222 ‒ How nutrition impacts longevity | Matt Kaeberlein, Ph.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.

2. 0:08 – 5:26

   Challenges with understanding the effects of nutrition and studying interventions for aging

   1. PAPeter Attia0:09

      Matt, it's great to finally be able to do one of these in person with you. We've done a lot of these remotely. Uh, we're taking advantage of the fact that you're in Texas for, uh, filming a documentary about aging, which is pretty awesome. Um, so when we knew that this was gonna happen, we said, "Well, let's take advantage of you being here, and let's, let's come up with something that we both talk about so much, uh, over email," which I-- is to say, I don't think a week goes by that we aren't exchanging an email about some aspect of the relationship or the interface between nutrition and longevity. Uh, does that speak to our ignorance?

   2. MKDr. Matt Kaeberlein0:41

      [laughs]

   3. PAPeter Attia0:41

      Does that speak to the ubiquity of such content? I don't-- What does that say about us?

   4. MKDr. Matt Kaeberlein0:44

      Yeah, I mean, it-- Well, I think, you know, it's an, it's an area that a lot of people are really interested in and, and, um, and it certainly intersects with, uh, popular culture. So, you know, I, I, uh, having been in the aging field for, for a long time, I certainly recognize how complicated that biology is, and I think the biology of nutrition is equally complicated. And, you know, when you get at the interface of those two, um, it's really hard, I think, sometimes to draw a definitive conclusion. So a new paper will come out, you know, and, [clears throat] and you usually read the papers before I do, and you're like, "Hey, what do you think about this?" And, and then, you know, we, we throw it back and forth. But I think it's, um, it's hard sometimes to get to concrete answers, so certainly we'll try to do that today. But I also think, you know, this will be a little bit of a theme that, that, um, there are many things we don't understand yet about optimal nutrition and how that intersects with optimal healthspan.

   5. PAPeter Attia1:38

      Yeah. And you and I have spent so much time on the podcast speaking about the molecules, right?

   6. MKDr. Matt Kaeberlein1:44

      Right.

   7. PAPeter Attia1:44

      The molecules, right? Um, of course, our favorite being rapamycin, but, but all sorts of them, right? We recently talked about NMN and our NAD. We've talked about metformin. And, you know, basically, it's easier almost to ask the questions in the stand- from the standpoint of geroprotective molecules because the intervention is much cleaner.

   8. MKDr. Matt Kaeberlein2:02

      Yeah. Absolutely.

   9. PAPeter Attia2:03

      Like, are you taking this drug, yes or no? And of course, what's interesting about that, and I think it speaks to what we're gonna talk about today, think about the one drug among those that stands out, which is rapamycin. Even within that, just I think yesterday or two days ago, you and me and David Sabatini had a back and forth about timing of the dose, you know, frequency within the dosing schedule, the dose itself. I mean, even with a drug, it's still very complicated to say, "Well, what about during this pha-" 'cause the study I think we were talking about was looking at mice, and it was asking the question of early exposure of rapamycin later in life, constant dosing, intermittent dosing.

   10. MKDr. Matt Kaeberlein2:43

       Yep.

   11. PAPeter Attia2:44

       That's for a drug-

   12. MKDr. Matt Kaeberlein2:45

       Yep

   13. PAPeter Attia2:45

       ... and we're still struggling to piece it together. Now imagine trying to ask that question of your food.

   14. MKDr. Matt Kaeberlein2:52

       Yeah. And I mean, I think, you know, we'll obviously talk a lot as well about the animal models and what they can tell us about, you know, what might affect human aging. But the big piece that gets lost with the animal models on top of all that complexity is the environment, right? So, you know, we keep these mice in a well-controlled environment, usually relatively pathogen-free, and they live in that same environment their entire life. Now you think about the human experience, where our environment is extremely complicated. We're constantly getting bombarded with all sorts of, you know, challenges and, and, uh, infectious agents, and our environment changes dramatically throughout our lives. In fact, you know, maybe this is something we wanna touch on. A lot of the epidemiological studies on optimal nutrition are from twenty, thirty, forty years ago, right? The average human environment is very different today than it was when those studies were done. And how does that potentially change the interaction between nutrition and health outcomes? I, I think it's a really interesting but challenging question to, to address to anybody's satisfaction, honestly.

   15. PAPeter Attia3:55

       Yeah, that's actually a great point. And, and I made a similar point on a totally different topic, which was [clears throat] all of the studies that use, uh, that talk about cancer screening are, are very backwards looking by definition, right?

   16. MKDr. Matt Kaeberlein4:08

       Yeah.

   17. PAPeter Attia4:08

       You have to look at controlled trials that were done in the past. But the technology of radiology is changing so much. You know, rad- radiology is a very, you know, physics-based, uh, field of medicine. And so when you read a study that talked about, you know, mammography for screening, well, and it, you know, was a fifteen-year study, right? So it's a great study. Well, by definition, it was done sort of based on thirty to twenty-year-old technology-

   18. MKDr. Matt Kaeberlein4:33

       Yep

   19. PAPeter Attia4:34

       ... that by the time the study has been completed, you have the follow-up data, you write up the paper, it doesn't necessarily represent what's happening today. And, and that's, that's a huge challenge of evaluating that type of data.

   20. MKDr. Matt Kaeberlein4:46

       Yeah. And in, and in people, because we age so slowly, you know, there's really not a lot you can do about that if you wanna try to do correlative longitudinal studies of aging, right? Because people age so slowly, the people who are in their seventies today were in their thirties forty years ago. And so the environment that they were in is probably quite different than the environment that thirty-year-olds are in today. So there's not a great way around that. I think the key is to recognize that limitation and be potentially even more careful about assuming causation from correlation over many decades.

   21. PAPeter Attia5:25

       Yeah.

3. 5:26 – 14:48

   How Peter’s and Matt’s convictions on nutrition and thoughts optimal health have evolved

   1. PAPeter Attia5:27

      So as, as a bit of a mea culpa on the topic of nutrition, which is really my least favorite topic despite the fact that it keeps coming up on this podcast and it's unavoidable, uh, I-- as I reflect back on my own understanding of this topic, the strength with which I held convictions over the past more than decade, I, I would say I've, I've gone in reverse, right? I have looser and looser convictions as time goes on.

   2. MKDr. Matt Kaeberlein5:54

      Yeah.

   3. PAPeter Attia5:54

      And I view fewer and fewer things with certainty as time goes on. And [clears throat] You know, when I think about this problem clinically, I have what I would consider to be an incredibly simple framework, which is if I'm looking at a patient, I'm asking a question: Are you overnourished or undernourished? Are you undermuscled or adequately muscled? And then on... So that's a two by two, right? And then are you metabolically healthy or not? That's sort of my first order question.

   4. MKDr. Matt Kaeberlein6:29

      Yeah.

   5. PAPeter Attia6:29

      Now, one of those spaces doesn't really have too many people in it. The, um, adequately muscled, undernourished, metabolically healthy bucket doesn't-- uh, metabolically unhealthy bucket doesn't really exist.

   6. MKDr. Matt Kaeberlein6:44

      Hmm.

   7. PAPeter Attia6:45

      So it's not-- these aren't-- people aren't uniformly distributed in those buckets, but it's a pretty good way to sort people, and you can't sort someone by looking at them into that bucket. But by looking at them, doing some functional testing, looking at their biomarkers, a- and that might include also doing things like a DEXA scan where you can actually get some objective data, you can pretty quickly figure that out. And the reason we think that's important is it helps us understand, do you need an energy deficit? Do you need an energy-

   8. MKDr. Matt Kaeberlein7:16

      Right

   9. PAPeter Attia7:16

      ... surplus? What's your protein intake need to be to achieve that in combination with your calorie needs? And, you know, the hardest, uh, of those to treat by far is over, uh, nutrition, under muscled. And unfortunately, that's a very common phenotype.

   10. MKDr. Matt Kaeberlein7:36

       [chuckles] That's, that's a lot of people these days. Yeah. No, I mean, I think that-- I think as a general approach, first order approach, that makes a ton of sense. Um, and I think, you know, one of the things that, that, that allows you to recognize, right, is that, that the optimal strategy isn't-- there's no one size fits all, I guess, would be the way I'd say it, right? Different people are gonna have different needs nutritionally, and what works really well for one person, you know, may not work at all for another person. And so I think, I think, you know, kind of looking at it at that level, um, allows you to, to, to not have to try to say everybody should be doing X, right? Um, so I think, I think that that is pretty similar to the way I think about it. Obviously, I don't practice medicine, and I, I try not to make recommendations for what people should do, but in my own life, that's generally the way that I try to a-approach it as well, and I, and I hope I'm doing okay. You haven't tested me yet, so you can't tell me which bucket I'm in, but I think I'm doing okay for my age, uh, with my, my nutritional strategies. And the other thing that I sort of have, have realized, similar to what, what I think you were saying before, is that, you know, it's an ongoing learning process. And so I think it's really important that we be willing to change our beliefs about nutrition and other aspects of health as more data comes in. Um, so I think if you take that strategy, then you can, you can be open to the possibility that what you believed ten years ago, you know, might not have been exactly right, and maybe we need to, to, to tweak it a little bit. Um, you know, my personal view on nutrition, I, I, I'll, I'll be honest, I have real trust problems with nutritionists, and I think it... You know, in part it stems from, I remember very vividly when I was, I think I was probably in my early 20s and I, I read, you know, one of these diet guru books, and it was sort of the, the sort of the, the, the theme, this was-- I'm gonna date myself, but this was, you know, early '90s, I guess. Um, the theme back then was, you know, you could eat anything you wanted as long as you cut out the fat, right? You could have this really high, simple carbohydrate diet, just keep it low fat and, you know, you'll be fine. And we now know that's, that's exactly wrong, right? [chuckles] I mean... So I think, you know, I, I can't help but look at a lot of what people, you know, the, the, the, the... what I would put sort of on the f- the, the fad diet side, the diet gurus, what they're saying today, how do we know 10 years from now we're not gonna look back on that and again be like, "That just makes no sense"? I think some of us today can look at some of what's out there and say, "That just makes no sense." But, you know, I think, again, this gets back to the-- to what I was saying before. It's not that I, it's not that I would say nutrition science is across the board low quality. I think there are actually really good scientists doing really good work in this area. It's just a really hard problem. And I g- and I do think to some extent the biology of aging and the biology of nutrition do share that in that they are-- these are extremely complicated biological systems that we're, we're trying to understand in the, in the context of sort of this, this changing environment over time, right? And so, so I don't, I don't blame the scientists. I just think we have to be really careful to recognize what the limitations are and not draw really strong conclusions like everybody should eat, you know, a low-protein diet, right? That's kind of one of the fads that are out there today. I think that's, that's a mistake to, to, to recommend across the board, you know, nu-nutritional strategies for everyone. Um, I guess the last thing... Sorry, I'm, I'm talking a long time here, but I guess the last thing that, that what you said, you know, makes, makes me think of as well, and I think this is really important 'cause people lose sight of this, is, you know, exactly what you said. If you can be, you know, somewhere close to uh, uh, optimal nutritional intake, right? We'll just say total calories regardless of composition. Body composition is somewhere close to where it should be. That's, that's a big chunk of what you need to give yourself the best chance of being healthy going forward, right? You don't have to optimize every single thing. Now, I know you're all into optimization, and I, and I respect that about you. I think if you can do that, that's great, but you don't have to to get most of the benefits. And so I think starting from that big picture perspective allows you to get most people most of the way there, and then when they're most of the way there, you can focus on how do we get that last 10, 20, 30%, whatever it is.

   11. PAPeter Attia11:52

       Actually, I, I, I couldn't agree with you more, Matt, and, and I would argue, and I do argue now in a very different way from w- where I used to be a few years ago You know, there are most things in my life where I don't like the 80/20 principle, you know? Uh, my good friend Tim Ferriss, like, he's the king of this, right? He's the king of, [clears throat] "How can I get 80% of the learning with 20% of the time?" And I've never seen anybody who can do it like Tim. Like, the guy can learn a language in a month.

   12. MKDr. Matt Kaeberlein12:23

       [chuckles]

   13. PAPeter Attia12:23

       He can be 80% proficient in a language in a month, right? Um, I'm the opposite. I'm the guy who loves the tail. I love the asymptote. I love the perfection of something. I would say in nutrition, that is exactly not where my interest lies.

   14. MKDr. Matt Kaeberlein12:39

       [laughs]

   15. PAPeter Attia12:40

       I agree that you can just get 80% of this right by focusing on, you know, exactly what we've talked about, and the, the details, the complete optimization are not worth it.

