#35 – Nir Barzilai, M.D.: How to tame aging

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [upbeat music]

2. 0:04 – 8:20

   Intro and Barzilai's path into aging research

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hey, everybody. Welcome to this week's episode of The Drive, and Happy New Year to everyone. We took a week off, as you probably noticed, so hopefully everybody's ready to jump back into this fun stuff. My guest this week is Nir Barzilai, and if you're at all into the space of longevity, he'll be no stranger to you. Nir is the founding director of the Institute for Aging Research, the Nathan Shock Center of Excellence in Basic Biology at Albert Einstein. He's completed two fellowships, one in metabolism at Yale, the other in endocrinology and molecular biology at Cornell. He directs the Longevity Genes Project, and in my estimate, Nir is probably the most knowledgeable person ever on the genetics of longevity, and we talk a ton about that during this episode. He also is leading the effort to test metformin in a prospective clinical trial for non-diabetics with respect to aging, and this is referred to as the TAME trial. We get into that obviously in detail here, and also we'll use a lot of the data for that in the show notes. This is-- In many ways, I think Nir is probably one of the most insightful people when it comes to understanding the clinical benefits of metformin, and we talk about that a ton. We also talk about insulin resistance. I can't resist the urge, no pun intended, I guess, to get into sort of a detailed discussion on what IR is with sort of people who are really deep in this space. We talk a lot about IGF and growth hormone, and I, I gotta tell you, this is a topic that you've probably heard me waffle on a little bit because I'm still really kind of on the fence about this relationship of IGF/GH. I think the centenarian data point in one direction. I think the epidemiology outside of centenarians point in a different direction. And of course, none of this really speaks to the question I get asked constantly, which is, "Do you think administration of growth hormone is beneficial from a lifespan or healthspan perspective, or do you think it's harmful?" And, you know, truthfully, I've always leaned towards the harmful side, but we get into this in detail, and Nir offers some great insights. Certainly for me, I was, I was really, uh, helped by this process. We do go back and talk about the centenarians, and because I'm in the midst, as some of you know, of writing this book, I'm knee-deep on all that literature. And so it was really great to kind of clarify a few things that I think even if you're not steeped in this stuff, what you'll find very interesting. And of course, we talk about all of my other favorite topics like autophagy, caloric restriction. We even get into a little bit of the stuff around NAD and nicotinamide riboside and things like that. So overall, I think this is a bit of a technical episode, but not that technical. We've certainly done more technical stuff. The show notes will be valuable as always, especially for a show of this nature. So with nothing else to add, please welcome to the show Nir Barzilai. [upbeat music] Hey, Nir. How are you?

   2. NBDr. Nir Barzilai3:34

      I'm terrific. How are you?

   3. PAPeter Attia3:35

      I'm good. I can't believe not only did you make it down here on time, but you made it down here ahead of me at my own place.

   4. NBDr. Nir Barzilai3:42

      Nice to stay young.

   5. PAPeter Attia3:43

      [laughs] Yeah, this is, mmm, uh, this-- I don't know. These, these days, this, this weather's so unpleasant, but yeah, you beat me here. I s-- I was a bit, I was, I was a bit embarrassed that-

   6. NBDr. Nir Barzilai3:52

      It, it's unpleasant for you because you're in California most of the time.

   7. PAPeter Attia3:56

      Yeah, yeah, I think that's part of it. But you're from Israel, so this has to be unpleasant for you too.

   8. NBDr. Nir Barzilai4:01

      Israel was too warm for me. I'm okay.

   9. PAPeter Attia4:03

      Got it. Well, speaking of which, so y-you were born in Israel. You spent how long there? Were you in a-- Did you serve military time there?

   10. NBDr. Nir Barzilai4:11

       Yes, I served military time. I was a nurse and a medical student. I went to the Technion Medical School. I went then to Hadassah Hospital for residency, which I finished, and only then I came to the United States. I was at Yale with, uh, Ralph DeFronzo doing, uh, metabolism. Actually, I was looking at the mechanism of action of metformin in 1987 before it was approved for use in the United States. There's a serendipitous connection to that later. And then I went to Cornell for an endocrine fellowship, and then I was recruited to Einstein. And so my first part of my life was metabolism, but then I started doing what I really was interested in, and this is aging and the biology of aging.

   11. PAPeter Attia5:02

       And I remember reading a quote once from you that said, I'm maybe paraphrasing, but, "Metformin is the reason I came to the United States."

   12. NBDr. Nir Barzilai5:10

       Well, in a way it was, but this is life in retrospect, right? I wasn't really expecting. I was done with metformin in 1988. I was done with metformin until it started again about, you know, three, four years ago.

   13. PAPeter Attia5:25

       Well, I can't wait to talk about metformin because they're probably... I'm trying to think. If I think of four or five exogenous molecules, which is just the terminology I use to describe anything that you ingest or take that comes from outside the body. So I would include drugs, supplements, hormones, anything in there. But when you lump all of these things together, if I were to say, what are the three or four of these that I am asked about the most frequently from patients Or frankly anybody. If I'm at, uh, if I'm at a party and I let it slide what I do for a living, the first question is, "Should I be taking metformin?" And there's usually a handful of others that they want to know about. "Should I be taking nicotinamide riboside?" Although they usually don't say that. They usually say, "Should I be taking NAD?" Or something to that effect. So it's wonderful that we will be able to speak today because few people can speak about metformin the way you can, and so I'm really looking forward to that. But before we go down that path, I, I do still want to kind of understand a little bit more about your journey and your interest in endocrinology. Did you know from day one when you entered the field of medicine that this was the area that you wanted to study?

   14. NBDr. Nir Barzilai6:30

       Yes. I was interested in aging from the time I was pretty much 13, and spend weekends with my grandfather, who was telling me his life story. And his life story wasn't easy, and he did lots of physical things, and he dried the swamp, and he did this and that. And I'm looking at a man who was then 68 years old, that walks slowly, he's obese, white hair, and he just didn't look like somebody who did everything he told me to do. And you know, they say that children have imagination, but most kids don't see their grandparents as what they will be, right? They see them as, "I don't know how they got there." And this really stuck with me, and I started to be interested in the biology of aging. When I was... For example, when I did my residency, I always was interested in how, not what's the age of the patient, but does he look older or younger than his age? I kind of realized intuitively that there's a chronological age and a biological age, and wh- what is this differences between the biological and chronological age? And of course, as a physician, it looked like endocrine is a good place to start because you knew that there is a lot of endocrinology in aging, and you assumed that hormones are going down or some are going up. But if you could fix that, maybe you could fix a lot of aging. Now, everything that happened in my life was fascinating from the biology of aging. Replacing the hormones wasn't really [chuckles] part of it, but we'll get to it.

3. 8:20 – 12:02

   Skepticism about hormone replacement and the WHI

   1. PAPeter Attia8:20

      Going back to the hormone thread, the most obvious example of changes in hormones with aging, of course, occur in women, where, you know, they have this very abrupt change in one of their endocrine systems, this androgen system. Did you think about it even more broadly than that? For example, like, what was happening in thyroid hormone, and what was happening in fuel partitioning hormones, and other things like that?

   2. NBDr. Nir Barzilai8:41

      Oh, absolutely. Absolutely. But I'll tell you to the point when there was a discussion whether to do the Women Health Initiative. You know, may- many people thought, "This is a waste of time." You know, we know that estrogen is good for women. There's lots of studies like that. Of course it's major in aging. And I didn't look at it this simply for maybe two reasons. One is men are also aging, and in several ways similar to women, and that's not an estrogen story, and it wasn't... The testosterone decrease wasn't really as dramatic as the estrogen decrease. So I, I didn't-- I thought that there's a lot of aging that's done without estrogen. Let's start with that.

   3. PAPeter Attia9:25

      Yeah.

   4. NBDr. Nir Barzilai9:26

      And also, you're replacing just one hormone with lots of hormones or changing it. It didn't look like a good study to me.

   5. PAPeter Attia9:32

      Well, and especially at the time, and I, I, I'm, I try to be, temper my criticism for that study by trying to have some empathy for the fact that the investigators were dealing with what the treatment protocols were at the time. But to use oral estrogen that's, you know, conjugated equine, to use synthetic progestin and not even actual progesterone. I mean, there, you, you could come up with a list of 18 things that, in retrospect, are so obvious why that study was a failure.

   6. NBDr. Nir Barzilai9:59

      Absolutely true. But the other part of that is that the way to show effect of estrogen in animal models was to take their ovaries out and give them estrogen.

   7. PAPeter Attia10:13

      Right.

   8. NBDr. Nir Barzilai10:13

      And then you could show... You could do lots of provocation. It was good. So estrogen is a good hormone on a young body. But then there were studies that were hardly published, but I was aware of them, of taking old animal. You know? So you could take the young animals, in just one center in Houston they did it. You took the young animal, you took their ovaries out, you gave them estrogen, and you, you employed a stroke model. Okay? And when you gave estrogen, the stroke was smaller and everything. When you did the same in older animals, the stroke became worse. Okay? And they couldn't publish it for a while because they said, "Well, it's old animals, so they have other diseases or other things." But every experiment that had estrogen in old model [chuckles] wasn't, was the opposite. Not only that it didn't affect, it was the opposite, which what happened, you know, to the WHI in a certain ways.

   9. PAPeter Attia11:11

      Yeah. Although I still think that the, it was probably the breast cancer that garnered the most headline in the WHI. And, and actually, that's an interesting topic which I'll be, um, going into in great depth on another episode. There's a great book that just came out that tackles this, that goes through the history of the WHI. At what point... Well, let's go back to the metformin thing, actually. So it's 1987, and you're thinking like, "Okay, metformin is the next line of agent we will use to treat type 2 diabetes." So, so metformin was already in, in, uh, clinical practice in Europe. Is that correct?

