I, I gotta be honest with you. I- if you look at that paper, I don't know how the editors let the title of that paper slide with the actual data. I, I mean, let's, let's call a spade a spade.

    21. NBNir Barzilai2:03:28

        [laughs]

    22. PAPeter Attia2:03:28

        You had two groups of mice, one of them getting 0.1%, one of them getting 1%. The group getting 1% were assassinated, to your point. I mean, these animals were killed by the toxicity-

    23. NBNir Barzilai2:03:42

        Right

    24. PAPeter Attia2:03:42

        ... of metformin. The group getting one pers- 0.1% lived a staggering 0.4... or four, 4% longer.

    25. NBNir Barzilai2:03:51

        Right. Right.

    26. PAPeter Attia2:03:52

        I mean, the, it was basically a null trial that was touted as the definitive animal study for why metformin works. It was kind of like-

    27. NBNir Barzilai2:04:01

        Right

    28. PAPeter Attia2:04:01

        ... it's, it's like an Onion article when you dissociate the title from the actual data.

    29. NBNir Barzilai2:04:06

        Right. I, look, the average, when I took and make a table with all the longevity data, the, the, the effect of metformin across studies were between 7 and 10%, not a huge effect.

    30. PAPeter Attia2:04:19

        Well, that's, that's pretty good. 7 to 10% in animal studies, if it's consistent, would be pretty good.
17. 2:07:27 – 2:14:54

    How data from the TAME trial could provide insights into biomarkers of aging and facilitate a future study on proteomics

    1. PAPeter Attia2:07:27

       Will TAME allow you, on its current budget, which I think is 50 million, is the bare bones budget. [laughs] Sounds crazy, right?

    2. NBNir Barzilai2:07:37

       Right.

    3. PAPeter Attia2:07:37

       On the $50 million budget, how much will you be able to look at mitochondrial function and omics that are associated with other-

    4. NBNir Barzilai2:07:49

       Yeah

    5. PAPeter Attia2:07:50

       ... you know, deeper markers that go beyond the hard outcomes that-

    6. NBNir Barzilai2:07:53

       Yeah

    7. PAPeter Attia2:07:53

       ... feed into your primary outcome?

    8. NBNir Barzilai2:07:55

       Well, the NIA, the NIA has, eh, given us a grant that is now delayed to do basically the biomarker part of TAME. So even with this 50 million, and with the NIH money, w- and with AFAR, we're going to store lots of plasma DNA, um, um, and, and other resources like cells and other things that will then be open for omic studies, and we wrote a beautiful grant about that. In part, it was, eh, preliminary data from our centenarian studies on proteomics.

    9. PAPeter Attia2:08:39

       By the way, I just realized I used the word omics. Do you wanna tell people [laughs] what the full suite of omics means, uh, so that people listening to this know what we're talking about?

    10. NBNir Barzilai2:08:48

        Yeah. And, and it's really, it's really back to something that I said before when I talk about If I said my study, I mean our study. And when I talk about teams, I'm talking about teams that have computational capacity. I, I talked about Zhengdong Deng that ding, that did a lot of my study, about Yuxin Su that is doing functional genetics. I'm talking about, uh, Sophia Millman who are doing other studies. We're a really bet, big team. And the reason to have a big team is very simple. We have... You know, I was... All I knew when I started my training was insulin. I knew insulin. I know insulin signaling. [laughs] Now, I'm los- losing it at billions of dataset that are under my team. If you think of genetics only, whole exome sequencing for 3,000 people, or my proteomics, which is, uh, 5,000 protein for 1,000 people. It's all, uh, big data, and in order to do something th- with the big data, you have to ask the right questions because what we notice-