   16. MKDr. Matt Kaeberlein12:54

       Yeah.

   17. PAPeter Attia12:54

       And it's instead better to put that effort into exercise. That's where I think-

   18. MKDr. Matt Kaeberlein13:00

       Yeah

   19. PAPeter Attia13:00

       ... if you're going to really go down the rabbit hole and put more of your mental energy, more of your time, and more of your focus into something, you have far more of an ROI on the exercise front than eking out incremental value on the nutrition front. And I've joked about this before, other guests on the podcast, Layne Norton and I, have had riffs on this back and forth. The people who sit there on Twitter, which I realize is not-

   20. MKDr. Matt Kaeberlein13:24

       [laughs]

   21. PAPeter Attia13:24

       ... a representative sampling of the world.

   22. MKDr. Matt Kaeberlein13:26

       Yeah. [laughs]

   23. PAPeter Attia13:27

       It's simply a, an annoying vocal group of people who will waste endless hours debating the finer points of their dietary pet peeves who can't do 10 pull-ups-

   24. MKDr. Matt Kaeberlein13:38

       Yeah

   25. PAPeter Attia13:39

       ... is amazing.

   26. MKDr. Matt Kaeberlein13:40

       Yeah.

   27. PAPeter Attia13:40

       I mean, there, there should be a rule that says-

   28. MKDr. Matt Kaeberlein13:42

       [laughs]

   29. PAPeter Attia13:42

       ... if you can't deadlift twice your body weight and do 15 pull-ups, you shouldn't be allowed to pontificate endlessly-

   30. MKDr. Matt Kaeberlein13:49

       You're not allowed to be on Twitter
4. 14:48 – 21:05

   Calorie restriction for improving lifespan in animal models

   1. PAPeter Attia14:48

      so one thing that seems to be true is, at least from the animal literature, caloric restriction seems to reproducibly improve lifespan. And so, so let's, let's kinda talk about how that came to be as an understanding.

   2. MKDr. Matt Kaeberlein15:05

      Sure, yeah. So I mean, this, um, this area of research is actually quite old, so the-

   3. PAPeter Attia15:12

      So it's 100 years ago, right?

   4. MKDr. Matt Kaeberlein15:13

      Yeah. The first experiments were published in the early to mid-1930s, right? Which means they were probably started in the 1920s, right? So almost 100 years ago, people were going down this, this line of thinking, of asking, you know, what is the effect of, um, significant restriction of calories on the aging process in mammals? So the early studies were all done in rats, and actually, uh, if, if I remember correctly, these studies were originally designed from a developmental perspective, so they were really thinking about malnutrition, um, and its effects on development and, as a byproduct, made the observation that, yes, when you restrict calories in a, in a rat early on in life, they have a smaller body size. Um, uh, but then if you let them live out their entire lives, this is in the laboratory, and I think that's really important to keep in mind, you know, they live 40, 50% longer. So we're talking really significant increases in lifespan. And then the other thing that was appreciated pretty quickly was not only are they living longer, but they seem to be healthier as they're living longer. So you know, this concept of healthspan and the period of life that is, you know, spent in good health, free from disease and disability, it seemed as if caloric restriction was not only increasing lifespan but al- but also extending healthspan. So you know, that led to o- obviously, a, a large body of literature since then studying the effect of caloric restriction in not just rodents, rats and mice, but also all sorts of simpler organisms, invertebrates like fruit flies and C. elegans and yeast, and the common theme seems to be that, again, starting from laboratory conditions, if you restrict nutrients by a whole variety of different, different methods, um, you can increase lifespan and a- apparently increase healthspan proportionally, at least proportionally. Um, so there's a lot of nuance there, a lot that we can dive into and to unpack, but I think that's generally the, the take home, right? Is that over and over and over again across... You know, the, the evolutionary distance we're talking about is much, much greater than the evolutionary distance between rodents and humans, right? So, so over a very wide evolutionary distance in pretty much every organism where it's ever been studied, you can find evidence that caloric restriction slows aging. Um, uh, again, there are, there are cases where that didn't happen, where lifespan wasn't extended, where lifespan was shortened. Maybe we want to talk about this at some point, the interaction between genetics and environment and caloric restriction. But in general, that is, the, the, the take-home message is caloric restriction can slow aging in laboratory animals pretty much everywhere where it's been studied. Um, the one, I think, question, question that some people have is whether that's true in non-human primates, and so there w- you-

   5. PAPeter Attia18:03

      Yeah, so I was just about to say, uh, I was gonna say before we get to NIA Wisconsin-

   6. MKDr. Matt Kaeberlein18:08

      Yeah

   7. PAPeter Attia18:08

      ... which is- Perhaps the single greatest experiment that's ever been done to test this hypothesis, both in terms of its duration, level of control, and proximity to our genome. Let's spend a moment on that. Before we do, any things that come up from the rodent studies that are worth talking about? So for example, one of the things that I think is always important to point out is there's a very particular death that tends to fall on laboratory mice. They have... You know, if you look at the death bars for humans, there's much more heterogeneity.

   8. MKDr. Matt Kaeberlein18:43

      Yeah.

   9. PAPeter Attia18:44

      But the leading cause is atherosclerosis. Now, that's true in the United States. It's true across the globe.

   10. MKDr. Matt Kaeberlein18:51

       Yeah.

   11. PAPeter Attia18:51

       So when you mix in developed and undeveloped, it doesn't matter. Laboratory mice aren't that way.

   12. MKDr. Matt Kaeberlein18:56

       Right.

   13. PAPeter Attia18:56

       They die of pretty much one thing and one thing alone, and that is?

   14. MKDr. Matt Kaeberlein19:00

       Actually, it's euthanasia, but I know where you're going. [laughs]

   15. PAPeter Attia19:02

       Yeah, yeah, yeah, yeah. Good point.

   16. MKDr. Matt Kaeberlein19:03

       Uh [laughs]

   17. PAPeter Attia19:04

       Yeah.

   18. MKDr. Matt Kaeberlein19:04

       Cancer, right?

   19. PAPeter Attia19:05

       Yeah, cancer.

   20. MKDr. Matt Kaeberlein19:05

       So, yeah.

   21. PAPeter Attia19:05

       They all die of cancer, basically.

   22. MKDr. Matt Kaeberlein19:06

       Right. So, so, so certainly every, uh, old mouse at time of death will h- will have cancer. And again, th- because of the way animal studies are done, usually, um, you have defined endpoints where when a mouse reach that, reaches that endpoint, they have to be euthanized. But the, the expectation is that if, if they hadn't been euthanized, they would've died from the cancer.

   23. PAPeter Attia19:27

       Right.

   24. MKDr. Matt Kaeberlein19:27

       So I think you're absolutely right.

   25. PAPeter Attia19:28

       Yeah. They, th- they're not dying from atherosclerotic.

   26. MKDr. Matt Kaeberlein19:30

       That's right.

   27. PAPeter Attia19:31

       When you look at their arteries-

   28. MKDr. Matt Kaeberlein19:32

       That's right

   29. PAPeter Attia19:32

       ... they're not littered with plaques the way ours are.

   30. MKDr. Matt Kaeberlein19:35

       At least the commonly used inbred mouse strains-
5. 21:05 – 32:09

   Utility of epigenetic clocks and possibility of epigenetic reprogramming

   1. MKDr. Matt Kaeberlein21:05

      yeah, maybe the lifespan effect is primarily due to cancer, but caloric restriction is having an effect apparently on the underlying biological aging process, um, i- in all sorts of, of different ways. And I, and I really like the functional measures. A lot of people in the field these days are, are really enamored with, you know, the, the aging clocks, epigenetic clocks, biochemical markers. I think those are all useful and important, but from my perspective, what really gets my attention is if somebody shows that the heart is still functioning like a young heart or the immune system is still functioning-

   2. PAPeter Attia21:35

      Yeah. Let's, uh, I wasn't planning to go down that rabbit hole, but since you brought it up, um, c- can you convince me of the utility of the clocks absent the type of data that would actually demonstrate longitudinally their benefit, which to, to my knowledge, we really don't have yet?

   3. MKDr. Matt Kaeberlein21:52

      Yeah. So I, I would say a couple things on that. I think we, we need to be precise in what we mean when we talk about the clocks, 'cause there's lots of flavors of clocks, right?

   4. PAPeter Attia22:00

      Absolutely, yeah.

   5. MKDr. Matt Kaeberlein22:01

      Most people these days, if you just say aging clock, they, what they really mean are the epigenetic clocks that are showing, you know, the, the characteristic changes in the epigenome, the epigenetic marks that are seen with age. Again, in every, in every organism where it's really been studied, um, you do see these characteristic changes in the epigenome with age. And so I would say one place where their utility is clear, at least to me, is as a chronological measure, right?

   6. PAPeter Attia22:27

      Mm-hmm.

   7. MKDr. Matt Kaeberlein22:27

      Now, you might ask, okay, why would I ever wanna, you know, use a epigenetic clock to, to, to tell my chronological age? I know how old I am, right? But forensics, for example, might be a place where that's useful. Their crime has been committed. They want to know with some level of precision how old the, the perpetrator is. You could use an epigenetic clock for that reason. Um, you know, and in, in, in my world as part of the Dog Aging Project, there are many dogs, you know, that are rescued. An owner might wanna know their age. So I think that is a, that is a real use-

   8. PAPeter Attia22:56

      Mm-hmm

   9. MKDr. Matt Kaeberlein22:56

      ... and, and clearly the clocks will work for that. I think really what you're asking though is can I convince you that the epigenetic clocks and potentially other types of clocks are actually measuring biological aging, right?

   10. PAPeter Attia23:08

       Correct.

   11. MKDr. Matt Kaeberlein23:08

       And that's a harder... In my mind, that's a harder thing to prove, and personally, I have no interest in convincing you of that 'cause I'm not convinced, right? So I think this is an area where the field is, um, in flux a little bit, and there are certainly scientists who I respect a lot in the field who believe, you know, at their core that these epigenetic clocks tell us about biological aging or can be used to tell us about biological aging. Then there are people like me who want to see the proof, and I think the, the proof is really being able to show at an individual level, that could be in a mouse, could be in a person-

   12. PAPeter Attia23:44

       Yeah

   13. MKDr. Matt Kaeberlein23:44

       ... could be in a dog. At an individual level, you can predict someone's biological age at some point in their life and with some level of precision predict what's going to happen in the future. What are their future health outcomes? How are they, how long are they going to live? Nobody has done that yet. What they've done comes close, I guess. So what has been done is to look at longitudinal studies in people where we have samples from people 10, 20, 30 years ago Measure the epigenetic profiles of those people 10, 20, 30 years ago and ask how well does that correlate with mortality outcomes, for example, in the future? And they, they do work to some extent. I think people will debate how well they work. Are they any better than other markers you could look at, um, in predicting mortality? I think that's unclear, but there is some correlation there. So, you know, again, I think it, it really depends to s- to some extent maybe on how skeptical you are. I'm a skeptic by nature, and, uh, and I wanna actually see the proof. Um, I guess the last thing I would say, say about this, I'm, I'm, I'm talking mostly about the epigenetic clocks. Um, maybe it's worth talking about other types of clocks that, that people can make. The other thing I wanna caution people on though is assuming that the epigenetic clocks are the only important thing about aging. There is, again, you know, a small number of, um, very vocal and, and, uh, popular people in the field who talk as if changing the epigenome is going to change everything about aging. We have no data to support that. Just... There, there's like... I, I just have to say it. That is not true at this point. We have no data to support it. Um, if-- What we know about the biology of aging is that epigenetic changes are one of, depending on how you categorize things, you know, eight or nine or 10 molecular processes that seem to contribute with... That, that the field has reached consensus on. It's only one of those things. Is it possible that it, it is sort of in a hierarchy the most important and drives a lot of these other changes? Yes, that's possible. We don't have any data to support it. So this idea that reversing the epigenome is reversing aging is at best an exaggeration, at worst an outright lie. I mean, it's just not true.

   14. PAPeter Attia26:09

       How could that be... What, what a set of experiments technology-wise would you need to be able to do to even-

   15. MKDr. Matt Kaeberlein26:16

       Yeah

   16. PAPeter Attia26:16

       ... test that hypothesis, say, in a, in a mouse, right?

   17. MKDr. Matt Kaeberlein26:18

       We're close.

   18. PAPeter Attia26:18

       Yeah.

   19. MKDr. Matt Kaeberlein26:19

       Well, maybe close. I, I guess I should qualify that a little bit. Um, conceptually we're close. So there have been these factors called the Yamanaka factors that can, um, reprogram the epigenome. So this has been done in cells.