   10. NBDr. Nir Barzilai11:42

       Oh, correct, for many years.

   11. PAPeter Attia11:44

       How many years? Like 20 or 30 years?

   12. NBDr. Nir Barzilai11:45

       So metformin, few years ago, was 60 years. So we're talking about, you know, 1950 or something. 1950, 1960. When I was in Israel, I prescribed metformin. You know? That was the first line for type 2 diabetes.

4. 12:02 – 21:28

   Metformin's history, FDA delay, and mechanism of action

   1. PAPeter Attia12:02

      What took so long for it to come to the US?

   2. NBDr. Nir Barzilai12:04

      That's a, a terrible story that, that still continues. You know, the FDA said, "We, we don't know, we don't know that metformin is going to be effective in the population in the United States, so you have to do the studies." And it was Bristol-Myers, really, that got to do the studies, and basically they had to do a phase III study again to show that metformin is effective as sulfonylurea as a, as an indication for type 2 diabetes. And if even then, the idea was that it will be good only in obese people, which happened not to matter much because all the type 2 diabetes [laughs] in the United States were obese. But it was really a matter of regulation, and part of having regulation was that the FDA asked more studies to understand the mechanism of aging and metformin. And in a certain way, maybe they are right because metformin mechanism of action is really complicated, and I'm not sure that today, as a new drug, it would be approved.

   3. PAPeter Attia13:19

      Interesting. Why do you-- where do you think it would fail, in safety or efficacy?

   4. NBDr. Nir Barzilai13:23

      No, it's not. In mechanism, okay?

   5. PAPeter Attia13:26

      In the, in the inability to elucidate the mechanism.

   6. NBDr. Nir Barzilai13:27

      Right. When, when you come to the FDA and you say, "You know, we've done that, and we've done this in animal, and we've done this in cells," and you're trying to show what is the major mechanism of action, you, you would have failed. So what I showed in humans is that metformin targets hepatic glucose production or the insulin sensitivity of the liver, and that's the major mechanism of action, unlike, for example, sulfonylurea that increase insulin secretion, right? Or TZDs that increase the insulin sensitivity in the muscle more than in the liver. So this was a mechanism that you could pack to the FDA, but it's really not the intracellular mechanism of metformin.

   7. PAPeter Attia14:11

      So at the time, was it understood what metformin's activity was on complex one of the mitochondria?

   8. NBDr. Nir Barzilai14:19

      No, not really. This came later. I, I don't, I don't know what year, but it came later. It came when the seahorses assays were developed to show really which mitochondria, in which pathway of mi- mitochondria you have changes.

   9. PAPeter Attia14:37

      Maybe for the listener, tell-- explain what a seahorse assay is.

   10. NBDr. Nir Barzilai14:41

       Seahorse assay is an assay to look at mitochondrial action, whether you extract mitochondria or even tissues. It really shows some relationship between oxygen consumption in relationship to polarity, and it's very sensitive to look at some of the effects of drugs that are interfering with mitochondria action or decreased mitochondrial activity.

   11. PAPeter Attia15:10

       It's almost like the indirect calorimetry of the mitochondria.

   12. NBDr. Nir Barzilai15:12

       Right. Right. Indirect because it's a provocative test-

   13. PAPeter Attia15:16

       Yeah

   14. NBDr. Nir Barzilai15:16

       ... really. So yes.

   15. PAPeter Attia15:17

       Metformin was discovered from a plant as well, correct?

   16. NBDr. Nir Barzilai15:21

       Right. It's a French lily.

   17. PAPeter Attia15:22

       And it was a French lily, obviously, uh, and this was discovered in the '40s or '50s?

   18. NBDr. Nir Barzilai15:26

       Correct. The first thing that happened, there was, um, a drug by the name of phenformin, a cousin of metformin. And-

   19. PAPeter Attia15:35

       Which apparently is much more potent.

   20. NBDr. Nir Barzilai15:37

       It's much more potent because unlike metformin, it doesn't need a transporter to get into the cells. On the other hand, it was associated with a lot of lactic acidosis, and it was considered unsafe eventually, and then metformin was a safer part with much less of a lactic acidosis side effects.

   21. PAPeter Attia16:02

       What is the mechanism by which metformin cause lactic acidosis? Because in all the use I've seen of metformin clinically, I've never seen a case of it, which is not to say it doesn't happen. I'm sure it does, and you could stack risks by taking someone with renal insufficiency, giving them contrast and tons of metformin. But in medical school, this was like the board question you got asked every single test. "What do you have to worry about with lactic acidosis?"

   22. NBDr. Nir Barzilai16:28

       Right.

   23. PAPeter Attia16:29

       What's the putative mechanism by which that happens?

   24. NBDr. Nir Barzilai16:31

       So first of all, I would tell you that in my study in the '80s, every patient that we gave metformin had an increase in lactic acid.

   25. PAPeter Attia16:41

       From what to what in millimolar?

   26. NBDr. Nir Barzilai16:43

       Within the normal range. So if it's two was the-

   27. PAPeter Attia16:47

       Yeah, the cutoff

   28. NBDr. Nir Barzilai16:47

       ... the cutoff. So it was, you know, between, went from one, 1.5 towards the two, and sometimes even went over the two. But it wasn't really anything associated with acidosis.

   29. PAPeter Attia17:01

       And there was no change in pH?

   30. NBDr. Nir Barzilai17:02

       No. No. No anion gap, not, uh, anything like that. And it probably has to do... I, I, I don't know that I can tell you for sure, but it has to do with what happens when complex one, part of the metabolic effect when complex one is inhibited. But there's lots of speculation, and I don't really care [laughs] to comment on-
5. 21:28 – 34:58

   What insulin resistance really means

   1. PAPeter Attia21:28

      Let's talk about this idea of insulin resistance. I think there are a few terms that leave me scratching my head more than that one. So this is an example of, um, something where maybe five years ago, I thought I really knew what insulin resistance was, and I think today I'm pretty sure I don't know what it is. In the sense that when you take the typical phenotype of someone who's insulin resistant, what do they look like biochemically and anthropomorphologically, right? So they're hyperinsulinemic. They have elevated levels of glucose. They probably have some degree of obesity or adiposity. So what does that mean? Because clearly their fat cell is quite sensitive to insulin. If a fat cell ever became resistant to insulin, you could not re-esterify fatty acids, and you would have an endless stream of lipolysis exiting fatty acids from the fat cell. So you'd actually be quite lean. There's something going on in the muscle that clearly is resistant to the effect of insulin, but of course, there are both insulin-dependent and insulin-independent means by which we can dispose of glucose. And this is where, coming back to what you said a moment ago, I actually wanted to ask you that question, which is... But we'll park it, but the question was, does metformin participate in the AMPK-driven insulin-independent modality of glucose disposal? You're nodding, so I think that's a yes, and we'll come back to it. And then there's the liver, and this is the one to me that is the most complicated and the one I'd like to begin with. So before I ask you to elaborate on the, specifically what is meant by insulin resistance in the liver, am I a complete moron for not understanding this?

   2. NBDr. Nir Barzilai23:04

      No, but l- can I make it a little bit more interesting even?

   3. PAPeter Attia23:07

      Always.

   4. NBDr. Nir Barzilai23:07

      Because I need to bring it to aging.

   5. PAPeter Attia23:09

      Yes.

   6. NBDr. Nir Barzilai23:09

      I would love to talk about diabetes, but let me just put upfront, I, I don't, I'm not sure that the diabetes property of metformin are really the aging properties of metformin.

   7. PAPeter Attia23:21

      Hmm. Okay.

   8. NBDr. Nir Barzilai23:22

      Okay? This is my provocation. But let me go back to insulin resistance because in, in 1997, a science paper appeared that made it the best day of my life and the worst day of my life, okay?

   9. PAPeter Attia23:39

      Wow.

   10. NBDr. Nir Barzilai23:40

       What was the paper? The paper was taking a nematode, okay, so a primitive, uh, model, decreasing the insulin sensitivity. This is known as the daf-2 model. And when you do that, the nematode accumulates fat in their intestinal cells, so they are becoming visceral obese, and they live several times longer. So why is it my, the best day in my life? Because you could, with one genetic manipulation, extends lifespan significantly. That meant going from hope, uh, w- actually from nothing, from-

   11. PAPeter Attia24:21

       Was this Cynthia's paper?

   12. NBDr. Nir Barzilai24:22

       Well, no, that's, uh, Gary Roofkin. But at the same time, Cynthia had her DAF-16. Tom Johnson has, had the, the H1 model. There are several papers that came, and all of them said, "Hey, we can change, uh, lifespan," and the example was always insulin sensitivity.

   13. PAPeter Attia24:37

       And this mutation, to be clear, 'cause between DAF-2, DAF-16, and the dietary manipulations, there are several permutations of that C. elegans model. But just to make sure I know which paper we're talking about, this was only attenuation of DAF-2, nothing to DAF-16, and nothing to dietary changes.

   14. NBDr. Nir Barzilai24:57

       Right. Right.

   15. PAPeter Attia24:58

       Can you just, uh, for the listener, define what is the analog of DAF-2, DAF-16 in us?

   16. NBDr. Nir Barzilai25:03

       So DAF, DAF-2 is the insulin receptor, and DAF-16 is the FOXO, the FOXO transcription factor. But the point is, at that time-

   17. PAPeter Attia25:14

       Yeah, you took a worm that normally lives two weeks, and you turned down its insulin receptor slightly. Not off, correct?