    11. PAPeter Attia2:09:55

        Yeah. Otherwise, you can find anything. Yeah

    12. NBNir Barzilai2:09:57

        ... you are... [laughs] The, the first paper that came out of the UK Biobank for aging said that longevity is all about assortative mating. Okay? Now, now, yes, if, if you, if you're a smoker, you may marry a smoker. If you're obese, you will marry obese. If you're poor, you will marry poor. It all's a, all has consequence of health. But we knew that without the UK Ba- [laughs] Biobank. We knew that obesity is a risk for diabetes without the [laughs] Biobank too. So you have to ask the right, uh, question, and it's really only asking the right question that you get the answers. So the question that is very important for us... There are two question. What are the biomarkers for aging? You know? How can we do a test at 50 years old and know if we're 40 or we're 60? If we're 40, we skip colonoscopy, [laughs] okay? If, if we're 60, we have to do something about it already. And the second part, and it's more important for me, is biomarkers that change with treatment. We wanna make sure that we, when we try all those treatments, that we have in two, three months an answer, are they likely to work? And then maybe we can get to phase two and phase three trial, but we need something more immediate, and that's what TAME will try to provide. Now, in my study, we did this proteomic, and it was really incredible for, for many reason, and I'll give you a tidbit. But we have those, uh, thousand people and 5,000 proteins, and we asked what changed between 65, the age of 65 and 95. This didn't include our centenarians.

    13. PAPeter Attia2:11:47

        Mm. Right.

    14. NBNir Barzilai2:11:48

        And the a- [laughs] the answer is a lot of proteins are changing, but this is, I think, the most important part. A lot of the proteins that we're capturing... By the way, number one is IGF-related proteins. Okay? Number one that comes up, even in the proteomic, not only in the genomics. But then a lot of what you see is breakdown. You see breakdown of collagen. You see degranulation of the thrombocytes. You see breakdown of extracellular [laughs] metrics. Lots of things like that. And at first I said, "Okay, that doesn't tell me anything," until I thought, "You know, whatever it i- w- no matter what we do, we have to stop the breakdown." You know? This is probably going to be the best marker for any treatment. You just stop the breakdown.

    15. PAPeter Attia2:12:38

        It's funny. That seems so obvious, doesn't it? I mean, like, it's... When you're talking about collagen breakdown and you think about... This gets back to what we talked about earlier. You wanna really know what healthspan is? It's not some nonsense definition that the NIA gives us about freedom from disability and disease. Who cares? Who cares if you have cancer, but you're living in remission with it, and you can climb three flights of stairs with a bag of groceries in your hands? That's living, right? It's... Yeah. When your collagen is breaking down, your knees aren't working. I mean, this is the essence of what we're talking about.

    16. NBNir Barzilai2:13:17

        Right. Right.

    17. PAPeter Attia2:13:18

        It, it, it... I, I think the pr- I think the proteomic story is very interesting, and I hope it gets its appropriate funding.

    18. NBNir Barzilai2:13:26

        And by the way, the other part of proteomic, there are few other aspects that are important. The, the proteomics that are, the proteins that are 10 to the minus 80 significance.

    19. PAPeter Attia2:13:37

        Mm-hmm.

    20. NBNir Barzilai2:13:38

        The two top ones. When you express them in animal, they live long. In other words, they're protective protein. Uh, when you get those proteins, you don't know which are protective and which are causing problems, and, and that's a challenge because we are saying, "Let, let's bring it to normal." No, you don't wanna lower the protective mechanism. [laughs]

    21. PAPeter Attia2:14:01

        Right.

    22. NBNir Barzilai2:14:01

        The third thing that is really cool is the proteome of females is much more stable. In other words, it's only half of the proteins are significantly changing in women than in men-

    23. PAPeter Attia2:14:17

        Mm

    24. NBNir Barzilai2:14:17

        ... between those ages. So you'd need to look at actually different biomarkers for women and men. And by the way, this is, this is something... This is eureka. This was eureka moment for all of us. Mice... From ITP and on, female and males have different biology as far as aging. Some of the gerotherapeutics both work for both, like metformin and rapamycin. Maybe not equally, but work for both, and some are not.

    25. PAPeter Attia2:14:46

        Yeah. Look at, look at the 17 alpha or sev- 17 alpha estradiol.

    26. NBNir Barzilai2:14:51

        Estradiol.

    27. PAPeter Attia2:14:51

        Is it beta? 17 beta estradiol. I mean, that's a remarkable

18. 2:14:54 – 2:26:29

    The search for biomarkers to identify who can benefit from treatment

    1. PAPeter Attia2:14:54

       story.

    2. NBNir Barzilai2:14:55

       And then the last thing that is interesting, those thousand people that I had, uh, 500 are what we called OPUS. They are off- offspring of parents with usual survival. No longevity in the family. And one are OPEL, offspring of parents with exceptional longevity.

    3. PAPeter Attia2:15:11

       Mm.