   20. PAPeter Attia26:32

       Mm-hmm.

   21. MKDr. Matt Kaeberlein26:32

       So if you take cells in culture in a laboratory and you passage them many, many times, you can see changes in the epigenome-

   22. PAPeter Attia26:39

       Yep

   23. MKDr. Matt Kaeberlein26:39

       ... just like you might see changes in the epigenome in an animal, in tissues. And you can put these reprogramming factors into the cells and turn them on.

   24. PAPeter Attia26:48

       Now, there are four Yamanaka factors?

   25. MKDr. Matt Kaeberlein26:49

       There are four Yamanaka factors, and pe- but people are trying different-

   26. PAPeter Attia26:52

       Yep

   27. MKDr. Matt Kaeberlein26:53

       ... different cocktails, adding some other stuff in, taking some stuff out, but yes, there are the four classic Yamanaka factors. And what those factors do is they basically wipe clean the epigenetic changes that have happened over time. Um, and also what's amazing is that they restore those cells back to a, if you take it far enough, back to a pluripotent state. So essentially you get, you know, virgin new cells that could differentiate into any cell type in the body, right? So this has been known for many years. What is relatively more recent over the last, you know, eight or nine years are people are trying to express these reprogramming factors in an animal. So, so instead of doing it in cells in the laboratory, do it in an animal. And I think the most compelling work, um, uh, is work in a premature aging mo- model of mice, so it's called a progeroid model, um, where they're very short-lived, they're very sick, but these, these reprogramming factors can, you know, extend lifespan by... I don't remember what the exact numbers are, but a significant amount, maybe 40, 50, 50%.

   28. PAPeter Attia27:58

       Wow.

   29. MKDr. Matt Kaeberlein27:58

       Which seems like a lot, except you have to recognize these mice live, you know, maybe 25% of the length of a normal mouse, right?

   30. PAPeter Attia28:05

       Yeah.
6. 32:09 – 36:21

   Mutations and changes to the epigenome with aging

   1. MKDr. Matt Kaeberlein32:09

      matter, right? So the idea is you're getting things turned on and turned off inappropriately as we get older. So there's a loss of regulation, which probably contributes to a loss of homeostasis. And homeostasis is, I think, a really useful way to think about aging, right? If you're healthy, you, your body is generally in homeostasis, right? And what happens as we get older is it becomes harder and harder for our body to maintain homeostasis. When you get out of homeostasis, if your, your defense mechanisms are working right, you can get back in, right? So you get COVID, for example. Your immune system works, you're out of home- homeostasis, but you come back in, and then you're okay again. I think as we get older, it gets harder to come back into homeostasis, and that's why we start to see pathology and mortality. So-

   2. PAPeter Attia32:51

      So let me differentiate two states of pathology. Um, my five-year-old son was on his scooter two weeks ago, going down the steepest hill in the world, which I had no idea how I didn't see that he was about to do that. Li- like, face-planted.

   3. MKDr. Matt Kaeberlein33:06

      Yeah.

   4. PAPeter Attia33:06

      And when he came up, all I could think is, "How quickly can we get to the hospital?" I mean, he... It was a bloodbath.

   5. MKDr. Matt Kaeberlein33:12

      Yeah.

   6. PAPeter Attia33:13

      I'm not making this up, Matt. Six days later, there was one little tiny-

   7. MKDr. Matt Kaeberlein33:19

      Yeah

   8. PAPeter Attia33:19

      ... scar. Eight or nine days later, you, you c- you would have had no idea this kid ripped his face off on pavement.

   9. MKDr. Matt Kaeberlein33:29

      Yeah.

   10. PAPeter Attia33:29

       He's five. I get a cut, it's like nine months until the scar is gone.

   11. MKDr. Matt Kaeberlein33:35

       Yeah.

   12. PAPeter Attia33:35

       So there's a very clear distinction between a five-year-old's DNA and a 50-year-old's DNA in terms of how he can literally make new proteins that are better than my proteins.

   13. MKDr. Matt Kaeberlein33:46

       Yeah. Let me, let me stop you there just for a second.

   14. PAPeter Attia33:48

       Yeah.

   15. MKDr. Matt Kaeberlein33:48

       'Cause I think this is actually the crux of the question, right?

   16. PAPeter Attia33:50

       Yeah.

   17. MKDr. Matt Kaeberlein33:50

       You said it's a different in your, difference in your DNA.

   18. PAPeter Attia33:52

       Well, I'm asking.

   19. MKDr. Matt Kaeberlein33:53

       Yeah.

   20. PAPeter Attia33:53

       I think what I'm trying to get at is, yeah, how much of... 'Cause that's a clear case of the protein that he makes is better than my protein, right? He's, he's making much better proteins.

   21. MKDr. Matt Kaeberlein34:02

       Certainly functions better.

   22. PAPeter Attia34:03

       Yes.

   23. MKDr. Matt Kaeberlein34:03

       Absolutely.

   24. PAPeter Attia34:04

       Yeah.

   25. MKDr. Matt Kaeberlein34:04

       Yeah. So, so, um, w- I guess what I was getting at though is the question, one question I think that's really important here is there can be changes to the DNA to the sequence, right? So the sequence of the DNA is the information.

   26. PAPeter Attia34:15

       Yep.

   27. MKDr. Matt Kaeberlein34:15

       Right? Those are called mutations, and those accumulate as we age, and that's, that's honestly what drives a lot of cancer, right?

   28. PAPeter Attia34:21

       Yep, yep.

   29. MKDr. Matt Kaeberlein34:22

       So we've known this for a long time. The epigenetic changes are sort of on top of that, right?

   30. PAPeter Attia34:27

       Yeah. And while it more regulates expression-
7. 36:21 – 44:43

   Epigenetic reprogramming: potential benefits and downsides and whether it can work in every organ/tissue

   1. MKDr. Matt Kaeberlein36:21

      you can point to, but-

   2. PAPeter Attia36:21

      Well, cancer for sure, but let's now talk about something else, which is near and dear to your heart, no pun intended, but ejection fraction. Again, because you study dogs.

   3. MKDr. Matt Kaeberlein36:29

      Yeah.

   4. PAPeter Attia36:30

      Uh, not only is cancer a big problem, but so is heart failure. So now we're dealing with a muscle, a set of cells that really aren't being turned over the way skin is.

   5. MKDr. Matt Kaeberlein36:40

      Yeah.

   6. PAPeter Attia36:40

      So when we think about the example of my son, when you think about your gut epithelium being sloughed off when you get sick, when you think about your fingernails and your hair, boy, it's really easy to think about those things as rapidly being turned over. But neurons, cardiac myocytes-

   7. MKDr. Matt Kaeberlein36:55

      Right, right

   8. PAPeter Attia36:55

      ... these things don't get turned over a whole heck of a lot. So what is it about reprogramming that we think is going to fix an aging neuron or an aging cardiac myocyte?

   9. MKDr. Matt Kaeberlein37:07

      Yeah. So th- I mean, again, I think again, this is an area where the biology of what's really happening, a- a- at least to my knowledge, is so poorly understood that, that I think the real answer is we don't completely know.

   10. PAPeter Attia37:17

       Yeah.

   11. MKDr. Matt Kaeberlein37:17

       I'm gonna give a very simplistic answer, um, uh, which is that what people are trying to do is not reprogram all the way back to the pluripotent state. So this is called partial reprogramming.

   12. PAPeter Attia37:31

       Right.

   13. MKDr. Matt Kaeberlein37:31

       Right? So, so certainly-

   14. PAPeter Attia37:32

       Which would be pretty dangerous.

   15. MKDr. Matt Kaeberlein37:33

       Well, that's what I was gonna say. If you're a single-celled organism, no problem going back to the, the pluripotent state.

   16. PAPeter Attia37:38

       Yeah.

   17. MKDr. Matt Kaeberlein37:38

       Right? You can then, you can then-

   18. PAPeter Attia37:40

       Yeah

   19. MKDr. Matt Kaeberlein37:40

       ... you know, start over. In a complicated animal, if we reprogram you back to the pluripotent state, that's not gonna end well for you.

   20. PAPeter Attia37:47

       No. [laughs]

   21. MKDr. Matt Kaeberlein37:47

       Right? So, so I think the idea is to go back far enough that you, uh, restore the epigenome to its, uh, pristine state, young state, and then hope that when you do that, you restore gene expression to where it's supposed to be. Maybe one way to think about it is you restore the homeostatic mechanisms to a more youthful state, where then the homeostatic mechanisms that all of our cells have can basically clean up the rest of the mess, right? Because we know as we get older, for example, we all accumulate damaged mitochondria, right? Changing the epigenome, which is the nuclear genome, isn't gonna fix anything that's wrong with your mitochondria directly, but maybe by fixing the epigenome, you restore the homeostatic mechanisms that then maintain mitochondria in a healthy state, and you can fix the damage to the mitochondria, right? So that's the, that's the concept. Um, and again, you know, I would say the evidence is suggestive that if you do it just right, you can improve function in at least some aged tissues and or- or, uh, organs by partial reprogramming. I- I've yet to see anything that convinces me that anybody has made, you know, uh, an old heart into a young heart in an old animal with partial reprogramming in a, in the heart, but you can improve function. I would also say the same thing's true with rapamycin, right? We don't-- I would not argue... We see that short-term treatment with rapamycin in mice makes an old heart function functionally, to some extent, more like a young heart. I would never argue that we have, you know, taken that heart and now it's young. It's just in an old body. We don't know that, and that's hard to prove.

   22. PAPeter Attia39:27

       Yep.

   23. MKDr. Matt Kaeberlein39:27

       But I think you can s- you, you can see some evidence that it should be possible with partial reprogramming to do that. And, you know, the question is will it work everywhere? Will it work in some tissues and organs and not in others? We don't really know. The brain is the one... So let's just say 10, 20 years from now, people have figured out a lot of the complexity. We're starting to move these things into the clinic. You know, maybe, maybe we will see really, um, uh, large effects on lifespan and healthspan in mice. Uh, what I've yet to hear anybody give a convincing explanation of is how you do that in the brain. Because so much of who we are and what we are comes from our experiences and our memories, and, and so how do you ensure that you can reprogram somebody's brain in a way that isn't gonna change that? And I, I, I, I just think that's gonna be a really hard, um, problem to overcome. But, you know, maybe somebody will figure it out. There are, there are tons of really smart people working in this area, lots of resources going into this area. So I think it's exciting. Again, my, my big, um, concern is that we don't mislead people into thinking that, you know, that we're close to reversing aging. Um, and I think it's a problem from the perspective of the general public. I think it's a problem from the perspective of the scientific community. Sci- sci- other scientists look at that, and they're like, "This is snake oil," right? S- this is just not true.

   24. PAPeter Attia40:51

       Y- yeah, and my, my concern with it is actually in terms of the impact it has on people-

   25. MKDr. Matt Kaeberlein40:56

       Yeah

   26. PAPeter Attia40:56

       ... which are, "Hey, this is awesome. This thing's gonna get worked out. I can basically-"

   27. MKDr. Matt Kaeberlein41:03

       [laughs] I can do whatever I want.

   28. PAPeter Attia41:04

       "I can do whatever..." I mean, literally.

   29. MKDr. Matt Kaeberlein41:05

       Yeah.

   30. PAPeter Attia41:05

       It's like I can sort of do what I want because in 10 years they're gonna reprogram me. And my view on that is even if that is true-
8. 44:43 – 49:40

   First potential applications of anti-aging therapies and tips for for aging well

   1. MKDr. Matt Kaeberlein44:43

      So I think it's a long road before we have, you know, reprogramming strategies that get into the clinic. Maybe somebody will identify a small molecule that can do some of this.

   2. PAPeter Attia44:53

      Mm-hmm.

   3. MKDr. Matt Kaeberlein44:53

      And I know people are working on that. Maybe that'll be an easier path. But, um, but for now, I think it's gonna, I think it's gonna take a while. And that's, that's the best case scenario. That's if we really can, you know, partial- I'm gonna say partially reverse aging, reverse aspects of aging. Um, it's still gonna be a long road.

   4. PAPeter Attia45:08

      And I wonder if the first wins are gonna be things like what David Sinclair has done, where-

   5. MKDr. Matt Kaeberlein45:13

      Yeah

   6. PAPeter Attia45:13

      ... you, you've got one very niche application.

   7. MKDr. Matt Kaeberlein45:15

      Yeah.

   8. PAPeter Attia45:15

      I think another one that would be amazing would be osteoarthritis.

   9. MKDr. Matt Kaeberlein45:18

      Yeah.