   18. NBDr. Nir Barzilai25:23

       Right, right. But you made it insulin resistant, and it was accumulating fat, and what was I bringing into the field? I was saying the major reason for aging is this insulin sin- uh, resistance syndrome, and the main part of the insulin resistance is a accumulation of visceral fat. And so the premise was good. The example was disaster to me. I had a JCI paper at that time in press really showing with MRI pictures how caloric restriction decreases the visceral fat. I was talking about the biology of those fat and stuff, and it was a major paradox for us in the field and how we continue if we're saying insulin resistance is good for longevity, and everybody in diabetes knew that this is a disaster. Why am I telling you that? Because I learned later, I was thinking later on experiments that I've done. Oh, so first of all, the experiment that I've done that was very conclusive was I took bunch of rats, 150 actually, and all of them underwent surgery after puberty. In some of them, I removed their visceral fat depots by surgery, and in the other, it was a sham procedure, so I just moved it but didn't remove it. And we had three groups in the experiment. One was ad libitum feeding. The second was caloric restriction. This is the control. They would live 40% better. And the third group was ad libitum feeding of the rats that their visceral fat was removed. And I said, "You know, without the visceral fat, even with nutrients, they live longer." And they actually lived significantly longer than the ad libitum by 20%, but not as much as the caloric restriction.

   19. PAPeter Attia27:18

       So just to make sure I understand, you had a two-to-one ratio of your animals because you had, um-

   20. NBDr. Nir Barzilai27:24

       No, I had three groups

   21. PAPeter Attia27:25

       ... three groups, but one of them-

   22. NBDr. Nir Barzilai27:26

       Ad libitum

   23. PAPeter Attia27:26

       ... was all ad lib feeding of the visceral fat removed. That was-

   24. NBDr. Nir Barzilai27:31

       Right

   25. PAPeter Attia27:31

       ... and then of the ones that had sham surgery, they were randomized to ad lib versus CR.

   26. NBDr. Nir Barzilai27:36

       Correct. It really showed that visceral fat, the removal of visceral fat had major effect.

   27. PAPeter Attia27:41

       And when the animals who had the visceral fat removed were autopsied or whatever the word is for rat autopsies, um, had they re- figured out a way to re-accumulate visceral fat, or where had they accumulated fat?

   28. NBDr. Nir Barzilai27:54

       No. In fact, when you do this procedure after puberty, if you do it before puberty, they accumulate visceral fat. Otherwise, they don't accumulate much visceral fat.

   29. PAPeter Attia28:05

       Did they have changes in subcutaneous fat?

   30. NBDr. Nir Barzilai28:07

       That's a good question. Mice have it when you do it, and rats do not.
6. 34:58 – 49:25

   Glucose uptake, hepatic insulin sensitivity, and hyperinsulinemia

   1. PAPeter Attia34:58

      let's talk about exactly how the muscle takes in glucose. So we are walking around. If I bolus you with glucose right now and, uh, your blood glucose rises from wherever it is right now, 90 to 200... Let's say I give you an enormous bolus of glucose. I double it, so you're up to 180 milligrams per deciliter. That's a very high, screaming high level, which by the way only amounts to an extra few grams of glucose, but nevertheless. What is the chain of events that leads to insulin being secreted and the muscle ultimately disposing of that glucose, both actively or passively?

   2. NBDr. Nir Barzilai35:32

      W- well, there'll be obviously a secretion to insulin that's relative to your glucose level, and, and hopefully-

   3. PAPeter Attia35:37

      So the ins- so the beta cell is the sensor-

   4. NBDr. Nir Barzilai35:40

      Right

   5. PAPeter Attia35:40

      ... and out comes insulin. And now what is insulin doing to the muscle?

   6. NBDr. Nir Barzilai35:44

      And insulin, through the insulin receptor, will get translocation of the GLUT4. Those are the glucose transporters that are the major glucose transporters in muscle. It will go from an intracellular pool into the plasma membrane, integrate it, and starts getting glucose like crazy into the cells.

   7. PAPeter Attia36:04

      And that happens quite passively, meaning once the GLUT4 transporter is translocated across the cell membrane, glucose can passively rush in, correct? It doesn't require ATP to take- Bring it in against a gradient of any sort

   8. NBDr. Nir Barzilai36:18

      Correct. Correct

   9. PAPeter Attia36:18

      Um

   10. NBDr. Nir Barzilai36:19

       And, and, and in fact, it has its own intrinsic activity that's not e- energy dependent, so it can go faster or slower by, by different ways.

   11. PAPeter Attia36:28

       Now, is there another method by which, without insulin, we can get glucose into a cell that somehow relies on AMP kinase?

   12. NBDr. Nir Barzilai36:36

       Not on AMP kinase, but there's non-insulin-mediated glucose uptake. In other words, there's a way for glucose to get up without the insulin, and we know that from hyperglycemic clamp and from other things that when, when we can move the insulin or keep insulin level at basal, and still there's a substantial glucose uptake that's happening. So yeah, we know that.

   13. PAPeter Attia36:59

       What's the mechanism of that?

   14. NBDr. Nir Barzilai37:00

       I, I'm, I'm, I'm not sure I know, okay?

   15. PAPeter Attia37:03

       It also seems to be enhanced by exercise.

   16. NBDr. Nir Barzilai37:06

       That's true. That's true. This NINJA is the non-insulin-mediated glucose uptake is something that is exercise dependent, too.

   17. PAPeter Attia37:14

       And it seems to-

   18. NBDr. Nir Barzilai37:15

       And oh, that's why ... Now I understand your question. Is AMP kinase-

   19. PAPeter Attia37:18

       Yes

   20. NBDr. Nir Barzilai37:19

       ... part of the then that, and I, I, I don't know that.

   21. PAPeter Attia37:22

       Yeah. I only have one patient in my practice who has type 1 diabetes, but he is such an interesting patient because of his incredibly strict dietary control and his unbelievable appetite for exercise, and he-- I've never seen a higher level of adiponectin in a human. I've never seen a higher level of sex hormone binding globulin in a human, which are basically, and we know how much insulin he has because he injects it in. He injects so little insulin into himself, and yet can seem to, you know, he has a hemoglobin A1C below six using six to eight units of insulin a day, and so what got me, it got, that's what got me very interested in this non-insulin dependent glucose uptake.

   22. NBDr. Nir Barzilai38:08

       Yeah. I'm not doing this research anymore. [laughs]

   23. PAPeter Attia38:10

       [laughs]

   24. NBDr. Nir Barzilai38:11

       I used to be in front of that. I-- glucose itself can modulate glucokinase activity in the liver. There's a lot of things that happening, and of course, there's coordination between the fat and, and the liver. And, and then I started be interested because we can do things to the hypothalamus and take over this insulin and muscle and fat and liver. We can do it all from the brain. It's at the-

   25. PAPeter Attia38:37

       Isn't that amazing? Well, just because I'm so fascinated by this, and I think it will help the listener to understand the complexity of what you just said, if I took an animal and put a lesion into the ventral part of the hypothalamus, a normal animal, what could that do? What would that change about its metabolism?

   26. NBDr. Nir Barzilai38:55

       Well, that would increase basically food intake and change a lot of the peripheral physiology, but we do basically the opposite. We give insulin to the hypothalamus or glucose or IGF or leptin.

   27. PAPeter Attia39:12

       Mm-hmm.

   28. NBDr. Nir Barzilai39:12

       Okay? And then we see what happens to the peripheral, though in the periphery, those hormone levels are not increasing at all.

   29. PAPeter Attia39:19

       Right.

   30. NBDr. Nir Barzilai39:19

       And not only that, the liver is a good target to follow because what you can do with the liver, you can do selective hepatic vagotomy, and everything that you did through the brain doesn't work anymore because it needs the nerves.
7. 49:25 – 57:46

   Origins of metformin as an aging drug: the UK mortality study

   1. NBDr. Nir Barzilai49:25

      So first of all, there were studies on the biology of aging in rodents, and the first guy, which I'll be embarrassed now to forget, he's a guy from Leningrad that was the first to say, "I've done a rodent studies and animals with metformin," uh, Anatoly? I'll remember it maybe later. And he showed that a life extension, extension increases in variety of animals to which he gave metformin. That led to some studies-

   2. PAPeter Attia49:59

      What was his hypothesis? Do you remember why would he, what would he, what drove him to do that?

   3. NBDr. Nir Barzilai50:03

      There was never any hypo- clear hypothesis

   4. PAPeter Attia50:06

      This was just a pure fishing expedition?

   5. NBDr. Nir Barzilai50:08

      It's even wasn't related to glucose metabolism necessarily. He thought that maybe there's an an- anti-cancer effect, and he looked at that. But then he got models that were hypertensive, and they also lived longer, so he thought those are different effect, and then he considered to aging. But at that time, this was in the '80s when he started that, and [laughs] it bothers me that I don't remember his name.

   6. PAPeter Attia50:34

      That's okay. You'll remember it.

   7. NBDr. Nir Barzilai50:35

      I should take more metformin.

   8. PAPeter Attia50:36

      [laughs]

   9. NBDr. Nir Barzilai50:37

      Uh, and he was pushing, he was showing up in, in meeting and showing. And so people have tried to do it in the United States, and they showed that there is a significant effect on insulin. By the way, the effect of insulin in animals is 10%, not like m- rapamycin is 24%.

   10. PAPeter Attia50:57

       Mm-hmm.

   11. NBDr. Nir Barzilai50:58

       So there's a milder effects, but in every study, they showed that healthspan is improved, you know, by 50%. [laughs] So the effect on longevity was less than the effect of health. By the way, that's perfect for what I'm trying to say. I'm, I'm not for longevity. I'm just for healthspan, right? So if we can live healthy, healthy, healthy, die, that's fine with me. [laughs]

   12. PAPeter Attia51:21

       Yeah, the so-called squaring of the longevity.