    4. NBNir Barzilai2:15:12

       The offspring of parents with exceptional longevity have half of the biomarkers, uh, of, of, of the control group because they're younger. [laughs] They'll get those biomarkers later.

    5. PAPeter Attia2:15:25

       Mm-hmm.

    6. NBNir Barzilai2:15:26

       So, uh, I, I think... Look, I don't know that methylation is going to be the best biomarker for treatment. I think, uh, methylations are, are complicated. They're kind of stable. They are going up, they're going down, but they're kind of stable. I think proteomic is going to be a better biomarker. I think metabolomic is very complicated because it so depends on how you establish the sample. You know, if somebody was fasting less or more, if their insulin level was less or more, you're done.

    7. PAPeter Attia2:16:09

       That's sort of my problem with these biomarkers is... And you know, I mean, I don't know, you've probably heard me rail on these, um, these, uh, biological clocks. I've never seen a worse biomarker than a biological clock. These are so easy to manipulate and game. Uh, i- in fact, I need to do this just to demonstrate it, but I'm too lazy, is get five copies of a biologic clock and do five different self-experiments, and I promise you I can change my biologic age by 20 years, right? When fasting glucose and vitamin D level factor into a biologic clock, I'm sorry, that's useless. It might be valuable at the population level. It is as useful as a warm bucket of hamster vomit at the individual level. So we have to have things that can't just change on a day-to-day basis. Your fasting glucose, the difference between 95 and 105 has everything to do with the meal you had last night, how much cortisol was coursing through your veins, if your water heater broke that night, if you got startled in the morning when you, before you got your blood draw. I mean, I'm just amazed, Nir, at the attention. I'm sorry I'm going off on this tangent, I... But I'm amazed at the attention that is being given to these clocks, and the entire cottage industry of businesses that are spinning out this type of... I, I think, I think this is complete buffoonery.

    8. NBNir Barzilai2:17:35

       Peter, I, I have more positive, uh, outlook of life maybe because I'm so much older than you.

    9. PAPeter Attia2:17:40

       So much older, yeah.

    10. NBNir Barzilai2:17:41

        [laughs] But, you know, at least it's good for the economy.

    11. PAPeter Attia2:17:46

        [laughs] Yeah, exactly. Hey, Theranos was good for the economy until it wasn't.

    12. NBNir Barzilai2:17:51

        [laughs]

    13. PAPeter Attia2:17:52

        Right? No, um, the other thing is even with methylation, um, and, and I thought methylation was very interesting until the twin astronaut brother experiment. Then I stopped thinking it was very interesting, right? Remember you had the twins, right? The one astronaut went to the ISS for a year. His twin brother stayed down here. You then looked at methylation clocks of them after a year, and they were vastly different. And then three days later, after the twin brother was back on Earth for three days, they repeated the test, and it was right back to his twin brother.

    14. NBNir Barzilai2:18:25

        Right.

    15. PAPeter Attia2:18:25

        I mean, come on. H- how biologically relevant can this be when it changes like that?

    16. NBNir Barzilai2:18:32

        Right, and I, I think, uh... Have you had Morgan Levine?

    17. PAPeter Attia2:18:35

        No, and, and I-

    18. NBNir Barzilai2:18:36

        Do you know about her?

    19. PAPeter Attia2:18:36

        I, I, I do, of course, and, and, and I haven't had Steve Horvath on as well. I, I've communicated with him a little bit via email, and I would certainly, uh, love the opportunity to, to speak with him about this. But, um, there's probably something interesting there. I'm just having a hard time seeing that... G- 'cause again, what's the purpose of doing this? We have to never lose sight of the purpose of biomarkers of aging. It's not so that you have bragging rights that, "Oh, I just took this test, and it says I'm 37 when I'm 50." No. The only reason you do this test is if it can guide therapeutics. The only reason you do this test is if it helps you determine, "If I'm doing this thing, is it making me better or worse?" And my fear is I haven't seen a single test that is validated at a level that would give me even a modicum of confidence in that.

    20. NBNir Barzilai2:19:23

        Right. Right. And you know-

    21. PAPeter Attia2:19:25

        Have you... I mean, again, I'm look-

    22. NBNir Barzilai2:19:25

        No, no

    23. PAPeter Attia2:19:26

        ... I'm, I'm saying this in a very deliberately provocative way 'cause I'm waiting for you to say, "Oh, no, no, Peter, you need to look at this test."