   10. PAPeter Attia45:18

       Like, if you could reg- if you could figure out a way to regenerate-

   11. MKDr. Matt Kaeberlein45:22

       Yeah

   12. PAPeter Attia45:22

       ... human cartilage-

   13. MKDr. Matt Kaeberlein45:23

       Yeah

   14. PAPeter Attia45:23

       ... um, without joint replacements, you know, again-

   15. MKDr. Matt Kaeberlein45:27

       Yeah

   16. PAPeter Attia45:27

       ... those are huge wins that seem at least a little more feasible. But again, I, I agree with you. I think this stuff takes four times as long and costs four times as much-

   17. MKDr. Matt Kaeberlein45:39

       Yeah

   18. PAPeter Attia45:39

       ... as we think.

   19. MKDr. Matt Kaeberlein45:40

       Well, and I mean, you know, again-

   20. PAPeter Attia45:41

       It's like building a house, right? It's like-

   21. MKDr. Matt Kaeberlein45:42

       Yeah, and, and you and I are, are... I mean, honestly, we're pretty lucky, right? Because we know about a lot of this stuff. We actually can start practicing some of this stuff, like rapamycin, before it gets out there, right? Again, I'm not, I'm not recommending anybody take rapamycin necessarily, um, without talking to your physician first. But, you know, we know this, this stuff, and we ha- I think have at least, you know, a pretty good idea of the relative risk-reward. But in, before it gets out to where, you know, it, it hits the, the, uh, the mainstream, right, from a clinical perspective, yeah, it's a, it's a really long path. I totally agree with what you said, though, about, um, uh, specific indications where you can target it very precisely, hopefully, um, and where there's no other solution currently, right? I think those are opportunities. Um, that's exactly the strategy that people have tried to take with senolytics, right? The, these molecules-

   22. PAPeter Attia46:33

       Yeah

   23. MKDr. Matt Kaeberlein46:33

       ... that will clear senescent cells, and even that's been hard, right?

   24. PAPeter Attia46:36

       Yes.

   25. MKDr. Matt Kaeberlein46:36

       I mean, Unity is the, the, the, the sort of largest, uh, company in, in this space, and their first f- clinical trial for osteoarthritis failed, right? So now they're looking at the eye because, again, it's a, it's a, it's a nice indication where for some of these eye diseases, there isn't any solution, and you, you can, in principle, target it quite precisely to the eye. So yeah, I think that is-

   26. PAPeter Attia46:58

       Yeah

   27. MKDr. Matt Kaeberlein46:58

       ... exactly the strategy that people will be taking, um, and hopefully it'll be successful. Um, I mean, I, look, I, I, I, I want this stuff to work. I just, uh, I try to be a realist at the same time.

   28. PAPeter Attia47:09

       Yeah, I guess the, the, the way I would kind of describe this to people is if you want to bring it back to a financial analogy, it's a lottery ticket, and so if your entire financial planning system is based on winning the lottery-

   29. MKDr. Matt Kaeberlein47:21

       [laughs] That's the problem

   30. PAPeter Attia47:23

       ... the odds that you're going to win are pretty low.
9. 49:40 – 59:34

   Impact of calorie restriction on the immune system, muscle mass, and strength

   1. PAPeter Attia49:41

      So let's go back to the CR stuff.

   2. MKDr. Matt Kaeberlein49:43

      Yeah.

   3. PAPeter Attia49:43

      So what do we know about the effect of CR in the laboratory animals on the immune system?

   4. MKDr. Matt Kaeberlein49:50

      Right. So it's a little bit complicated. Um, uh, so first of all, laboratory, uh, animals in the laboratory are kept in, in what's called a specific pathogen free environment. So that doesn't mean there's no pathogens, but it's a relatively low pathogen en- environment where they are not obligated to really use their immune systems against all the challenges that, you know, we would face in the real world. So one question has come up, uh, are animals that are on calorie restriction immune compromised? And again, I think the data's a little bit mixed, but certainly people have-- there have been studies where people have done pathogen challenges on CR animals, and they respond better. At least the old animals respond better than, than age-matched, ad libitum fed control. So ad libitum just means as m- eat as much as you want. Um, but then for certain types of challenges, they, the ca- caloric restriction clearly causes a deficit. So-

   5. PAPeter Attia50:44

      Yeah, the sepsis experiments are pretty clear-

   6. MKDr. Matt Kaeberlein50:46

      Yeah

   7. PAPeter Attia50:46

      ... with the, the CR animals compared to controls when you induce sepsis in them, the, the CR animals-

   8. MKDr. Matt Kaeberlein50:51

      Right

   9. PAPeter Attia50:51

      ... die much more quickly.

   10. MKDr. Matt Kaeberlein50:52

       Right. And so of course, the obvious, uh, implication of that is that maybe CR would impair immune function in people and lead to higher risk of all, all sorts of infectious diseases.

   11. PAPeter Attia51:03

       Yeah.

   12. MKDr. Matt Kaeberlein51:03

       And this, this gets additionally complicated though by the, the, the question of, you know, optimal CR with optimal nutrition. So you might sometimes you'll see this CRON, C-R-O-N, right? Caloric restriction with optimal nutrition or CRAN, caloric restriction with adequate nutrition, right? So that, that can be done in a mouse, right? We can control all of that. So we make sure that they get all the micronutrients and vitamins that they need when they're on this CR diet. When you move into the real world and people start practicing caloric restriction, that all goes out the window, right? Like I wouldn't-- if I wanted to do caloric restriction off the top of my head, I wouldn't even know what to do to make sure [chuckles] that I'm getting optimal nutrition, right? And so in that state where you are CR without optimal nutrition, I think that's where I really become worried about the side effects, particularly as, as you raised, um, immune deficits because you may not, you may not be, be getting the nutrient value or the specific micronutrients and vitamins that you need to maintain a functioning immune system. Sure, you may affect some aspects of the biology of aging in a way that you're aging biologically more slowly. That doesn't matter if you get influenza and die, right? So again, I think that's an additional complication that comes into play when we start talking about... We haven't talked about all the other, you know, anti-aging nutritional strategies. When we start talking about recommending those nutritional strategies to the general public based on solely on mouse studies, I get really concerned because of this environmental complexity that humans live in. Um, not, and we haven't even talked about the genetic complexity, right? So there's all sorts of things that are just different about laboratory animals compared to people living in the real world.

   13. PAPeter Attia52:51

       And then what can we say about frailty, sarcopenia-

   14. MKDr. Matt Kaeberlein52:56

       Mm-hmm

   15. PAPeter Attia52:56

       ... as it changes in, uh, an animal in a, in a CR environment? And, and can that be extrapolated also?

   16. MKDr. Matt Kaeberlein53:03

       Yeah. So I think it's, it's pretty clear, I think, that, um, uh, most, much like rapamycin, most functional measures of aging seem to be preserved in calorically restricted animals-

   17. PAPeter Attia53:15

       Yeah

   18. MKDr. Matt Kaeberlein53:15

       ... including measures of frailty and measures of sarcopenia. And you know, this, uh, the same thing again is true with rapamycin. This actually surprised a lot of people-

   19. PAPeter Attia53:23

       Right

   20. MKDr. Matt Kaeberlein53:23

       ... when the first studies were done because, you know, the expectation was because mTOR plays such a big role in muscle synthesis, that if you inhibit mTOR with rapamycin or caloric restriction, which is a potent inhibitor of mTOR, that you would actually, uh, see accelerated sarcopenia. And, and that just isn't the observation in laboratory animals. Um, again, we have to be careful not to extrapolate to people, but, but it doesn't seem to be the case that you lose muscle, uh, muscle mass and function in the way that people would define sarcopenia. I think the important complication here is that all of the caloric restriction studies that I'm aware of when they look at muscle function normalized to body weight.

   21. PAPeter Attia54:03

       To weight. Yeah.

   22. MKDr. Matt Kaeberlein54:03

       Yeah. And the calorically restricted mice weigh substantially less than the ad libitum fed mice. Usually, I think it's on the order of 30%, 35% less.

   23. PAPeter Attia54:11

       Yeah.

   24. MKDr. Matt Kaeberlein54:12

       So what-

   25. PAPeter Attia54:12

       Yeah, so it's usually grip strength normalized to weight.

   26. MKDr. Matt Kaeberlein54:15

       Right. So what you're actually seeing is that the calorically restricted mice have maintained muscle function proportionate to their body weight.

   27. PAPeter Attia54:26

       Yeah.

   28. MKDr. Matt Kaeberlein54:26

       And, and I don't know the answer to this, but it's something that I thought of when, when we were ... talking about this show, um, you know, is let's just say you did that in a person, right? So you've got... You would, you would be able to answer this, I'm sure. You've got a 60-year-old person, you know, who needs to lose 30% of their body weight, but of course you want to maintain their muscle mass-

   29. PAPeter Attia54:45

       Yeah

   30. MKDr. Matt Kaeberlein54:45

       ... right, their muscle function. Would it, would you view it as a good thing or a bad thing if they lost 30% of their body weight-
10. 59:34 – 1:09:18

    Insights from famous calorie restriction studies in rhesus macaques

    1. MKDr. Matt Kaeberlein59:34

       closer to 40.

    2. PAPeter Attia59:34

       Yeah.

    3. MKDr. Matt Kaeberlein59:35

       Yeah.

    4. PAPeter Attia59:35

       So let's talk about the experiment to end all experiments with respect to, to caloric restriction, which is the, uh, very famous one we alluded to earlier at the University of Wisconsin and the NIA. So it... And, and I, like I've [laughs] I've read this study 1,000 times. If I can get the details right once-

    5. MKDr. Matt Kaeberlein59:51

       [laughs]

    6. PAPeter Attia59:51

       ... I'll be happy. But between the two of us, I hope we can do this.

    7. MKDr. Matt Kaeberlein59:55

       Yeah.

    8. PAPeter Attia59:55

       You had two groups of animals, one at the University of Wisconsin and one directly in Bethesda, Maryland. This was obviously a huge NIH-funded effort. It ran for a couple of decades, given the lifespan of rhesus monkeys. The Wisconsin animals were fed, uh, the controls and the treatment, uh, CR animals were fed a very processed diet.

    9. MKDr. Matt Kaeberlein1:00:17

       Right.

    10. PAPeter Attia1:00:18

        Uh, at least after the fact, the examiner, the, um, investigators there suggested they wanted to more mimic a standard American diet. Uh, of note, I recall the amount of sugar, pure sucrose in their diet, was 28 and a half percent of total calories. So This is, this is, this is a, a, a high-quality diet, facetiously. The CR animals, the calorically restricted animals, were fed 25%, uh, uh, of what the control animals were fed, and in that experiment, we found a benefit to caloric restriction.

    11. MKDr. Matt Kaeberlein1:00:53

        That's right.

    12. PAPeter Attia1:00:53

        The CR animals outlived the control animals.

    13. MKDr. Matt Kaeberlein1:00:57

        And they had fewer age-related diseases. So I think if you, if you go back to that original 2009 paper, you know, the lifespan effect is compelling and it, and it looks real, but, but what, again, you know, is I think really indicative of, of that it might be having an effect on biological aging is that they saw reduced rates of cancer, again, not surprisingly-

    14. PAPeter Attia1:01:17

        Yep

    15. MKDr. Matt Kaeberlein1:01:17

        ... as we talked about in mice, but also heart disease, um, and, uh, metabolic disease.

    16. PAPeter Attia1:01:21

        Yep.

    17. MKDr. Matt Kaeberlein1:01:22

        So, you know, it's consistent with the idea that in that cohort of monkeys, again, given what you mentioned about the dietary composition, caloric restriction was in fact having a beneficial impact on the aging process.

    18. PAPeter Attia1:01:37

        And those animals all came in at about the same age.

    19. MKDr. Matt Kaeberlein1:01:40

        Right.

    20. PAPeter Attia1:01:40

        So that was sort of an apples to apples comparison. Now we go down the road to Bethesda. We have a totally different experiment in a way, and I, I don't know how much of this was deliberate and how much of it was not. The diets were different-

    21. MKDr. Matt Kaeberlein1:01:54

        Yep

    22. PAPeter Attia1:01:54

        ... so that's, that's maybe a good contrast. These animals were actually fed the closest diet that could mimic their real diet. Um, so it didn't have any, you know, sugar in it really. I think it was, like, about 3% sucrose. Um, you know, it was almost kind of like a, you know, a, a vegetarian/pescatarian sort of diet. Uh, fish was the dominant source of protein, but it, you know, it was a high-quality diet-

    23. MKDr. Matt Kaeberlein1:02:19

        Right

    24. PAPeter Attia1:02:19

        ... relative to the Wisconsin animals.