   13. NBDr. Nir Barzilai51:23

       Squaring, right.

   14. PAPeter Attia51:24

       Yeah.

   15. NBDr. Nir Barzilai51:24

       Squaring of the longevity. So he, he started, uh, Asimov. His name is Asimov. So that's what Asimov showed. People have started looking at that. They f- There are s- several studies, three studies that gave it also to nematodes. They also lived longer, and there's several effects on healthspan in the biology of aging. Now, the reason, th- th- there's a lot of needle threading here in my story [laughs] here, okay? But I wanna tell you the, the moment that I knew we have to do this study was a publication, not in a very high impact journal, but it was an amazing study that could be done only in the UK because in the UK, you can go into pharmacies and look at prescription that they gave, and you could follow the mortality of those patients.

   16. PAPeter Attia52:27

       Oh, b- because the NHS system allows you to centralize everything from prescription to usage to mortality.

   17. NBDr. Nir Barzilai52:35

       Exactly. And they're probably, they don't need to de- to be de-identify after mortality. When you're dead, you, you're not private anymore.

   18. PAPeter Attia52:46

       [laughs] Okay.

   19. NBDr. Nir Barzilai52:47

       So they did this study. So what they've done, there are four arms to this study. They came and took patients who are on sulfonylurea, 12,000 patients, okay? And they matched them to 12,000 people without diabetes. Okay? Same pharmacies, same doctors, controlling for some other things. And of course, the people on sulfonylurea had higher mortality than their control, you know?

   20. PAPeter Attia53:16

       Right.

   21. NBDr. Nir Barzilai53:16

       Double, double-

   22. PAPeter Attia53:16

       Because of course they had-

   23. NBDr. Nir Barzilai53:17

       Because they had diabetes

   24. PAPeter Attia53:17

       ... they had a reason to be taking the sulfonylurea.

   25. NBDr. Nir Barzilai53:20

       Right, right. They had diabetes, so that's okay. Then they took 78,000 people on metformin and 78,000 people who were non-diabetic, again sh- matching them.

   26. PAPeter Attia53:34

       And the 78,000 on metformin was metformin monotherapy.

   27. NBDr. Nir Barzilai53:37

       Monotherapy.

   28. PAPeter Attia53:38

       First line.

   29. NBDr. Nir Barzilai53:39

       Right. And they watched their mortality. So just to m- underline again, the people on metformin had diabetes.

   30. PAPeter Attia53:49

       Yes.
8. 57:46 – 1:11:52

   Designing TAME: FDA hurdles, composite outcomes, and funding

   1. PAPeter Attia57:46

      Can you tell people what TAME stands for?

   2. NBDr. Nir Barzilai57:48

      TAME stands for Taming or Targeting Aging with Metformin, and it, it's a study that's designed to prove the concept that aging can be, uh, targeted, but also, or mainly for me, is for the, uh, FDA to give an approval to an indication that's like aging.

   3. PAPeter Attia58:05

      The first time I heard about TAME was actually here in this city. I was having dinner with Steve Austad. It must have been in 2015 maybe, '14, '15. Steve is a, a gem of a human being. I consider him certainly one of the most important mentors in my, uh, exploration of this field of aging.

   4. NBDr. Nir Barzilai58:23

      He's-- We're partners-

   5. PAPeter Attia58:24

      Yeah. He's-

   6. NBDr. Nir Barzilai58:24

      ... in many ways. He's a great guy.

   7. PAPeter Attia58:26

      He is. He is one of these guys that has-- His knowledge is out of control. You, you can't ask him a question that he doesn't know where to go for the answer. I have the highest respect for Steve and can't wait to interview him here as well. But I remember him telling me about this, and my first thought was, "Steve, that's a crazy idea. The drug is free. Who the hell is going to pay for this study? NIH can't pay for it 'cause they don't consider aging a disease. Pharma can't pay for it 'cause there's no way to make money on it. I mean, I th-- I might pay, like, 10 cents a year for my supply of metformin. It's a free drug." I said, "You're doing the wrong study, man. You gotta do this with rapamycin." So talk to me about the challenges of this. This is-- You're proposing something that is really never been done before.

   8. NBDr. Nir Barzilai59:12

      Can I just ask you, are we going back to metformin? Because you asked me about diabetes but not metformin action. Will you c- ask me later?

   9. PAPeter Attia59:19

      Absolutely.

   10. NBDr. Nir Barzilai59:20

       Oh, okay. Okay.

   11. PAPeter Attia59:20

       I cannot wait to dive-

   12. NBDr. Nir Barzilai59:22

       Okay

   13. PAPeter Attia59:22

       ... into metformin. Yeah, we're not gonna-

   14. NBDr. Nir Barzilai59:23

       Okay

   15. PAPeter Attia59:23

       ... get off this topic for a while.

   16. NBDr. Nir Barzilai59:24

       So yeah. So, so look, i- if I'm answering now why, why metformin and not, uh, rapamycin-

   17. PAPeter Attia59:31

       Oh, you don't need to answer that question.

   18. NBDr. Nir Barzilai59:32

       Eh.

   19. PAPeter Attia59:32

       I was just sort of teasing Steve that day, but-

   20. NBDr. Nir Barzilai59:34

       Yeah. Well, there are people who are asking, and of course, metformin, we have preliminary data. We have the cancer. We have clinical studies. You know, clinical studies of metformin, the Diabetes Prevention Program, it prevents diabetes. The UKPDS, it prevents cardiovascular disease. The Alzheimer literature, there are two clinical studies to suggest that in mild, uh, cognitive impairment, it improves some domain, by the way, like name recalling.

   21. PAPeter Attia1:00:03

       [laughs]

   22. NBDr. Nir Barzilai1:00:04

       Asimov. [laughs]

   23. PAPeter Attia1:00:04

       We'll, we'll up, we'll up your dose after dinner.

   24. NBDr. Nir Barzilai1:00:07

       Uh, so there's lots of... And safety. Look, if we're going to have a new indication, we don't wanna kill anybody [laughs] on the road. With rapamycin, we won't be sure, and it causes diabetes, and it cause, uh, testicular atrophy and cataracts in animals, okay? So we have to play it safe. So-

   25. PAPeter Attia1:00:27

       I w- I would only add one caveat in defense of rapamycin, which is with constitutive dosing

   26. NBDr. Nir Barzilai1:00:32

       Right

   27. PAPeter Attia1:00:32

       Yes, yes

   28. NBDr. Nir Barzilai1:00:32

       And, and you're, you're aware of the studies from John Manick, right?

   29. PAPeter Attia1:00:37

       Yes, of course.

   30. NBDr. Nir Barzilai1:00:37

       The, the last ones that-
9. 1:11:52 – 1:16:27

   TAME logistics: enrollment, dose, and power

   1. PAPeter Attia1:11:52

      So when... Realistically, when is the soonest you would begin enrolling for TAME?

   2. NBDr. Nir Barzilai1:11:58

      You know, I'm waiting for something to know next week, and if next week goes well... So I, I, I just want to let you l- know that we have an alternative. The alternative is non-for-profits, that the reason they haven't joined us is that their charter is not to fund anything that the NIH funds. They want something riskier.

   3. PAPeter Attia1:12:20

      Of course.

   4. NBDr. Nir Barzilai1:12:21

      So if the NIH is not funding because they feel it's risky, those will fund. So we can start anywhere, and it's the, the, the answer is early, uh, 2019, okay? We're, we're basically, all our centers are ready to go.

   5. PAPeter Attia1:12:37

      How many centers?

   6. NBDr. Nir Barzilai1:12:38

      14.

   7. PAPeter Attia1:12:39

      How many subjects?

   8. NBDr. Nir Barzilai1:12:40

      3,000.

   9. PAPeter Attia1:12:41

      Age?

   10. NBDr. Nir Barzilai1:12:42

       65 to 80.

   11. PAPeter Attia1:12:43

       Any limitation on comorbidities?

   12. NBDr. Nir Barzilai1:12:45

       No. In fact, well, there are a lot-

   13. PAPeter Attia1:12:47

       I mean-

   14. NBDr. Nir Barzilai1:12:47

       There are a lot of limitations-

   15. PAPeter Attia1:12:48

       You, you, I mean-

   16. NBDr. Nir Barzilai1:12:48

       ... but we're very inclusive.

   17. PAPeter Attia1:12:50

       But, but no, no existing diagnosis of cancer?

   18. NBDr. Nir Barzilai1:12:53

       Uh, no, un- uh, unless they're cured.

   19. PAPeter Attia1:12:55

       Okay, so you could be in remission, but you can't-

   20. NBDr. Nir Barzilai1:12:57

       Yes

   21. PAPeter Attia1:12:57

       ... have active cancer. You-

   22. NBDr. Nir Barzilai1:12:58

       Yes. You could have ca-

   23. PAPeter Attia1:12:59

       Uh, is it secondary prevention or primary prevention?

   24. NBDr. Nir Barzilai1:13:01

       You, you could have cardiovascular disease, you know-

   25. PAPeter Attia1:13:03

       Okay

   26. NBDr. Nir Barzilai1:13:03

       ... in the past if you're, if you're okay now. You could have mild cognitive impairment, and low speed walk will be a criteria. So in other words, we don't want the people, like in my study, who will become centenarians because we're wasting, [laughs] we're wasting, uh-

   27. PAPeter Attia1:13:21

       Yes

   28. NBDr. Nir Barzilai1:13:21

       ... time on them. We want people who we know are kind of in the midst of aging, and we know that it's never too late to target aging, and that's what we're targeting.