    24. NBNir Barzilai2:19:32

        No. So I'm, I'm, I'm telling you, I, I don't wanna be a, a spokesperson. I, I... All I'm saying is I don't think, uh, methylation, because it's not mechanistic, I don't think it's going to help us, uh, when we come to gerotherapeutics, even if there are examples, okay? I, I don't know what the examples mean. Just like the example you gave, I, I don't know what it means. Uh, Morgan Levine and Steve Horvath, by the way, they're, they're, they're really good, and they're responsible. And they understand exactly what they did and what they didn't do. And, uh, Morgan Levine has a mechanistic way of looking at epigenetics.

    25. PAPeter Attia2:20:08

        Remind me what the inputs are to the Levine clock.

    26. NBNir Barzilai2:20:12

        The way they are moving is... So one, one, one thing that Morgan Levine is doing is she's saying, "Well, if the me- if methylation has a function, then I wanna, uh, cause methylation and see that there's change in the expression, right, of those genes, and, and that those genes are something that we know are relevant to aging, uh, et cetera, et cetera, and then build a clock that is mechanistic." Because the only way this clock was built was to be, uh, uh, to measure chronological age. [laughs]

    27. PAPeter Attia2:20:45

        Will you guys be using any of the biologic clocks through TAME as well?

    28. NBNir Barzilai2:20:50

        So what's going to happen with TAME is there are two things. We're going to, we're going to have a committee that we time, and we didn't decide. We're going to, to do the right epigenetic test. And by the way, we're going to do epigenetic, not the clock epigenetics, but enough epigenetic, uh, uh, data on a genome, you know, on the genome wide in order to then discover which are the ones that have changed with treatment, okay? That way.

    29. PAPeter Attia2:21:22

        But it would also be good, Nir, to have a clock running in parallel, wouldn't it? Because if you can do this longitudinally with multiple data points, you sample people every three to six months with multiple different versions of these clocks, and then you can look at how well those clocks predicted the actual outcomes you will see over five to seven years. That strikes me as a very valuable way to get at something that no one is doing today because-

    30. NBNir Barzilai2:21:49

        Right
19. 2:26:29 – 2:39:36

    The impact of metformin on exercise, and finding the right indication for the use of metformin

    1. NBNir Barzilai2:26:29

       reason.

    2. PAPeter Attia2:26:29

       So let's talk a little bit about this other issue, which is, um, uh, you know, I've talked with you about my experience, right? So I took metformin for, I don't know, eight years or something like that. Um, but three years ago, when I really began checking and, and constantly monitoring my lactate levels both in and out of exercise, it became clear to me that my lactate levels were too high. So my fasting lactate level was typically above one millimole. It was between one and two millimole, and as a result of that, my perceived mitochondrial efficiency was lower. Um, and there's ample data to suggest that fasting lactate level... Now, of course, this is not necessarily in people taking metformin, but if you take lactate levels in people at rest there's a high association between what that tells you about their general health. So the less healthy an individual is, the higher their lactate level is. Um, [lip smack] so for me, I just said, "Well, boy, there sure, there sure looks like a lot of compelling reasons why metformin could be beneficial," but if I really stop to look at it, none of the cohorts of people in whom we would infer that look anything like me, right? These are not people who are exercising constantly, doing all of these other things. So that was the decision for me three years ago. I'm not gonna take metformin anymore until I have better data. Um, so now we have a couple of studies that have looked at the impact of metformin on cardiorespiratory fitness, and we see that it is indeed impaired, and then we have studies that look at the impact on metformin of strength training, and we see a mixed response. We see that it does not appear to impact strength gains. It only appears to impact hypertrophy. The good news is we know that strength matters more than hypertrophy in longevity. I had a whole AMA on that, which you probably heard, so I think it was pretty clear that we can say strength matters more. So what do you make about these potential limitations with respect to metformin on cardiorespiratory fitness, and what do you think it says about people who exercise a lot?