    25. MKDr. Matt Kaeberlein1:02:20

        Higher quality for sure.

    26. PAPeter Attia1:02:21

        Yep.

    27. MKDr. Matt Kaeberlein1:02:21

        Yeah.

    28. PAPeter Attia1:02:22

        The complicating factor here was the animals didn't come in at all the same age. So you had some animals that came in young, some animals that came in old. The net result of the study was there was no difference. The CR animals did not outlive, and so while the Wisconsin study was first published in 2009 and it said CR works, the 2012 publication for NIA said CR doesn't work.

    29. MKDr. Matt Kaeberlein1:02:48

        Right.

    30. PAPeter Attia1:02:48

        At least that's the lay press interpretation of it. So how do you kind of reconcile these findings?
11. 1:09:18 – 1:19:10

    An evolutionary perspective of the human diet

    1. MKDr. Matt Kaeberlein1:09:18

       there.

    2. PAPeter Attia1:09:19

       And the other thing that just kind of gets off into weeds that we don't need to necessarily go into is I don't really have a great understanding of even how we differ from the, the rhesus monkeys. So, y- you know, I recently read Herman Pontzer's book where he... I don't know, have you read it by the way?

    3. MKDr. Matt Kaeberlein1:09:35

       Mm-mm. No.

    4. PAPeter Attia1:09:35

       So he kind of goes into the ecology and evolution of, of humans as a species-

    5. MKDr. Matt Kaeberlein1:09:40

       Yeah

    6. PAPeter Attia1:09:40

       ... and, and how different we are even from our closest evolutionary cousins, and one of the fundamental differences, our incredible capacity to store excess energy.

    7. MKDr. Matt Kaeberlein1:09:51

       Yeah.

    8. PAPeter Attia1:09:52

       So our metabolic rate, so this is, you know, he documents this through lots of assessments of doubly labeled water on n- not just ourselves, but also kind of, you know, hunter gatherers that are still around today, and then of course all the primates, is, you know, we're really kind of unique in our energy expenditure. Our, our energy needs are far greater than anything else, and y- you know, people like that would argue, hey, that was kind of an advantage that we took to allow our development, including our brain development.

    9. MKDr. Matt Kaeberlein1:10:23

       Yeah.

    10. PAPeter Attia1:10:23

        So there's kind of a reason we're at the top of the food chain, which is we have a much greater brain, and the price we pay for that is higher energy expenditure, and the price we pay for that is we better be able to store energy because we will have a much harder time tolerating a low energy environment.

    11. MKDr. Matt Kaeberlein1:10:44

        Yeah.

    12. PAPeter Attia1:10:45

        And so he, he talks about how even when you put these animals in captivity and you overfeed them, they're not getting that much fatter, right? They're, they're actually putting on lean mass. Now, they, you know, I think what you could argue, and he doesn't talk about this, but knowing what we know about human biology, you might argue that they're still getting metabolically sick.

    13. MKDr. Matt Kaeberlein1:11:03

        Right.

    14. PAPeter Attia1:11:05

        Just as humans, when you're overfed, the real metabolic sickness comes not with the inflation of your subcutaneous fat. It's when that spills out into the viscera, into the liver, into the peripancreatic space, into the perinephric space, into the pericardial space. It's that fat that escapes the normal depot of subQ fat that is truly inflammatory and truly metabolically disturbing. So I throw all that in there just to say, like, it's just one more confounding variable that makes it-

    15. MKDr. Matt Kaeberlein1:11:34

        Yeah

    16. PAPeter Attia1:11:34

        ... difficult to compare us even to an organism as complex as a rhesus monkey.

    17. MKDr. Matt Kaeberlein1:11:39

        Yeah. Uh, yeah, and I mean, people certainly have made that criticism of the caloric restriction literature, you know, writ large, not even taking into account the monkey studies, but, but the mouse studies, right? That there are, you know, all sorts of differences i- between people and, and mice, and the, the, the metabolic state that people have evolved to fill is just completely different. Having said that, you're absolutely right that even mice in the laboratory as they get older will show metabolic syndrome, right? You will see many of the same changes, insulin resistance, for example, that you see in, in people. And I don't-

    18. PAPeter Attia1:12:15

        And do you see it absent the adiposity? Can you see it-

    19. MKDr. Matt Kaeberlein1:12:18

        Well, mice, mice gain adiposity with age too.

    20. PAPeter Attia1:12:20

        Yeah.

    21. MKDr. Matt Kaeberlein1:12:20

        They, they do in fact, uh, uh, become obese with age.

    22. PAPeter Attia1:12:24

        Mm-hmm.

    23. MKDr. Matt Kaeberlein1:12:24

        Right? On a, again, on a pretty crappy diet, right? A stand-

    24. PAPeter Attia1:12:27

        Yeah.

    25. MKDr. Matt Kaeberlein1:12:27

        Well, I don't know if it's crappy or not. The standard mouse diets, right?

    26. PAPeter Attia1:12:30

        Yeah.

    27. MKDr. Matt Kaeberlein1:12:30

        So, and, and I don't remember what the number is. You may, you may, but in the Wisconsin study, right, a significant fraction of the control fed monkeys developed diabetes, right? So-

    28. PAPeter Attia1:12:40

        Yes. Uh, I, I wanna say, like, a quarter of the controls were pre-

    29. MKDr. Matt Kaeberlein1:12:44

        Yeah

    30. PAPeter Attia1:12:44

        ... diabetic by the end of the study. Again, which probably speaks to even though they weren't overweight When they get a, when you get 28.5% of your calories from sugar-
12. 1:19:10 – 1:27:39

    Antiaging diets: Separating fact from fiction—Matt’s 2021 review in Science

    1. PAPeter Attia1:19:10

       So let's, let's talk about kind of more broadly a paper you wrote, how long has it been, two years?

    2. MKDr. Matt Kaeberlein1:19:19

       Well, we probably wrote it longer than two years ago. I think it came out at the end of 2021.

    3. PAPeter Attia1:19:24

       Oh, okay, okay.

    4. MKDr. Matt Kaeberlein1:19:25

       Yeah, so it's fairly recent. You're talking about the sci-

    5. PAPeter Attia1:19:26

       I feel like I... Yeah

    6. MKDr. Matt Kaeberlein1:19:27

       ... about the Science paper.

    7. PAPeter Attia1:19:27

       Yeah, and I'd read it before-

    8. MKDr. Matt Kaeberlein1:19:28

       It was maybe November 2021 or so

    9. PAPeter Attia1:19:30

       ... so I've lost track. All right, so, so talk about the impetus for that paper, which was, I thought it was a great paper and we should discuss it in, in some detail.

    10. MKDr. Matt Kaeberlein1:19:35

        Yeah, so, um, so I, I was asked by one of the editors at, at Science to write a review, I think on m- mTOR actually, and, and I was like, well, lots of people have written reviews on mTOR. I've been thinking a lot about, you know, caloric restriction, um, and particularly other nutritional strategies that, that people have been studying in the field, um, like ketogenic diet, protein restriction, time-restricted feeding, intermittent fasting. Um, and you know, what do we actually know about those diets and, and their effects on aging, right? Because I was of the... Before I started to really dive into it, and, and this isn't something that my lab researches directly. So we've previously done work on caloric restriction in, in, in vertebrates and C. elegans, but we never really have done a lot of dietary interventions in, in mice. And so, you know, before I kind of dove into the literature, I had this impression, you know, that all of these diets were similar in some ways and had maybe comparable effects on lifespan. At least that's the way it gets portrayed if you read some of these reviews, and I don't even like to call them reviews because I don't think, honestly, much of what gets into the literature as review articles are actually reviews. It's more one person's opinion piece on their specific thing that they study, which is unfortunate. But if you read most of the reviews on caloric restriction and other dietary interventions, they're very one-sided and they, they, they, they usually have phrases like, you know, fasting is known to have all of these fantastic benefits and, you know, slows aging in all, every place where it's been looked at, and you can see that for all these different dietary strategies. So, so I, I proposed to the editor that, you know, maybe we should do a critical review of this space and think about what do we know, what do we don't know, are they equivalent? And to the extent possible, can we gain any insights into whether or not these, um, nutritional strategies, that whether there's evidence that they have an impact on the aging process in people? So that's kind of where we started, and I knew it was an ambitious thing to tackle when I said it, and I'm not sure I really appreciated exactly how challenging that was gonna be, 'cause it's a huge area, um, of literature. Um, a- a- and it turns out, maybe not shockingly, that there are m- many more questions than there are answers when you really dive into it. Um, so we really just started-

    11. PAPeter Attia1:22:02

        So what was your process?

    12. MKDr. Matt Kaeberlein1:22:03

        Yeah. So we really just start... The first step was, and I should say I had a fa- fantastic set of, um, co-authors, all, you know, really great early career scientists who d- who really helped me with this and did a lot of the, the legwork. Um, I just want to mention them by name-

    13. PAPeter Attia1:22:17

        Please do

    14. MKDr. Matt Kaeberlein1:22:17

        ... because I want... So, so Alessandro Bitto, who was a postdoc with me, um, uh, Mitchell Lee, who was a former graduate student with me, and Crystal Hill, who's at the Pennington Biomedical Research, uh, Institute, and she works on FGF21 and protein restriction. So those three were co-authors on this paper with me, all just, just really fantastic early career scientists. So, so we started by, um, asking ourselves, okay, what are the different popular dietary interventions that people have claimed have an effect on aging? And we, we came up with, I don't know, six or seven. Um, and they were the, the ones I've already mentioned. So there's true caloric restriction, which is pretty straightforward. That, you know, really just means limiting the overall caloric-

    15. PAPeter Attia1:23:01

        Mm-hmm

    16. MKDr. Matt Kaeberlein1:23:01

        ... intake that an animal gets, you know, by somewhere between 20, towards the low end, and up, the, the, the most I've ever seen is 65% of calories.

    17. PAPeter Attia1:23:10

        You were doing this in animals and humans, or you were trying-

    18. MKDr. Matt Kaeberlein1:23:12

        We started, we were mostly focusing on mice.

    19. PAPeter Attia1:23:15

        Okay.

    20. MKDr. Matt Kaeberlein1:23:15

        We, we narrowed it pretty quickly when we realized the scope of what, [laughs] what we had undertaken. So we could have tried to do it in, you know, fruit flies-

    21. PAPeter Attia1:23:23

        Yeah

    22. MKDr. Matt Kaeberlein1:23:23

        ... worms and all that stuff. We said, let's start with mice, see what's known, and then try to look into humans and ask, are there parallels?

    23. PAPeter Attia1:23:32

        Yep.

    24. MKDr. Matt Kaeberlein1:23:32

        Right? Okay. So caloric restriction, pretty straightforward. We actually don't go very deep into caloric restriction 'cause that, that literature is huge and other people, I think, have done a pretty good job of, of reviewing true caloric restriction. Um, but there are some points though that we probably want to touch on that are important. And then there are variants of caloric restriction which include, um, uh, intermittent fasting, uh, uh, time restricted feeding. Um, I-

    25. PAPeter Attia1:23:57

        How did you differentiate those two?

    26. MKDr. Matt Kaeberlein1:23:59

        Right.

    27. PAPeter Attia1:23:59

        I, I have a definition, but I want to make sure yours is clear.

    28. MKDr. Matt Kaeberlein1:24:01

        Right. So in mice, um, I think... Well, so first of all, the first differenti- differentiator we need to put across all of these things is, uh, is it isocaloric or is it a flavor of caloric restriction? 'Cause it turns out, I would say the vast majority of studies in mice, of all of the things that we're gonna talk about, are flavors of caloric restriction. And what I mean by that is the, the experimental group ate less calories than the-

    29. PAPeter Attia1:24:27

        Right

    30. MKDr. Matt Kaeberlein1:24:27

        ... control group.
13. 1:27:39 – 1:36:38

    Mouse models of time-restricted feeding in the context of calorie restriction

    1. MKDr. Matt Kaeberlein1:27:39

       Yep.

    2. PAPeter Attia1:27:40

       Let's go back to the, the circadian one. I wanna kind of get the, the insights there. Um, how do... So first of all, let's talk about what you know in mice.

    3. MKDr. Matt Kaeberlein1:27:49

       Yeah.

    4. PAPeter Attia1:27:50

       And then let's figure out-

    5. MKDr. Matt Kaeberlein1:27:51

       Yeah

    6. PAPeter Attia1:27:51

       ... if there's any extrapolation.