   29. PAPeter Attia1:13:31

       So 65 years and up, five years studied, and you're gonna randomize one to one or two to one?

   30. NBDr. Nir Barzilai1:13:38

       One to one.
10. 1:16:27 – 1:28:03

    How metformin may act on the pillars of aging

    1. PAPeter Attia1:16:27

       So let's go back to what we really glossed over, but now I wanna dive into. Why do you believe at the cellular mechanistic level metformin is an anti-aging drug?

    2. NBDr. Nir Barzilai1:16:40

       So let me take you through that in a, I don't wanna say schematic, uh, way because we don't have the scheme here, but in a, in a way that maybe I think will be easy to think. So I wanna start by saying that studies have shown that some of the effects of metformin are through AMP kinase, and some of them are independent of AMP kinase.

    3. PAPeter Attia1:17:03

       Yes.

    4. NBDr. Nir Barzilai1:17:03

       Okay? Is it important not for metformin, but I don't know which are the ones who are relevant more for aging, okay? And it's hard to know, and it'll get complicated in a second more. So metformin gets into the cell through a transporter that's called OCT1, okay? This transporter is not equally, e-equal in every cells. So unlike phenformin that goes without a transporters and affect everything, metformin is peculiar in this way, but we have the preliminary data, and it binds to complex one in the mitochondria.

    5. PAPeter Attia1:17:47

       Does it do so preferentially? Does it gain entry preferentially into the liver in humans?

    6. NBDr. Nir Barzilai1:17:53

       Only in the sense that there's a nice concentration of OCT1 in the liver, but not, not be- but it's not-- I don't think it's the top. Other organs have-

    7. PAPeter Attia1:18:03

       So basically, it's more about OCT distribution and expression maybe than-

    8. NBDr. Nir Barzilai1:18:08

       Well, it's more-

    9. PAPeter Attia1:18:08

       ... than tissue specificity

    10. NBDr. Nir Barzilai1:18:09

        ... it's more that I want, I want metformin everywhere, [laughs] okay? I want metformin everywhere, and I, and I'll tell you how I, I kind of proved that. So now, metformin binds to complex one in the mitochondria. I'll tell you that metformin has some action, epigenetic action, that are independent of the mitochondria. You can do it with what's called rho zero cells. You can, you can deplete mitochondria and see and measure things, and you can measure things even without mitochondria. Okay. Again- Do I need the mitochondria?

    11. PAPeter Attia1:18:44

        What, what type of epigenetic changes do you see in the rho cell?

    12. NBDr. Nir Barzilai1:18:48

        In histone deacetylation.

    13. PAPeter Attia1:18:49

        [laughs]

    14. NBDr. Nir Barzilai1:18:50

        Okay? So I cannot argue that this can be important. It's not important if we use metformin, but it's important if you want to ask me, are the mechanism of metformin AMP-dependent, mitochondria-dependent [chuckles] dependent? I, I don't know.

    15. PAPeter Attia1:19:05

        So there's an HDAC property that we may not have even thought of before.

    16. NBDr. Nir Barzilai1:19:09

        Right.

    17. PAPeter Attia1:19:10

        Okay.

    18. NBDr. Nir Barzilai1:19:10

        So it gets to the mitochondria, and i- in the mitochondria, it basically changes ADP/ATP ratio, and that's, a lot of it is important in the liver, but not only to the extent that there is an activation of AMP kinase.

    19. PAPeter Attia1:19:28

        And, and Nir, is there a demonstrable reduction in NAD to NADH in that cell when complex one is inhibited?

    20. NBDr. Nir Barzilai1:19:37

        Yes. Yeah, absolutely. Those studies have been s- have been done. So there's a lot that's going through AMP kinase, and I would tell you that downstream of AMP kinase, there is mTOR, [laughs] okay? And it depletes, uh, it decrease mTOR activity and increase autophagy, and there's a whole pathway that will go to the pillars of aging, right?

    21. PAPeter Attia1:20:00

        You know, I asked David Sabatini this question a month ago, and we're-- he doesn't know the answer, but I'm hopeful that maybe one of the postdocs in his lab will start to figure this out. I'm very curious about what the dose equivalent is between... In terms of purely looking at the readout of mTOR inhibition, what is the dose-to-dose equivalence of metformin via AMPK versus rapamycin directly? And I haven't-- I mean, David didn't know the answer, which tells me nobody probably [chuckles] knows the answer.

    22. NBDr. Nir Barzilai1:20:32

        Right. Look, it's, it's really difficult. First of all, for example, lots of the non-AMP kinase activities are on much higher doses of metformin, okay?

    23. PAPeter Attia1:20:41

        Well, that's my point, is can you clinically match them and, and-

    24. NBDr. Nir Barzilai1:20:45

        No, because you, you really don't know at the end how much metformin is in the cell. What we're doing now, we're doing isolated cells. In other words, we treated animals with metformin, and we're taking isolated cells to just see the variability of m- of metformin in individual cells. And-

    25. PAPeter Attia1:21:07

        Even amongst homogeneous tissues?

    26. NBDr. Nir Barzilai1:21:09

        Yeah.

    27. PAPeter Attia1:21:10

        Yeah.

    28. NBDr. Nir Barzilai1:21:10

        Like, we take hepatocytes and look at the, at the hepatocyte.

    29. PAPeter Attia1:21:12

        The variability of expression.

    30. NBDr. Nir Barzilai1:21:14

        Right.
11. 1:28:03 – 1:34:16

    Centenarians: compressed morbidity and genetics

    1. PAPeter Attia1:28:03

       This is a beautiful pivot to something else I wanna discuss with you, because unfortunately I could talk about metformin for three hours, but there's so many other things I wanna discuss with you, Nir, based on your work, and you just alluded to one, which is the work that you and your colleagues have done on centenarians has been very influential in my thinking. So as I think about aging clinically, I ask the question, start with the existence principle. What does it mean to live a long life? Is there proof of this having existed? And there is. We have centenarians. They exist. My hypothesis when I first started reading your literature, which was only about five years ago, my hope I should say, not my hypothesis, my hope was that whatever genetic benefit they had, which it became very clear to me very quickly that this wasn't about what they did. In fact, they seemed to have almost near immunity to the worst behaviors imaginable. My fear [chuckles] when I read your first paper, which was a review paper, I can still see it, and I still remember where I was sitting in a Sheridan Hotel reading it. My fear was whatever blessing they had, it was n- it had nothing to do with chronic disease, and it had to do with something nebulous, and they had complete immunity from chronic disease, and they just died in car accidents. Like, they eventually just died because something else tripped them up. And what I took away from your work was no, their genetic gift was a phase shift in when they got chronic diseases. They still died of heart disease. They still died of cancer. They still died of Alzheimer's disease. They simply got a 20-year bonus, if not more. Maybe 29 on average you could calculate. Call it a close to 30-year bonus.

    2. NBDr. Nir Barzilai1:29:53

       Well, of healthspan, you know?

    3. PAPeter Attia1:29:56

       Yes. Yes.

    4. NBDr. Nir Barzilai1:29:56

       Because-

    5. PAPeter Attia1:29:56

       Of completely functional life

    6. NBDr. Nir Barzilai1:29:57

       ... because they had compression of morbidity. So it's not only that they lived, uh, longer and they lived healthier, but they died [chuckles] sooner.

    7. PAPeter Attia1:30:06

       They died quicker.

    8. NBDr. Nir Barzilai1:30:07

       Quicker at the end of that. And you know, it's interesting, the CDC, the Center for Disease Control, have looked at the last two years' cost of life of people, you know, with different stuff.

    9. PAPeter Attia1:30:18

       Yeah.

    10. NBDr. Nir Barzilai1:30:18

        So they looked at people who die at 70 and after 100. And the cost of dying after 100 was third of that of dying in 70. So it's not only in our study. There's actually evidence-

    11. PAPeter Attia1:30:33

        Wow, I didn't know that

    12. NBDr. Nir Barzilai1:30:33

        ... to suggest that the medical go-- And by the way, those when they were 70, they didn't go to the doctor [chuckles] , okay? So the, and, and this is the base of this concept that's called the longevity dividend, okay? What, what will happen to society if we'll actually be healthier for two and a half years? And, and the benefits are immense. You think only of, uh, you know, so we pay Social Security more and stuff, but there are seven trillions dollars just in saving of medical costs if you could just live healthier.

    13. PAPeter Attia1:31:04

        So I know you don't spend an enormous amount of time anymore thinking about the centenarians. You know, your literature, I follow it very closely. You, you definitely are spending much more time talking about and writing about the things that we just discussed. But if you could go back in time a little bit for me-

    14. NBDr. Nir Barzilai1:31:18

        By the way, that's not true. [laughs]

    15. PAPeter Attia1:31:21

        Maybe it's just selectively where I'm reading.

    16. NBDr. Nir Barzilai1:31:22

        That's what... Well, no, I think that's what's interesting to people now, and I'm very happy about that. But I just got the, you know, the longevity, the Ipsen Longevity Prize, and my talk was actually about centenarians with a little bit of my hypothalamus, uh, stuff that was related to something.

    17. PAPeter Attia1:31:38

        Okay.

    18. NBDr. Nir Barzilai1:31:38

        But the centenarians are... And, and we have lots of grants on the centenarians because, you know, the-

    19. PAPeter Attia1:31:44

        Is that talk, by the way, uh, a, is it something that people can watch?

    20. NBDr. Nir Barzilai1:31:48

        No, no.

    21. PAPeter Attia1:31:49

        It wasn't recorded?

    22. NBDr. Nir Barzilai1:31:49

        It wasn't recorded.

    23. PAPeter Attia1:31:50

        Oh, that's a shame.