    3. NBNir Barzilai2:28:46

       First of all, I think one point that is very important is when we go, uh, from, um, a drug that has certain cap- cap- ca- capabilities to personalized medicine, and all of a sudden it becomes about the person, okay? And I think what, uh, there's nothing I can say about what you're observing except that, uh, lactate is one of the biomarkers of giving metformin. In every patient, we ... 1990, uh, '87 when I did the metformin study, metformin went from below one to above one in everyone who took metformin.

    4. PAPeter Attia2:29:26

       Lactate-

    5. NBNir Barzilai2:29:26

       Okay?

    6. PAPeter Attia2:29:26

       ... you mean, yes.

    7. NBNir Barzilai2:29:27

       Uh, lactate. Sorry.

    8. PAPeter Attia2:29:28

       Yeah.

    9. NBNir Barzilai2:29:28

       What did I say? [laughs]

    10. PAPeter Attia2:29:29

        You said metformin, but I know what you mean.

    11. NBNir Barzilai2:29:30

        Uh, but yeah, lactate went up in every, in every patient.

    12. PAPeter Attia2:29:33

        It's almost a way that in, I hope in TAME you are measuring lactate, if for no other reason than to determine compliance.

    13. NBNir Barzilai2:29:39

        Absolutely. By the way, there is a better taste, test. It's called GDF15. Uh, it's one of those peptides that goes up with aging. It's a protective pep- peptide. It goes by three and a half fold in people who take metformin. So there are other, other-

    14. PAPeter Attia2:29:53

        Other good biomarkers

    15. NBNir Barzilai2:29:53

        ... yeah, other ways-

    16. PAPeter Attia2:29:54

        Yeah

    17. NBNir Barzilai2:29:54

        ... other ways to look at it. So, okay, but this is the point with exercise, and let me make the most important point, okay? Uh, we can talk about muscle, but remember, just like with exercise itself, exercise is not only about muscle. It improves brain function, okay?

    18. PAPeter Attia2:30:12

        Mm-hmm.

    19. NBNir Barzilai2:30:12

        It decrease cancer, okay? Metformin has many other effects, okay? So let's remember that metformin has other effects than its effects on the muscle. As far as the muscle is concerned, what we've done with Charlotte Peterson, which you reviewed two papers of her during, during the time, we took the biopsies, and look at the transcript-

    20. PAPeter Attia2:30:36

        Mm-hmm

    21. NBNir Barzilai2:30:36

        ... of the people who were on exercise and metformin versus exercise only, right? That's the only thing we had. And, and the reason we did that was because in supplement four of her first paper, she showed that the strength of the muscle didn't change. [laughs]

    22. PAPeter Attia2:30:58

        Right.

    23. NBNir Barzilai2:30:58

        Which means that per gram muscle you did better, okay? And we tried to understand what is the biology, and it became very clear. Look, uh, in order for muscle to grow, it needs to activate mTOR, okay? So mTOR is good for muscle and for muscle growth. It's not good for aging, [laughs] but it's good for mus- muscle growth. A huge transcripts of, of mTOR has been decreased by metformin, which was not news for us. On the other hand, there are other transcripts that had to do with inflammation and autophagy and s- oxidative markers that were, were in people with metformin and not with exercise. So there was, there were trade-offs, okay? There were trade-offs. You get less muscle, but the muscle is healthier, okay? So it's up to you. If you want, if you want to-

    24. PAPeter Attia2:31:55

        Is healthier? Can we really say that or can we just say-

    25. NBNir Barzilai2:31:57

        Well, okay

    26. PAPeter Attia2:31:58

        ... is as strong?

    27. NBNir Barzilai2:31:59

        It's bio- it's biologically younger or as strong. Yeah, what- whatever. They're trade-offs, so you-

    28. PAPeter Attia2:32:05

        Wait, wait, h- how, but how do we say it's biologically younger?

    29. NBNir Barzilai2:32:08

        Because the transcript, the change in transcript that we saw is from an old transcript to young transcript, okay? So in our studies-

    30. PAPeter Attia2:32:18

        Mm-hmm
20. 2:39:36 – 2:48:00

    Are NAD precursors geroprotective?

    1. PAPeter Attia2:39:36

       We're almost out of time, but one thing I want to just touch on before we go, we've talked a little bit about rapamycin, a lot about metformin. We didn't talk about the other one you and I probably get asked about a lot, which is the NAD precursors. Where are you in your thinking on the efficacy of these as geroprotective agents? They're in a different class because they're not pharmaceutical, they're nutraceutical. How, how is your appraisal of the, of the data in that space?