    7. MKDr. Matt Kaeberlein1:27:52

       So, so when we wrote the paper, there wasn't much on this. I mean, people were thinking about it, particularly in the context of, um, uh, time-restricted feeding, right? That, that there might be differences in the window of time-restricted feeding for-

    8. PAPeter Attia1:28:05

       That's right

    9. MKDr. Matt Kaeberlein1:28:06

       ... like for in humans, right? Early in the day, late in the day. Um, there's been a couple of papers that have come out, uh, since we wrote the review in mice that I think make a pretty compelling case that the lifespan benefit from, say, a 30% caloric restriction diet is a combination of when the animals are eating and how much they're eating. Most of the benefit seems to come from the ca- calories. So, you know, let's just say, uh, th- this may not be exactly right, but I think it's close. Let's just say that you get a 30% lifespan extension from 30% caloric restriction, that the two-thirds of that benefit comes from the calories.

    10. PAPeter Attia1:28:46

        Yep.

    11. MKDr. Matt Kaeberlein1:28:46

        But one-third of the benefit actually comes from the fact that those mice eat all their food in a short window and are fasted essentially the rest of that 24-hour period. And if you force them to... I mean, and I say force 'cause if you give a calorically restricted mouse its food, it's gonna eat it right away.

    12. PAPeter Attia1:29:03

        Yep.

    13. MKDr. Matt Kaeberlein1:29:03

        So if you force them to eat little bits throughout the day, you lose a portion of that lifespan benefit, which is really interesting.

    14. PAPeter Attia1:29:11

        Now, a mouse eating in an hour and then going 23 hours without food, what would we even compare that to in a human?

    15. MKDr. Matt Kaeberlein1:29:20

        I don't know. Yeah, I mean, this is... I, I, I really don't, don't feel comfortable even speculating. So I mean, I think that the, the, you know, the, the first simplistic, uh, approach would be to say, well, a mouse lives about three years, a human lives about, you know, 90 years.

    16. PAPeter Attia1:29:35

        I was thinking more of like how long does a mouse take before it dies from starvation?

    17. MKDr. Matt Kaeberlein1:29:38

        Yeah, so that's where I was gonna go next. I think that, that sort of length of lifespan is not the approach-

    18. PAPeter Attia1:29:43

        No

    19. MKDr. Matt Kaeberlein1:29:43

        ... you take when it comes to, to metabolism. So, so I would say that, uh, and this is total back of the envelope calculation, but a one-day f- maybe it's like a one to, one to four ratio. So a one-day mouse fast might be a four or five-day fast in, in people. Um, but that's not even perfectly true because a mouse, you know, a mouse will go into ketosis relatively quickly, within 24 hours, right?

    20. PAPeter Attia1:30:07

        Sure.

    21. MKDr. Matt Kaeberlein1:30:07

        Uh, and a human can go into ketosis that quickly d- depending a little bit on-

    22. PAPeter Attia1:30:11

        Depending on their incoming diet

    23. MKDr. Matt Kaeberlein1:30:12

        ... yeah, exactly.

    24. PAPeter Attia1:30:13

        Yeah.

    25. MKDr. Matt Kaeberlein1:30:13

        Right. So, so it, it's not a, it's not a perfect equivalency, but, but, but maybe one to four or five. Um, I hope I'm not saying something totally stupid here, but I think that's probably pretty close. Um, so yeah. So again, it's very different, uh, potentially these kinds of studies in mice. The other thing that I think most people don't appreciate unless they've actually done these caloric restriction experiments is that if you go back to the, you know, the classic experiments of, of, uh, uh, Rick Winedruck and R- Roy Walford, um, those were, those mice are fed a calorically restricted diet. They're also fed three times a week. So, so they are in fact, you know-

    26. PAPeter Attia1:30:48

        I mean, it's insane

    27. MKDr. Matt Kaeberlein1:30:49

        ... fasting.

    28. PAPeter Attia1:30:49

        It's like they're, they're basically doing a two-week fast between their meals.

    29. MKDr. Matt Kaeberlein1:30:53

        Yeah. And so what you see, even in 24 hours in a fasted mouse, is you see pretty dramatic reductions in organ size, right?

    30. PAPeter Attia1:31:00

        Right.
14. 1:36:38 – 1:41:46

    Nutritional interventions that consistently impact lifespan in mice, and concerns around efficacy in humans

    1. MKDr. Matt Kaeberlein1:36:38

       the same way i- in humans.

    2. PAPeter Attia1:36:39

       What did you learn about the protein restriction and the ketogenic diet mechanistically in the mice?

    3. MKDr. Matt Kaeberlein1:36:43

       Yeah. So, so again, the, the couple things to say about that, the ketogenic diet studies, there have really only been two that I'm aware of that looked at lifespan and healthspan in, in mice. Um, they were s- they were slightly different, uh, but in mice, you have to go to really, really low sugar to actually get the mice to go into ketosis.

    4. PAPeter Attia1:37:02

       Yeah. I mean, these all have to eliminate it.

    5. MKDr. Matt Kaeberlein1:37:03

       These are essentially 1% or less-

    6. PAPeter Attia1:37:05

       Yeah

    7. MKDr. Matt Kaeberlein1:37:05

       ... carbohydrate diets. So again, that's a difference from, from people. Um, the, the stu- one of the studies that fed a ketogenic diet lifelong saw no effect on lifespan, but they did an intermittent ketogenic diet. I don't remember the exact protocol, but it was something like every other day or maybe once every three days or something. Um, and there, there was about a, I think, a 15% increase in lifespan.

    8. PAPeter Attia1:37:28

       And I'm sorry, what did they do on the other days, the animals?

    9. MKDr. Matt Kaeberlein1:37:31

       Ad li- uh, regular diet. Sorry.

    10. PAPeter Attia1:37:33

        Oh, interesting. Wow.

    11. MKDr. Matt Kaeberlein1:37:33

        Regular diet. Yeah. So it was just back and forth between the control diet-

    12. PAPeter Attia1:37:35

        Hmm

    13. MKDr. Matt Kaeberlein1:37:35

        ... and the ketogenic diet.

    14. PAPeter Attia1:37:36

        Okay.

    15. MKDr. Matt Kaeberlein1:37:36

        Yeah.

    16. PAPeter Attia1:37:37

        And that didn't result in caloric restriction, the-

    17. MKDr. Matt Kaeberlein1:37:39

        That's the thing. The mice were calorically restricted. So it's-

    18. PAPeter Attia1:37:41

        Oh

    19. MKDr. Matt Kaeberlein1:37:41

        ... in some ways it's a intermittent caloric restriction, right? And this is what I would say. It's also interesting because the fasting mimicking diet papers are intermittent ketogenic diets. So, so I think that, you know, maybe that's one thing to agree on is that intermittent ketogenic diets in mice can increase lifespan and seem to have benefits for healthspan. Um, but, uh, but the ketogenic... The, the effects aren't huge, right? Again, that's the other, uh, take-home, I would say, from, from our study. There are two nutritional interventions that relatively consistently give big effects on lifespan. One is caloric restriction and one is protein restriction. And they, you know... Again, caloric restriction, the, the most extreme study that I've seen is 65% restriction.

    20. PAPeter Attia1:38:34

        Yeah.

    21. MKDr. Matt Kaeberlein1:38:34

        And that gave about a 65% increase in lifespan. So these are big, big effect sizes.

    22. PAPeter Attia1:38:40

        Wow.

    23. MKDr. Matt Kaeberlein1:38:41

        Um-

    24. PAPeter Attia1:38:41

        I, I, I wasn't aware of that. And that-

    25. MKDr. Matt Kaeberlein1:38:42

        Yeah, that's this Wa- Wa- uh, uh, wa- uh, Wa- Wal- Walford and... Weindruch and Walford paper.

    26. PAPeter Attia1:38:48

        Okay.

    27. MKDr. Matt Kaeberlein1:38:48

        Okay.

    28. PAPeter Attia1:38:48

        And, and when did they start that, and how long did that restriction last?

    29. MKDr. Matt Kaeberlein1:38:51

        That's a good question. I don't remember. I... It was probably six or nine months. I think most of their studies were, you know, early onset caloric restriction. Um, and they... Th- this study was, uh, really interesting because they did, you know, a graded response from, you know, 90%, 80%, 60%, 50%, 40% of ad lib. And you get essentially a graded response in lifespan, and it's roughly linear. So, so I think... You know, that's why I said about 60-

    30. PAPeter Attia1:39:21

        So 90% animals? 90% of the-
15. 1:41:46 – 1:49:02

    Differing impact of calorie restriction when started later in life

    1. MKDr. Matt Kaeberlein1:41:46

       psychological consequences are.

    2. PAPeter Attia1:41:47

       And, and, and what do we know about caloric restriction later in life in the mice versus earlier?

    3. MKDr. Matt Kaeberlein1:41:51

       Yeah.

    4. PAPeter Attia1:41:51

       I mean, the, the sort of traditional thinking is you, you have a window in which you can do it early, and beyond that it's not as effective.

    5. MKDr. Matt Kaeberlein1:41:58

       Yeah.

    6. PAPeter Attia1:41:58

       Uh, I think we're gonna talk about some data that counter that. And then of course you have the NIA experiment we talked about earlier-

    7. MKDr. Matt Kaeberlein1:42:04

       In the monkeys

    8. PAPeter Attia1:42:05

       ... where, in the monkeys-

    9. MKDr. Matt Kaeberlein1:42:05

       Yeah

    10. PAPeter Attia1:42:05

        ... where the early fast-

    11. MKDr. Matt Kaeberlein1:42:07

        Yeah

    12. PAPeter Attia1:42:07

        ... didn't improve longevity.

    13. MKDr. Matt Kaeberlein1:42:09

        Yeah.

    14. PAPeter Attia1:42:09

        The late fast appears to have, although-

    15. MKDr. Matt Kaeberlein1:42:11

        Right

    16. PAPeter Attia1:42:11

        ... that was sort of a subgroup analysis.

    17. MKDr. Matt Kaeberlein1:42:13

        It's hard to, hard to draw a causation there. Yeah.

    18. PAPeter Attia1:42:15

        Yeah.

    19. MKDr. Matt Kaeberlein1:42:15

        Um, so, so what I would say about the mice is that for a long time, the sort of dogma was that caloric restriction didn't work if, if you started it, you know, past, I don't know, 15 months of age, which is maybe the mouse equivalent of a 40, 50-year-old person. Um, so most of the early caloric restriction studies were done, like I said, starting sometimes pre-development. Uh, the early rat studies were pre-development and then sometimes, you know, six, nine months of, of age. Um, so that was sort of... When I first started in the field, that's kind of what I was told, like this is a settled question. Um, late-- more recent studies that have been done in s- in some ways more carefully, different diets, uh, certainly. Um, if you do a graded onset of caloric restriction, in other words, don't go right from ad lib to 40% restriction-

    20. PAPeter Attia1:43:03

        Yeah

    21. MKDr. Matt Kaeberlein1:43:03

        ... the next day. If you do sort of a graded onset, you can get lifespan benefits from caloric restriction, you know, 20, 22 months of age. So whether it's as good as starting early, I think the consensus is still that the answer's no. You're never gonna get the same magnitude of benefit from caloric restriction starting late as you do starting early. But m- that could be wrong. So I would say that's the consensus, but I don't think we know, we know for sure whether it's possible if you did it just right that you could get, you know, most or all of the benefits from starting late in life.

    22. PAPeter Attia1:43:43

        So Matt, on this topic of CR in mice, you know, um, again, the, the dogma has generally been, and I've been victim of this just sort of blindly assuming it to be the case that, you know, CR in mice only works early in life. Uh, again, i- is that- How, how applicable is that to humans? I don't know. Um, but, you know, a listener of the podcast actually pointed, uh, out that, you know, in fact there are some data that, that try to get at this question elsewhere. So there, there's, there's this Han study t- 2019, which we'll link to, that looked at, um, 800 female, uh, mice. Now, this is a pretty elegant experiment, right? So for the first three months, they ran these mice out, uh, on a ad libitum diet, and then at three months they were split, randomized to, I believe a 40%, yeah, calorie restriction versus ad lib. They ran that out until 24 months, and then each of those groups was further sprit- split ad lib versus continued on. So you had one group that was everybody's the same till three months, one group that spent the rest of their life on dietary restriction, one group that spent the rest of their life ad lib, and then you had the middle groups. Uh, t- 21 months calorie restricted, then to ad lib.

    23. MKDr. Matt Kaeberlein1:44:54

        Right.