    24. NBDr. Nir Barzilai1:31:51

        It's a re- I, I thought about it, about this talk. It was fun for me to give because it was reflective a little bit. You know, one of the things that's always funny for me is people say, "Oh, you know, I have-- I can measure this thing. I'm sure that centenarians, they have, they have high level because high levels are good." And I had to put into rest the fact that the genetics of centenarians is really great for me, but the phenotype is not, because you have 100 years old, and you can measure something that can reflect what brought him here, or the fact that 30% of them are going to die in the next year. So it could be a marker of, of death [laughs] and not of longevity. Yeah, their phenotype makes m- doesn't interest to me. That's why I have their offspring, because their offspring will have the phenotype, or half of their offspring will have the phenotype. But those things were something that was nice because so many people are saying, you know, "We should measure in centenarians." No, we are, we're doing a longitudinal study on their offspring, and their offspring are equal everywhere to our control group. They just have half of the diseases. [laughs]

    25. PAPeter Attia1:32:59

        Although you... And by the way, that's a really interesting point, Nir. I never once thought of that. I never-- What you just said, that if I have a 100-year-old centenarian in my study, and he or she has a CETP mutation or an APOC3 mutation, and I look at the f- predictable phenotype because I know what you should have if you have that mutation, hypofunctioning APOC3 should have low triglyceride. But technically, without a little more longitudinal legwork, I don't actually know if what I'm measuring is a result of that. But that said, there must still be some benefit in... You know what? Now that I'm saying it, I realize you can't do it. The dream state would be to have health records and phenotypes for centenarians that go 30 years back. In other words, it would be beautiful to follow a centenarian from 70 to 100-

    26. NBDr. Nir Barzilai1:33:50

        So the-

    27. PAPeter Attia1:33:50

        ... with phenotypic data.

    28. NBDr. Nir Barzilai1:33:51

        Right. So that's why we have the longevity study. It's a longitudinal study of offspring of centenarians and people without longevity, and we're going forward. We're already 10 years into the study [laughs] and we're starting, you know, to see the differences between those guys. It's different population. They are aging slower, okay? The children of centenarians. So we have some of these things in mind.

12. 1:34:16 – 1:55:18

    Growth hormone/IGF genetics and sex differences

    1. PAPeter Attia1:34:16

       What are the most important genetic differences between those either centenarians or offsprings of centenarians and the rest of us?

    2. NBDr. Nir Barzilai1:34:25

       So it's very interesting, and, and so this is a part that you haven't heard so from, [laughs] but it's actually the growth hormone IGF axis. We have probably 60% of our centenarians have genomic reasons.

    3. PAPeter Attia1:34:43

       So let's explain the normal path of that. So the pituitary gland makes GH. It tells the liver primarily to make IGF.

    4. NBDr. Nir Barzilai1:34:50

       Right. It binds to a receptor-

    5. PAPeter Attia1:34:52

       Yes

    6. NBDr. Nir Barzilai1:34:52

       ... right in the liver, an IGF. And so some of the effects of the growth hormone system are through growth hormone itself, and some of it is through IGF-1 level. Both of them are decreasing with aging. So in this system, we identi-- you know, more than 60%, and I, I think I'm underestimating, okay? It, it's more, it's probably more, but I didn't really calculate who has several mutations. You know, I can calculate how many mutation there are, but not the overlap of the mutation. So I'm, I'm saying 60%, but it's the most common genomic alteration in our centenarians. And I have to tell you-

    7. PAPeter Attia1:35:33

       And where is it specifically?

    8. NBDr. Nir Barzilai1:35:35

       I, I'll tell you in a second. And I, I wanted just to tell you, I never-- I wrote grants on that because I thought because there's preliminary data in nature, right? The, the small dogs live longer-

    9. PAPeter Attia1:35:48

       Yes

    10. NBDr. Nir Barzilai1:35:48

        ... and the ponies live longer, and when you mutate growth hormone or, or they're born dwarf, they live longer, and when you give more growth hormone, they live shorter. So there is a lot in nature. But the human data was really confusing. Some diseases, you know, when you have high IGF, you have more cancers, but you have less cognitive-

    11. PAPeter Attia1:36:06

        Less Alzheimer's disease.

    12. NBDr. Nir Barzilai1:36:07

        Right.

    13. PAPeter Attia1:36:07

        Less cancer. I mean, sorry, less heart disease and less diabetes, but more cancer.

    14. NBDr. Nir Barzilai1:36:11

        Right. And mortality, in mortality, it's like in the middle, you know, a little bit tending to more from can- you know, from cancer and stuff.

    15. PAPeter Attia1:36:18

        By our analysis, which I think pulls all of your data, we found that there was an, a U-shaped mortality curve with the nadir being between 60th and 80th percentile of all-cause mortality.

    16. NBDr. Nir Barzilai1:36:31

        So I want to tell you the problem with this association.

    17. PAPeter Attia1:36:34

        Yeah.

    18. NBDr. Nir Barzilai1:36:36

        On one hand, an individual that age quickly, okay? Their growth hormone IGF goes down quickly, okay? So you would measure falsely low IGF-1 level that would-

    19. PAPeter Attia1:36:54

        If you catch them on the wrong side of their aging curve.

    20. NBDr. Nir Barzilai1:36:56

        Right. That wouldn't fit our theory that low IGF is good because that's their, uh, their accelerated aging.

    21. PAPeter Attia1:37:04

        Yeah.

    22. NBDr. Nir Barzilai1:37:04

        So this is a problem with an association study like that. We discovered, first of all, that when we take our centenarians -- So they're, they're in our study because they've been healthy at age 95, living independently. We take them at any age, but that's what they have to do.

    23. PAPeter Attia1:37:24

        Yeah.

    24. NBDr. Nir Barzilai1:37:25

        And we just look at those with the highest IGF and the lowest IGF-1 level. Those with the lowest IGF-1 level live twice as long. Those are already the centenarians.

    25. PAPeter Attia1:37:36

        Mm-hmm.

    26. NBDr. Nir Barzilai1:37:36

        But only women. Men do not. And every example that I gave you, there's a sex difference. The growth hormone IGF is very sensitive for women or for females.

    27. PAPeter Attia1:37:49

        Sorry, Nir, let me ask you another question. It's very difficult clinically to measure GH because it's pulsatile.

    28. NBDr. Nir Barzilai1:37:54

        Right.

    29. PAPeter Attia1:37:55

        So whenever you're saying growth hormone, are you really saying IGF, which is easier to measure?

    30. NBDr. Nir Barzilai1:38:01

        No, because I'm going to talk soon about not I'm me- what I'm measuring, but where the mutations are.
13. 1:55:18 – 2:05:30

    CETP, Lp(a), and the puzzle of protective genotypes

    1. PAPeter Attia1:55:18

       Do you think this at all explains the Lp (a) uptick we see? Because, you know, one of my favorite topics is lipidology, and of course Lp little a is a very virulent lipoprotein, and yet centenarians seem to have more of it than the general population.

    2. NBDr. Nir Barzilai1:55:33

       Exactly. So we actually, we actually showed in a, in a, in a paper, because we had a-- we, we found a way. So basically, um, we ca- ob- obviously we can have mutations that are protected because they have slow aging or longevity genes that protect them, right? So how do you prove that? So we noticed that when you look cross-sectionally -- I hope I can make it very simply. When, when, when we put any genotype cross-sectionally, in other words, we have all the ages from fifty to hundred and twelve is our oldest. We see patterns. If, if we see pattern that the genotype is declining with age, we know it's killing people, okay? If we see that it's kind of monotonically increased with age, like with the, with what-

    3. PAPeter Attia1:56:32

       Yeah, it's concentrating

    4. NBDr. Nir Barzilai1:56:33

       ... with... Yeah. Then means the people who are surviving are surviving with this mutation. That's why we have it more in hundred. Like the example of growth hormone receptor going from three to twelve in a, in a monotonic way. Um, so we looked at Lp little a. Exactly.

    5. PAPeter Attia1:56:52

       And this is the most confusing of them all because I don't see any compelling evidence that Lp little a is anything other than atherogenic. And so it begs the question, why would it concentrate in centenarians as opposed to just rise commensurate with the population?

    6. NBDr. Nir Barzilai1:57:10

       Exactly. So this is the answer, okay? First of all, we show cross-sectionally that Lp (a) drops until the age of eighty by half. In other words, it kills half of the people.

    7. PAPeter Attia1:57:22

       It's killing you like crazy-

    8. NBDr. Nir Barzilai1:57:24

       Peop- Right

    9. PAPeter Attia1:57:24

       ... until it's not.

    10. NBDr. Nir Barzilai1:57:25

        Right. And then, and then you look at it, and you kind of try to understand, just a minute, now this thing that killed, now all of a sudden centenarians have even more.

    11. PAPeter Attia1:57:35

        Right. It should stay flat after eighty.

    12. NBDr. Nir Barzilai1:57:37

        It should s- Right.

    13. PAPeter Attia1:57:38

        Yeah.

    14. NBDr. Nir Barzilai1:57:38

        It should be flat. Why is it increasing? Well, because it's a protected aging gene. In other words-

    15. PAPeter Attia1:57:46

        It was obviously during evolutionary times. Are you saying that the, the thing that Lp little a did for us five hundred thousand years ago that is no longer beneficial in this lousy environment, the centenarians have managed to tap into its properties of-

    16. NBDr. Nir Barzilai1:58:04

        No. No. No. So what we did, what we did, and it's all pub- published in computational biology journals, we took every one of the longevity gene that we have, and we did gene-to-gene interaction. In other words, we tried to see if there's interaction between the bad genotype and the good genotype, the good longevity genotype. And we did it to variety of those U shape, right? I'm, I'm, I'm telling you there is a U shape.