    2. NBNir Barzilai2:40:02

       You know, as a biologist, I have a problem understanding it. Okay? On one hand, uh, you give it to animals, and the animals are doing better. Okay?

    3. PAPeter Attia2:40:17

       Not, not in the ITP, but [laughs]

    4. NBNir Barzilai2:40:20

       Yeah, right.

    5. PAPeter Attia2:40:20

       Not in the single most important animal study.

    6. NBNir Barzilai2:40:22

       Right.

    7. PAPeter Attia2:40:22

       They didn't do better. Yeah.

    8. NBNir Barzilai2:40:24

       When you ask people, "Okay, follow, you know, follow the drug. Tell me where it goes. Where can you measure it?" You cannot measure it anywhere, and you cannot measure derivative of that. And so I don't know where is the biology. So Joe Bower, do you know Joe Bower from UPM?

    9. PAPeter Attia2:40:46

       No.

    10. NBNir Barzilai2:40:46

        He's a really good, uh, NAD biologist, and he basically thought, "You know what? The NAD goes... We swallow that. It goes to our microbiome."

    11. PAPeter Attia2:40:59

        Sorry. When he, when he says NAD, you mean the NR or NMN?

    12. NBNir Barzilai2:41:01

        The, right. The, uh-

    13. PAPeter Attia2:41:02

        Yes, yes, yes

    14. NBNir Barzilai2:41:03

        ... the precursor. Right.

    15. PAPeter Attia2:41:03

        Yep.

    16. NBNir Barzilai2:41:04

        It'll go to the microbiome, and the microbiome either transfer the NAD or does something, the microbiome itself does something and, you know, there, there's indirect health benefit from a different system. And he actually did a really good study where he discovered that the NAD for the microbiome comes not from the food, but from the gut, the gut walls. [laughs]

    17. PAPeter Attia2:41:29

        Mm.

    18. NBNir Barzilai2:41:29

        Okay? Everywhere, everywhere you try to understand what's the biology, I don't get it. And when I don't get the biology, I'm a little bit more worried [laughs] of, of what kind of a placebo is it? Uh, I, I... Actually, one of the studies I wanted to do, those short studies when I, I get elderly, do placebo control crossover, and do biopsies, and look at the biology, I wanted to do NAD. And then I said, "I just have so little belief here that I, I'm, I'm now doing inter- intermittent fasting one." But, uh, but, uh, I'm, I'm uncomfortable with it. Now, saying that, I started taking NMN at one point, and what I noticed is my REM sleep has improved a lot, and I stopped it, and my REM sleep wasn't so good. I restarted it, and my REM didn't get better again. [laughs] So-

    19. PAPeter Attia2:42:32

        Mm

    20. NBNir Barzilai2:42:32

        ... so, and then I tried another, uh... There's a Japanese company, I don't remember the name off the top of my head. That has really the best preparation. David Sinclair tells me about that, has the best preparation, uh-

    21. PAPeter Attia2:42:47

        Of NMN?

    22. NBNir Barzilai2:42:48

        Of NMN. $900 a month supply [laughs] for the low dose, 1,800 for the high dose. I g- I got, I got some of the supplement as a present.

    23. PAPeter Attia2:42:59

        More expensive than a PCSK9 inhibitor and rapamycin combined. Okay.

    24. NBNir Barzilai2:43:04

        Right. [laughs]

    25. PAPeter Attia2:43:05

        That's, yeah.

    26. NBNir Barzilai2:43:06

        Right. And, and, uh, and my REM sleep didn't return, so, so I'm currently not taking anyone. So what am I telling you? I'm telling you, I, I'm just, I'm just not convinced. I, I, I don't w- I don't know. It's not the whole truth. You never know the whole truth, but I don't know enough of the truth to make anything about it. Again, if people want to know, it's good for the economy.

    27. PAPeter Attia2:43:34

        [laughs]

    28. NBNir Barzilai2:43:35

        I, I'm not sure that the preparations out there... Look, they're very sensitive preparations. If they have a high time shelf, I think-

    29. PAPeter Attia2:43:43

        Yeah

    30. NBNir Barzilai2:43:43

        ... you lose a lot of it, and I don't know which to recommend.

Episode duration: 2:48:00