    24. PAPeter Attia1:44:55

        21 months c- uh, ad lib to then calorie restricted. Okay, so the ends of this were not interesting, right? Meaning the ad lib group lived the shortest. Uh, we, we were looking at the figure earlier today, 1,200 days roughly. Going back to-

    25. MKDr. Matt Kaeberlein1:45:08

        Maximum lifespan.

    26. PAPeter Attia1:45:09

        Yeah, maximum lifespan.

    27. MKDr. Matt Kaeberlein1:45:10

        Yeah.

    28. PAPeter Attia1:45:10

        That's right. Median lifespan would've been, looking at the graph, about 900 days.

    29. MKDr. Matt Kaeberlein1:45:13

        Yeah, which is pretty good. Again-

    30. PAPeter Attia1:45:15

        Yeah, so I was gonna say, how does that stack up-
16. 1:49:02 – 1:55:38

    Lifespan extension with rapamycin in older mice

    1. MKDr. Matt Kaeberlein1:49:03

       Th- I think maybe one thing that's, that's worth, um, adding to this too is it's, it's an interesting comparison to what we know about mTOR and rapamycin, right? So with rapamycin-

    2. PAPeter Attia1:49:12

       Yeah

    3. MKDr. Matt Kaeberlein1:49:12

       ... you know, the data are pretty clear that you can start rapamycin certainly well into middle age and maybe even into very old age and get most of the benefit. So if you compare the curve here where they started the mice on CR at 22 or 24 months, whatever it is, the effect is pretty small-

    4. PAPeter Attia1:49:29

       Yep

    5. MKDr. Matt Kaeberlein1:49:29

       ... compared to CR. With rapamycin, you get almost exactly the same benefit starting at 20, 22, 24 months as you do starting early in life. So that might tell us that there's a difference, right? There clearly is a difference.

    6. PAPeter Attia1:49:41

       There's a different mechanism potentially as well.

    7. MKDr. Matt Kaeberlein1:49:44

       It, it partially different at least.

    8. PAPeter Attia1:49:44

       It could be that rapamycin's doing something different-

    9. MKDr. Matt Kaeberlein1:49:46

       Yeah

    10. PAPeter Attia1:49:46

        ... or it's a different dose effect relative to-

    11. MKDr. Matt Kaeberlein1:49:48

        Yeah, exactly.

    12. PAPeter Attia1:49:48

        Yeah.

    13. MKDr. Matt Kaeberlein1:49:48

        So, so that, that's an open question exactly why it's different, but it seems to be, it seems to be different.

    14. PAPeter Attia1:49:54

        Yeah, I'm really glad you brought that up because, you know, we talked about that with Rich Miller on his podcast, which was A fortuitous accident, right? Basically because they couldn't-

    15. MKDr. Matt Kaeberlein1:50:02

        [laughs] Yeah, the first study

    16. PAPeter Attia1:50:02

        ... get the formulation-

    17. MKDr. Matt Kaeberlein1:50:04

        Yeah

    18. PAPeter Attia1:50:04

        ... of rapamycin for that first ITP study.

    19. MKDr. Matt Kaeberlein1:50:06

        My favorite story in science. One of my favorite stories in science.

    20. PAPeter Attia1:50:08

        Yeah.

    21. MKDr. Matt Kaeberlein1:50:08

        Yeah.

    22. PAPeter Attia1:50:08

        Yeah, tell people that story 'cause it's-

    23. MKDr. Matt Kaeberlein1:50:09

        Yeah, right. So, um, so take a step back. The, the NIA started this program called the Interventions Testing Program, um, must have been the early '90s, and the idea here was, was... Maybe it was early 2000s, sorry. I'm dating myself again, losing my decade. So early 2000s. Um, and the idea here was, I think, really smart. The idea was that we could create a tool where the scientific community could nominate interventions for lifespan testing in mice, and it was set up so that it would be done in, in triplicate, right? So there were three, three sites. There still are three sites for the ITP. Um, so anybody in the community can nominate any intervention. Uh, there's a selection committee that selects them every, every year. Um, and if an intervention is selected, then the, the Intervention Testing Program sites start the cohorts of mice on that intervention, you know, in whatever year it was selected for. So sometime back in the early 2000s, um, Dave Sharp nominated rapamycin. And, you know, some ways he was ahead of his time because this was... I think when he nominated rapamycin, it was even before the first invertebrate studies on mTOR and rapamycin. It was right around the same time they were being published. So, you know, he, I think, was thinking about it from a cancer perspective primarily. In any case, he nominated rapamycin. It got selected. It went into the cohort, and they typically test five or six interventions or drugs each year. So they have a huge number of animals at each of these three sites that are destined for these interventions to be tested in, and rapamycin was one of them. And, um, Randy Strong, who's one of the, the PIs on the ITP, um, who's also got a strong biochemistry background, I think recognized pretty quickly that the rapamycin wasn't stable in the food. We could actually come back to this if you want to, 'cause this is relevant for, for people as well. So-

    24. PAPeter Attia1:51:59

        Mm-hmm

    25. MKDr. Matt Kaeberlein1:51:59

        ... and it, and it gets broken down in the pH of the, the gut, right? So the... So basically, if they just put the, the powder in the food, there's no bioavailability. It doesn't get taken up by the mice. And so they recognized that right when they were supposed to start the experiment, and, you know, of course they were like, "Crap, what do we do?" You know, we could just not test rapamycin. Um, and I, and I don't know if it was Randy or who. Somebody said, "Well, I think I can figure out a way to m- to stabilize the rapamycin, put it in the food so that we can give it to the mice, and we can do the lifespan experiment." I think what they didn't recognize was that it was gonna take 18 months or so to figure this out. So once they finally developed this in what they call eRap, a encapsulated rapamycin, um, it, it, it's basically designed so that it won't break down in the, at the gastric pH. Once they developed that, they were now 18 months into this lifespan experiment. Before this, everybody, I think everybody, myself included, in the field thought you had to start early in life or you weren't gonna get much of a benefit. There was really almost no chance a drug was gonna increase lifespan starting that late in life. But fortunately, they went ahead with the experiment, starting at 20 months of age, and what they found was that they got this robust lifespan extension from starting with rapamycin treatment at 20 months of age. And just to give some context, that's about the mouse equivalent of a 60 or 65-year-old person. And I love the experiment. I love the outcome obviously because, you know, first of all, nobody thought it was gonna work-

    26. PAPeter Attia1:53:26

        Yeah

    27. MKDr. Matt Kaeberlein1:53:26

        ... except maybe Rich Miller. Maybe... I'll give Rich credit. Maybe he thought it was gonna work. Um, uh, and it was really the first time anybody had convincingly shown that you could start a intervention treatment-

    28. PAPeter Attia1:53:37

        Intervention. Yeah, not even a drug. Yeah

    29. MKDr. Matt Kaeberlein1:53:38

        ... in middle age in a mouse and get robust lifespan extension. And for me, honestly, I reviewed that paper, and when I f- when I first time I saw that result, I'm like, "This changes everything." We actually have a chance for translational geroscience, 'cause, 'cause you might be able to intervene late in the aging process and have significant impact. So i- uh, honestly, in, in... That was 2009-

    30. PAPeter Attia1:54:00

        '09, yeah
17. 1:55:38 – 2:04:07

    Relationship between protein intake and aging, and mouse studies showing protein restriction can extend lifespan

    1. PAPeter Attia1:55:38

       Yeah.

    2. MKDr. Matt Kaeberlein1:55:38

       Yeah.

    3. PAPeter Attia1:55:38

       So Matt, obviously one of the other things that came out of that review article in the animal stuff was, as you said, the protein restriction. And I think of all the topics in nutrition, this is the one I'm most interested in. Uh, I really don't care that much about fat and carbs.

    4. MKDr. Matt Kaeberlein1:55:53

       [laughs]

    5. PAPeter Attia1:55:53

       Don't tell anybody. But I care an awful lot about protein. Um, you know, in fact, when you came over today, you probably saw me chasing down what was left of a protein shake, and-

    6. MKDr. Matt Kaeberlein1:56:02

       [laughs] Right

    7. PAPeter Attia1:56:02

       ... I think I was mentioning to you or my wife, like, that's the only part of nutrition that is kind of Um, I don't want to say a chore, but it, it's a very deliberate part of how I go about the day, which is I really have to think about it. And the reason is I'm trying to eat a gram of protein per pound of body weight spread out into four buckets.

    8. MKDr. Matt Kaeberlein1:56:25

       Right.

    9. PAPeter Attia1:56:25

       Right? 'Cause if you... You know, I think there's reas- reasonable evidence to suggest that if you consume too much protein in one sitting, uh, and it's typically more than about .25 grams per pound is the general thinking, you're going to end up oxidizing some of that protein. So it's not that it's harmful, it's just that you're not getting the amino acids you need for muscle protein synthesis, which is, of course, our objective. So that means I'm kind of walking around trying to get 40 grams here, 40 grams there, 40 grams here, 40 grams there, and truthfully, that's, um, not trivial if you're not willing to consume a whole bunch of crap with it. I mean, i- if you're really just trying to focus on the protein quality. So, look, the RDA says I'm crazy, right? The recommended daily allowance of protein is 0.8 grams per kilogram.

    10. MKDr. Matt Kaeberlein1:57:17

        Right.

    11. PAPeter Attia1:57:17

        Which is less than half of what I would consume. Why, why, where do you see the... A- a- and by the way, it's not just that I'm making up the amount that I'm consuming. I, I'm doing it on the basis of other data that suggests that this is the amount of protein consumption you need for optimal muscle protein synthesis.

    12. MKDr. Matt Kaeberlein1:57:33

        Right. Right.

    13. PAPeter Attia1:57:33

        So where's this disconnect?

    14. MKDr. Matt Kaeberlein1:57:35

        Yeah. So, I mean, I think first of all, um, we can talk about the rodent studies, right, which is in the, the biology of aging. I think the RDA question, you know, they're, they're... That, that's a different question. It's my understanding that that actually was developed to be, uh, protein balance for 95% of the population when sedentary, right? So I think what that means, first of all, that's a minimum amount-

    15. PAPeter Attia1:58:01

        Yeah

    16. MKDr. Matt Kaeberlein1:58:01

        ... not necessarily the optimal amount, and it probably very much depends on lifestyle, right? Um-

    17. PAPeter Attia1:58:07

        And lean body mass to begin with-

    18. MKDr. Matt Kaeberlein1:58:08

        Ab- absolutely

    19. PAPeter Attia1:58:08

        ... even though it's sort of normalized to it, but, you know.

    20. MKDr. Matt Kaeberlein1:58:10

        Yeah. So I think, I think, I, I... But, and the reason why I, I bring this up is I think there's a lot, again, a lot of confusion among the general public about what the RDA means, and it's not, it's not necessarily a bad thing to be above the RDA in some areas, right?

    21. PAPeter Attia1:58:23

        Yep.

    22. MKDr. Matt Kaeberlein1:58:24

        Maybe a lot of areas. So I think that's just worth, worth, you know, uh, expanding on just, just a little bit.

    23. PAPeter Attia1:58:28

        Yeah, I think, I, I agree completely. I, I, I sort of jokingly think of the RDA for protein as what you need to not waste away and wither up and die.

    24. MKDr. Matt Kaeberlein1:58:36

        Right. Exactly, yeah. So, right, so you're not losing muscle mass.

    25. PAPeter Attia1:58:39

        Yeah.

    26. MKDr. Matt Kaeberlein1:58:39

        Yeah. So, so then the, the question of what is the relationship between protein and aging, I think, is a really im- important one.

    27. PAPeter Attia1:58:45

        Yeah.

    28. MKDr. Matt Kaeberlein1:58:45

        And it's gotten a lot of attention in the field. Um, uh, a- and like I think a lot of other things, there's a lack of clarity about what we actually know and what we should be recommending to people. So let's take a step back and start with the animal studies, the, the mouse studies. Um, I think there it's pretty clear that you can extend lifespan through protein restriction, and there are actually, again, a couple of flavors of protein restriction. You can restrict all protein down to, you know, some, some percentage, some low percentage, um, or you can restrict specific amino acids, particularly-

    29. PAPeter Attia1:59:21

        Branch chains

    30. MKDr. Matt Kaeberlein1:59:22

        ... um, tr- tryptophan-
18. 2:04:07 – 2:09:37

    Impact of protein intake on mTOR, and why inhibition of mTOR doesn’t cause muscle loss

    1. MKDr. Matt Kaeberlein2:04:07

       are causal in some, in some cases.

    2. PAPeter Attia2:04:07

       So let's talk about time course, right?

    3. MKDr. Matt Kaeberlein2:04:09

       Yeah.