    17. PAPeter Attia1:58:34

        Yeah.

    18. NBDr. Nir Barzilai1:58:34

        You know, it goes down with aging, and then it's good in centenarians.

    19. PAPeter Attia1:58:37

        Mm-hmm.

    20. NBDr. Nir Barzilai1:58:38

        And we really found the sta- statistically significant that Lp (a) is protected by people who are homozygous to a C/T mutation that is a longevity mutation that we, we found before.

    21. PAPeter Attia1:58:53

        That's the VV mutation, isn't it?

    22. NBDr. Nir Barzilai1:58:55

        The VV mutation. In other words, most of the people with the Lp little a that are centenarians were also C/T, C/T, uh, mutation.

    23. PAPeter Attia1:59:04

        So can we tell people what that phenotype is? So I've talked on this podcast a lot about CETP and its role in reverse cholesterol transport, et cetera. Talk to me about what, what does the lipid panel look like for someone who is CETP-

    24. NBDr. Nir Barzilai1:59:18

        Yeah

    25. PAPeter Attia1:59:18

        ... VV plus or minus Lp little a?

    26. NBDr. Nir Barzilai1:59:21

        So those with CETP VV, they have higher HDL levels.

    27. PAPeter Attia1:59:26

        Mm-hmm.

    28. NBDr. Nir Barzilai1:59:27

        They have larger lipoprotein particle size, and they have lower CETP levels. That's their phenotype. And this CETP has been protective against several age-related disease. The most dramatic is cognitive decline. And by the way, the two APOE4 are also CETP VV carriers.

    29. PAPeter Attia1:59:50

        So really the question is, it sounds to me like if you are CETP VV, that's a very protective phenotype, and the difference, if I remember the data going from seventy to eighty, was basically flat if you're CETP VV. It really goes up when you turn eighty, meaning the concentration of CETP VV-

    30. NBDr. Nir Barzilai2:00:11

        The genotype
14. 2:05:30 – 2:21:47

    Growth hormone, IGF receptor antibody, and fasting

    1. PAPeter Attia2:05:30

       Let's go back to the IGF/GH thing because this one still creates tremendous... Let's bring it back to clinical stuff. So I'm often asked by patients, "Hey, should I be on growth hormone?" And my answer is, "I don't think so." But if I'm gonna be brutally honest, I really don't know. I really have no insight into whether growth hormone is-- exogenous administered growth hormone is harmful, helpful, neutral, or what, because the clinical data certainly don't give us the answer, right? So the epidemiology, if you're in sort of, you know, Valter's camp, is that would be the worst thing you could ever do. Growth hormone is bad because IGF is bad. But again, the epidemiology tell a different story, tell a much more nuanced story that has to do with how high is too high, at what age, and for what gender, and with respect to what disease. So of course, how can you manipulate IGF? Well, you can manipulate it... The two easiest ways to manipulate IGF, the three easiest ways to manipulate IGF are to manipulate growth hormone exogenously, manipulate IGF dietarily, pro- predominantly through amino acids, and manipulate insulin to indirectly impair or enhance IGF binding proteins.

    2. NBDr. Nir Barzilai2:06:40

       Well, let me tell you, we just published a paper in Nature a month ago, a study that we're, we're going also for a while, and what we did is we got from Amgen. Amgen, as, as much as other pharmaceuticals try to develop antibodies against IGF receptor because IGF receptor is expressed in many cancers.

    3. PAPeter Attia2:06:59

       Yeah, this was the disaster drug that they tested against metastatic pancreatic cancer.

    4. NBDr. Nir Barzilai2:07:04

       Right. Right.

    5. PAPeter Attia2:07:04

       It failed.

    6. NBDr. Nir Barzilai2:07:05

       Right.

    7. PAPeter Attia2:07:05

       But if I recall, there was a very special little gift, which is no CNS penetration. Am I thinking of the right one?

    8. NBDr. Nir Barzilai2:07:14

       Yeah. Right. So it failed, but we're interested for aging, right?

    9. PAPeter Attia2:07:20

       Yes.

    10. NBDr. Nir Barzilai2:07:20

        And not only we're interested for aging, our hypothesis was that IGF, you know, that, that you need to decrease IGF action in the periphery, but increase it in the brain because of the data.

    11. PAPeter Attia2:07:33

        Yep.

    12. NBDr. Nir Barzilai2:07:33

        So we asked them to humanize their, uh, antibodies. Humanize means to-

    13. PAPeter Attia2:07:38

        Make it available for a mouse

    14. NBDr. Nir Barzilai2:07:39

        ... make it, right. And we got it, and we did a longevity study that we started at 22 months of age.

    15. PAPeter Attia2:07:46

        By the way, remind me in the human study, how much did it lower IGF in the periphery?

    16. NBDr. Nir Barzilai2:07:52

        It increased IGF.

    17. PAPeter Attia2:07:53

        I, I'm sorry. I know it in... I'm sorry. How much did it lower IGF activity in the periphery? Was it a reduction by what fold? Like, was it a twofold reduction?

    18. NBDr. Nir Barzilai2:08:00

        It's, it's very hard to measure. You don't measure it like that. You measure it in, in, you know, in vitro. It's very hard to measure how much.

    19. PAPeter Attia2:08:07

        Got it. Okay.

    20. NBDr. Nir Barzilai2:08:08

        And they rebounded a little bit with IGF, which is not the case with aging, because with aging you don't have the growth hormone secretion. So we gave it to 22 months old animals that are 70, 75 years of age equivalent. We increased their healthspan dramatically, and we increased their lifespan by 10% at an old age. Okay? So this is a drug that's already was-

    21. PAPeter Attia2:08:33

        And, and, and you were able to demonstrate... I, I'm sorry I missed this paper. It came out a month ago, so I'll be inhaling it, uh, this time tomorrow. You basically showed that you didn't change IGF levels in the brain, or you actually increased IGF levels in the brain?

    22. NBDr. Nir Barzilai2:08:46

        We, we really don't know. There is a little increase in IGF-1 level in the periphery, and we're assuming that we didn't make it a big... I'm telling you what we thought. We didn't make it such a big deal, but obviously the antibodies do not cross the blood-brain barrier. But the IGF wasn't lower, if anything, it was higher.

    23. PAPeter Attia2:09:08

        Right. So if anything, IGF went up in the periphery because it was being blocked, and-

    24. NBDr. Nir Barzilai2:09:12

        And, and therefore a little bit higher periphery

    25. PAPeter Attia2:09:13

        ... it could have got more into... So you could have had more CNS activity, less peripheral activity-

    26. NBDr. Nir Barzilai2:09:18

        Right

    27. PAPeter Attia2:09:18

        ... of IGF.

    28. NBDr. Nir Barzilai2:09:18

        Now, now again, those were aging... By the way, it was in females. In males, we started to do the studies in males, and since we didn't see any major effects, and we had relatively little [chuckles] you know, those are months of studies in many mice, so we eventually did the longevity only in females. We don't have data on males. But the extent of healthspan, and you, you'll see the paper. It's really, it's a great paper with lots of studies, and it's impressive how much they did better, the females with it. So there you have an example. We have all the pathway. You ask, "What do we do?" Here is... It's been in humans, okay? The IGF receptor antibody is there. The only problem for us is aging could be an indication what, what's before aging. Like, we need another indication in order to start selling it before.

    29. PAPeter Attia2:10:10

        But what's your hypothesis in those mice, in the female mice, that they... You said they live 10% longer, and what-

    30. NBDr. Nir Barzilai2:10:17

        And much healthier
15. 2:21:47 – 2:29:35

    Human metformin biopsy study and weight loss

    1. NBDr. Nir Barzilai2:21:47

       The, the one thing I should say, I just don't want to forget anything. Can I, can I?

    2. PAPeter Attia2:21:52

       Absolutely.

    3. NBDr. Nir Barzilai2:21:53

       And, and it's, it's back to the metformin. Just reminded me. It's back to me- the metformin studies. So our reviewers were saying, "You know, okay, all the data on the biology that you showed was from rodents, and we don't know that the biology is relevant to humans." Okay? Although, of course, the preliminary data in humans are much better than in rodents, right? The association with diseases. So we had a clinical study, a s- a small clinical study, which we took 15 people that are 75 years old, and we gave some of them metformin for six weeks and other placebos, and then we crossed over, and it was blinded. And we took it, at the end of each period, we took biopsy from their muscle and biopsy from their adipose tissue. Okay? So not liver. [laughs] And we looked at the transcript and the metabolomics, but m- mainly the transcripts in the tissues to see effects on metformin. And there are three interesting things. First of all, when they brought me their clinical results, you know, insulin, HOMA, glucose, and all, there were significant effects in many of them, statistically significant effects, but I was expecting more. I started to try and break it down, and then we found out that the people who were last on metformin, although it was half of the people, had much more significant results than the whole 15 people.

    4. PAPeter Attia2:23:28

       Wait, explain that again. The people in the crossover who started, who went placebo to metformin-

    5. NBDr. Nir Barzilai2:23:34

       Had better effects on metabolic parameters.

    6. PAPeter Attia2:23:38

       Relative to themselves or to their peers?

    7. NBDr. Nir Barzilai2:23:41

       Relatively to themselves.

    8. PAPeter Attia2:23:42

       'Cause every-- This was a person to person. This was an... Yeah.

    9. NBDr. Nir Barzilai2:23:46

       Person to person.

    10. PAPeter Attia2:23:46

        This was a paired T-test.

    11. NBDr. Nir Barzilai2:23:48

        And the reason is that probably the two weeks washover is not enough. When you fix this aging, [laughs] it lasts for a while. Okay?

    12. PAPeter Attia2:24:00

        Yeah.

    13. NBDr. Nir Barzilai2:24:00

        So if you got metformin and then placebo, you didn't really... You, you went halfway back. Also, by the way, because metformin is associated with weight loss and they lost a little weight, that on itself really made them on the second part.

    14. PAPeter Attia2:24:15

        What do... Yeah, yeah. No, what-- It's funny you bring that up. I'm glad you mentioned that. What do you think explains the weight loss phenotype of metformin? So when I started taking metformin, which was 2010, I didn't mess around. I just went straight to 2.5 grams a day. I didn't even mix it up. I don't think I took it BID. I mean, I took two 2,500 milligrams first thing every morning. And after a month, I lost quite a bit of weight, but I was also nauseous 24/7. I mean, the thought of eating was repulsive to me. I still ate. You know, I was exercising a lot and doing all my usual shenanigans, but I clearly ate less just because of that low-grade feeling of nausea. Today, when I prescribe metformin to patients, I have them start at 500 QHS, then 500 BID, then fif- you know, 500 in the morning, 1,500 before bed, then one gram BID is sort of standard dose. Um, and I see far less of that nausea, and I see far less weight loss. What, what other mechanisms do you think it could explain the weight loss?

    15. NBDr. Nir Barzilai2:25:16

        So could it be lactic acid going up? You know, just like ketones, you get a little bit-

    16. PAPeter Attia2:25:20

        As in a substrate, an additional substrate?

    17. NBDr. Nir Barzilai2:25:23

        Yeah. I don't know. But look, I started metformin several years ago because I was pre-diabetic. My doctor did it, so it's before [chuckles] ... I'm glad that he did, but it was before I thought much about it. And I was just surprised after three months to realize that I lost, uh, you know, seven or eight pounds. I was surprised because I couldn't-- I, I wasn't nauseated, I wasn't anything.

    18. PAPeter Attia2:25:48

        Mm.

    19. NBDr. Nir Barzilai2:25:49

        I must have eaten less. I, I was less hungry. I r- I reacted better. [chuckles] R- I reacted better to my body, right? To my leptin maybe. I reacted better, and I probably didn't eat as much, not n- totally not noticing it. It was a surprise to me.

    20. PAPeter Attia2:26:07

        Yeah. Yeah. Uh, it's funny, I tell patients not to expect that 'cause I don't, I don't like the idea of patients thinking of this as, like, a weight loss drug. To me, that sort of is, is not the, the right way to think about it. But I've never had a great explanation. And, and by the same token, I have had-- I, I, I should be clear, I've had also some patients who have, they've come back and they've lost 10 pou- And these are patients who are not overweight. This is not, you know, this is someone that by everybody's standard would be completely normal weight. You know, BMI is 24, body composition is reasonable, and comes back in, you know, in three months and they've lost 10 pounds. But I guess for, in my-- at least in my practice, that seems to be the exception and not the rule. But very, very interesting to h- you're... You know, I guess, of course, you wish that was more than a two by two, two week. You wish that was a 12 week by 12 week.

    21. NBDr. Nir Barzilai2:26:52

        Right. We're doing the same thing with acarbose now, and we're doing longer study with longer washing period because we wanna get away from that. But back to metformin, I said that's one thing is this-

    22. PAPeter Attia2:27:02

        Yeah

    23. NBDr. Nir Barzilai2:27:03

        ... uh, metformin last issue. The second thing that we showed that most of the transcript changes were relative to this, to the tissue. You know, in fat it was more free fatty acid metabolism. In the muscle it was more pyruvate metabolism. So it was appropriate. In other words, there wasn't the metformin, you know, the metformin part. But in both tissues, there were genes that are not metabolic genes, you know, like BRCA1 or myofibril genes and other things that are related to aging, but they are not metabolic. They change by metformin. In other words, the concept that metformin is not only metabolic, it's aging, okay?

    24. PAPeter Attia2:27:43

        Uh, BRCA1 changed?

    25. NBDr. Nir Barzilai2:27:45

        Yeah. You know, some other gene, genes that are associated with genet- with, uh, with DNA repair changed significantly. The second thing-

    26. PAPeter Attia2:27:55

        Did you see in the muscle, by the way-- If, if you still have biopsies, I'd be very curious to know if the lactate transporter out of the muscle... I'm, I'm blanking on it. It's, um, MCT2. Uh, in, in other words, as people make more and more lactate in the muscle, do they get more and more efficient at shuttling it back to the liver? And if so, you would expect MCT2 transport-

    27. NBDr. Nir Barzilai2:28:17

        And does the gene expression changes by that?

    28. PAPeter Attia2:28:21

        Yeah.

    29. NBDr. Nir Barzilai2:28:21

        You know, we have the raw data. It didn't come up, I'll tell you, it didn't come up as a winner, but that doesn't mean it's not, it's not changed.

    30. PAPeter Attia2:28:28

        And you looked at genome or you looked at, you looked at messenger as well? You looked at mRNA?
16. 2:29:35 – 2:47:45

    NAD precursors, remaining metformin thoughts, and where they could be wrong

    1. PAPeter Attia2:29:35

       it breaks my heart.

    2. NBDr. Nir Barzilai2:29:36

       And so, and so we, we really connected n- not only the clinical data, but the biological data in humans to the TAME study.

    3. PAPeter Attia2:29:45

       Yeah. It's, it's wonderful. Y- y- you know, s- it, um, a few years ago when my, my father was diagnosed with cancer, I immediately put him on metformin. And, um, you know, in his infinite wisdom, his primary care doctor took him off it because, you know, why would you put him on metformin? And in the end, my father decided his primary care doctor knows much more than I do, and so remains off metformin. But, uh, certainly this discussion, 'cause I, you know, I probably know more about metformin than the average person, but this discussion has been completely illuminating. There's one other thing I wanna ask you about, which is all of the discussion around NAD. I mean, you're, you know quite a bit about this. What is your take right now based on the state of the science that we have, which admittedly I think we're just scratching the surface of, a- as far as first and foremost, just at the mechanistic level, do-- what is your belief that orally administered nicotinamide riboside can actually make it into a cell? I don't know if you've seen it, but Josh Rabinowitz's paper over the summer would suggest, no, most of this is going to the liver.

    4. NBDr. Nir Barzilai2:30:49

       That it doesn't get... Right.

    5. PAPeter Attia2:30:49

       So wouldn't this sort of call into question the companies, there's two of them right now, ChromaDex and, uh, uh, Elysium, that sell basically nicotinamide riboside plus or minus pterostilbene. What do you think explains the reported efficacy of those agents in light of Rabinowitz's NAD tracer study?

    6. NBDr. Nir Barzilai2:31:10

       First of all, the Rabinowitz study was also criticized, okay? Time course and other things, which Okay, I'm just saying that. But I think really the biggest, uh, issue here, uh, I want just to use this opportunity to say that a lot of what we're doing is not based on clinical studies, okay? And it really just underlines the fact that unless you do a clinical study, you can remain guessing. Now, I'll tell you, I'm, I'm taking a good preparation of NMN, okay?

    7. PAPeter Attia2:31:51

       Tell the listener the difference between NR and NMN, because they're both precursors to NAD, but there's a, there's a subtle difference.

    8. NBDr. Nir Barzilai2:31:58

       Yeah, and I, I don't know. I, I don't know to explain that really well. I, I don't, I don't care [chuckles] that much-

    9. PAPeter Attia2:32:05

       Okay

    10. NBDr. Nir Barzilai2:32:05

        ... about it.

    11. PAPeter Attia2:32:05

        But in theory, one is slightly more stable than the other, but-

    12. NBDr. Nir Barzilai2:32:08

        Ri- right

    13. PAPeter Attia2:32:09

        ... yeah

    14. NBDr. Nir Barzilai2:32:09

        It's a stability issue, availability issue, but they'll fight, and we, we don't know which is the better, and we don't know which gets to the tissue, right?

    15. PAPeter Attia2:32:16

        Yeah.

    16. NBDr. Nir Barzilai2:32:17

        Um, but what I wanna, what I, I wanted to say is the following. So, so the answer is n- it could als- it could all be water, okay? It could all be this.

    17. PAPeter Attia2:32:29

        You say that as you hold up a bottle of Topo Chico.

    18. NBDr. Nir Barzilai2:32:31

        Right. Sorry. No, you didn't see that in the microphone?

    19. PAPeter Attia2:32:34

        [laughs]

    20. NBDr. Nir Barzilai2:32:35

        Okay. But what I'm doing now is I'm opening my Fitbit, okay? And one of the things that the Fitbit has is sleep, okay? Do you use Fitbit?

    21. PAPeter Attia2:32:46

        No, I use something called Oura, which works much better.

    22. NBDr. Nir Barzilai2:32:49

        Okay.

    23. PAPeter Attia2:32:50

        Yeah, this really measures sleep well.

    24. NBDr. Nir Barzilai2:32:51

        Do, do you get also the deep sleep and the-

    25. PAPeter Attia2:32:54

        Yes

    26. NBDr. Nir Barzilai2:32:55

        ... REM and all that?

    27. PAPeter Attia2:32:56

        Yeah.

    28. NBDr. Nir Barzilai2:32:56

        Okay. Since I started taking NMN, and it might be a coincidence, so I have to stop it and start again, but my sleep has been much better. That means I have... in the beginning of the night, I have much more deep sleep, and then the end of the night, I have much more REM.

    29. PAPeter Attia2:33:14

        Mm-hmm.

    30. NBDr. Nir Barzilai2:33:15

        And I thought if there's anything I can say about it, is that just because of this association, okay? But I don't believe it, right? Because it's not a... it's an... it's my... it's me and-

Episode duration: 2:47:45