    4. PAPeter Attia2:04:09

       So when you consume a protein-rich meal, um, do we have a sense of how long mTOR is being activated in response to that set of amino acids?

    5. MKDr. Matt Kaeberlein2:04:22

       I'm sure somebody does. I d- [laughs] I don't know the answer to that. I, I, I mean, I think again, uh, almost certainly it's going to depend on, um, what you eat in combination with the protein, when you eat-

    6. PAPeter Attia2:04:34

       Y- y- yeah, exactly

    7. MKDr. Matt Kaeberlein2:04:34

       ... you know, how active you are.

    8. PAPeter Attia2:04:35

       Like I, I, I, I remember talking to David Sabatini about this through the lens of BCAA drinks.

    9. MKDr. Matt Kaeberlein2:04:41

       Yeah.

    10. PAPeter Attia2:04:42

        So if you're gonna pound branched-chain amino acids during a workout-

    11. MKDr. Matt Kaeberlein2:04:46

        Yeah

    12. PAPeter Attia2:04:46

        ... because you want as much anabolic signal as possible... And this is a couple of years ago, so, so m- maybe things have changed, but based on that work, I think Bobby Sutton had done the work in his lab, if I'm getting his name right. Was it Bobby Sutton was the-

    13. MKDr. Matt Kaeberlein2:05:01

        Yeah

    14. PAPeter Attia2:05:01

        ... the guy who did that science paper that looked at the leucine sensor-

    15. MKDr. Matt Kaeberlein2:05:04

        Right

    16. PAPeter Attia2:05:04

        ... on mTOR?

    17. MKDr. Matt Kaeberlein2:05:05

        Right.

    18. PAPeter Attia2:05:07

        The answer was it didn't stay on long at all.

    19. MKDr. Matt Kaeberlein2:05:09

        Yeah.

    20. PAPeter Attia2:05:10

        Free amino acids were so short in their ability to turn on mTOR that unless you had an intravenous drip of this stuff, it was gonna be very difficult. So much so that the idea of using BCAA analogs to treat sarcopenia was going to require drugs-

    21. MKDr. Matt Kaeberlein2:05:29

        Yeah

    22. PAPeter Attia2:05:29

        ... that could stay on-

    23. MKDr. Matt Kaeberlein2:05:30

        Yeah

    24. PAPeter Attia2:05:30

        ... much longer. Is that kind of within your frame of thinking?

    25. MKDr. Matt Kaeberlein2:05:33

        Uh, I think so, and I think it also, it also makes sense in a, in a biological context, right? I mean, I mean, cells and tissues, you know, again, this gets back to the whole homeostasis concept, right? Cells and tissues have evolved to maintain metabolites, and amino acids are, are metabolites, right? They're involved in many different metabolic reactions within certain levels, and there are all sorts of mechanisms to ensure that if, if at a metabolite gets outside of that range, that we soak it up, we do something else with it, right?

    26. PAPeter Attia2:06:02

        Yeah.

    27. MKDr. Matt Kaeberlein2:06:02

        So I think it makes sense that you're probably not gonna have, you know, a, a persistent, uh, increase in branched-chain amino acids far outside the normal range. What I would say, though, is that slightly elevated branched-chain amino acids chronically can have big effects on the sort of downstream-

    28. PAPeter Attia2:06:21

        Yeah

    29. MKDr. Matt Kaeberlein2:06:21

        ... processes. And there are, there are some, you know, inborn diseases of childhood where you have elevated levels of branched-chain amino acids. We know that there are consequences to even having, you know, somewhat modest increases in mTOR s- hyperactivation of mTOR signaling chronically.

    30. PAPeter Attia2:06:37

        Yeah.
19. 2:09:37 – 2:22:16

    Low-protein vs. high-protein diets and their effects on muscle mass, mortality, and more

    1. MKDr. Matt Kaeberlein2:09:37

       we certainly don't understand a- all, all of it.

    2. PAPeter Attia2:09:38

       Now, what about the flip side of that is, uh, more protein versus less protein activating rap- uh, mTOR in a way that is counterproductive?

    3. MKDr. Matt Kaeberlein2:09:48

       I think it can. Um, I think there, I think there are probably certain, certainly cases where it can.

    4. PAPeter Attia2:09:52

       Mm-hmm.

    5. MKDr. Matt Kaeberlein2:09:52

       Um, again, you know, I don't, I don't know that anybody has really carefully done that study in mice. There, there was a study, it's a really interesting study by, um, Steve Simpson and colleagues where, where they did this nutritional geometry work where they-

    6. PAPeter Attia2:10:06

       Hmm

    7. MKDr. Matt Kaeberlein2:10:06

       ... basically looked at different compositions of carbohydrates, fats-

    8. PAPeter Attia2:10:09

       Steve Simpson

    9. MKDr. Matt Kaeberlein2:10:10

       ... and proteins

    10. PAPeter Attia2:10:10

        ... he's in Australia?

    11. MKDr. Matt Kaeberlein2:10:11

        Yeah, exactly.

    12. PAPeter Attia2:10:11

        Yeah, yeah.

    13. MKDr. Matt Kaeberlein2:10:12

        And, you know, looked at I don't remember how many diets. It was a whole range of diets, right? Different compositions of the three macronutrients. Tried to control for caloric intake, which is hard, as you can imagine, but I think they did a pretty good job. Um, and then asked, you know, what, what does it look like in terms of metabolism, energy expenditure, lifespan? So the lifespan studies I think are, are, are pretty clear that m- most of the diets where the mice lived the longest were towards the low end in protein. But there were some things that I think called into question exactly what was going on there, because it wasn't the case that the, the, the mice that were energetic, the diets that were energetically lowest gave the longest lifespan, as you might expect from caloric restriction, and the diet that actually gave the absolute longest lifespan had like, I don't know, it was like a 40% protein in it, right? So, so the way [laughs] I interpret that is that there are many ways to get to longevity.

    14. PAPeter Attia2:11:07

        And how calorie restricted was that?

    15. MKDr. Matt Kaeberlein2:11:09

        They li- w- they were not calorically restricted at all.

    16. PAPeter Attia2:11:12

        So you're saying that-

    17. MKDr. Matt Kaeberlein2:11:13

        They were all ad libitum

    18. PAPeter Attia2:11:13

        ... a diet that was ad lib with 40% protein had the best outcome?

    19. MKDr. Matt Kaeberlein2:11:17

        The, the best absolute lifespan, yes.

    20. PAPeter Attia2:11:20

        Again, h- how do we even reconcile-

    21. MKDr. Matt Kaeberlein2:11:22

        Well, and this is-

    22. PAPeter Attia2:11:22

        ... this body of literature?

    23. MKDr. Matt Kaeberlein2:11:23

        Yeah, and this is sort of what I, where I was just going, is I think that my view is there are probably multiple paths to longevity.

    24. PAPeter Attia2:11:29

        Mm-hmm.

    25. MKDr. Matt Kaeberlein2:11:30

        And we really don't understand the, the interrelationships of these macronutrients in, in the diet with enough sophistication to, to get beyond sort of broad general predictions. And again, you know, I sort of, this is an area where I, I really, I believe, like I can't prove it, but I, my intuition from, uh, from the, the data that I've seen and just my observations of people is that in humans it's probably very, this relationship between protein and health during aging is probably very different than it is in, in mice. I think mice are able to tolerate a very low protein diet without, you know, some of the consequences that-

    26. PAPeter Attia2:12:11

        Yeah

    27. MKDr. Matt Kaeberlein2:12:11

        ... we see in people. That's my intuition. I don't, you know, I, I don't know that that's true.

    28. PAPeter Attia2:12:16

        I mean, it's my intuition-

    29. MKDr. Matt Kaeberlein2:12:16

        But that's my intuition

    30. PAPeter Attia2:12:17

        ... well, uh, as well, because clinically, what we see in what I call the death bars, the death bars is our internal nomenclature for how people die. We just constantly look at death bars, and we double-click and double-click and double-click all the way to try to tease out everything that is reducing lifespan and healthspan. And the problems that occur in humans when they are under-muscled-
20. 2:22:16 – 2:37:23

    The impact of IGF-1 signaling and growth hormone on lifespan

    1. MKDr. Matt Kaeberlein2:22:16

       you're, you're probably right.

    2. PAPeter Attia2:22:16

       I think the other area where this gets very complicated is the, um, k- I don't want to say by necessity, but just by convention, we use IGF-1 as a biomarker for protein intake.

    3. MKDr. Matt Kaeberlein2:22:30

       Yeah.

    4. PAPeter Attia2:22:31

       And, uh, it's certainly associated with protein intake, but do you want to tell people what IGF-1 is? You know, a, a little bit of background of, you know, where it comes from-

    5. MKDr. Matt Kaeberlein2:22:39

       Sure

    6. PAPeter Attia2:22:39

       ... and what it's a proxy for?

    7. MKDr. Matt Kaeberlein2:22:41

       Sure. So IGF-1 is insulin-like growth factor 1. Um, it's a, a hormone that's in, in the growth hormone pathway. So when, so it's... You can think of it as a growth-promoting hormone, sort of, sort of part of this central pathway that, um, promotes, uh, growth in many, many different tissues. So if you have high growth hormone levels, you'll have high IGF-1 levels, and that, and high mTOR, right? So this is a, this is a, a, a part of the mTOR pathway as well, upstream of mTOR. So, um, the reason why people have been really interested in, in IGF-1 in the field of aging biology, it comes, you know, from studies, again, in the very simple laboratory, uh, model systems. So, um, the most famous and, and one of the first, uh, genes that was shown to, to clearly from a mechanistic perspective affect aging is it comes from Cynthia Kenyon and even Tom Johnson a little bit before her, which is the insulin-like receptor in C elegans called DAF-2. And Cynthia published a classic paper showing that if you make a mutation in DAF-2, you could double the lifespan of worms, and they seem to be healthier about twice as long. And what that mutation does is it turns down signaling through this pathway. Now, it's a little bit more complicated in worms because the, it's called the insulin/IGF-1-like signaling pathway, so it's not identical. And so there's one pathway in, in worms that kind of takes the place of both IGF-1 signaling and insulin signaling. But you can kind of think of them as equivalent. And then there are a whole bunch of studies in mice for mostly mutations in the growth hormone upstream signaling, uh, upstream of IGF-1, that lead to increased lifespan. So there are-

    8. PAPeter Attia2:24:20

       So this means GH does not activate the production of more IGF-1.

    9. MKDr. Matt Kaeberlein2:24:24

       That's right. So you have, you have l- f- through a variety of mechanisms-

    10. PAPeter Attia2:24:28

        You have high GH, low IGF-1 animals.

    11. MKDr. Matt Kaeberlein2:24:30

        Well, low GH signaling, right?

    12. PAPeter Attia2:24:32

        Yeah. Yeah, yeah, yeah.

    13. MKDr. Matt Kaeberlein2:24:33

        Yeah.

    14. PAPeter Attia2:24:33

        But they probably are high in IG- yeah.

    15. MKDr. Matt Kaeberlein2:24:34

        Oftentimes it's the receptor that's-

    16. PAPeter Attia2:24:36

        Yeah

    17. MKDr. Matt Kaeberlein2:24:36

        ... that's mutated.

    18. PAPeter Attia2:24:36

        Yeah.

    19. MKDr. Matt Kaeberlein2:24:36

        That's right.

    20. PAPeter Attia2:24:37

        Yeah.

    21. MKDr. Matt Kaeberlein2:24:37

        Yeah. So, um, so those animals tend to be very long-lived. They are, they rival caloric restriction in terms of the magnitude of lifespan extension. Um, and there are several different-

    22. PAPeter Attia2:24:47

        Yeah

    23. MKDr. Matt Kaeberlein2:24:47

        ... mutations in that pathway. Um, the, the mutations in IGF-1, I guess I should know this, the, the, the current state of that literature a little bit better. Um, it's complicated, and there have been some controversies in the field about the different mutations that directly affect IGF-1 itself and the effects on lifespan. So I'm not gonna wade into that because I think it still hasn't been resolved. But there's no question that mutations that reduce growth hormone signaling in mice extend lifespan. Now, it's important to understand, though, that with one exception, um, those studies are all cases where the animals are growth hormone signaling deficient through development. So they are very, very small animals, and then they have constitutively low levels of signaling through that pathway for the rest of their life.

    24. PAPeter Attia2:25:38

        Mm-hmm.

    25. MKDr. Matt Kaeberlein2:25:39

        Um, there's one study that, that, that, I think it used a monoclonal antibody to the IGF-1 receptor in mice. This is from Nir Barzilai-

    26. PAPeter Attia2:25:47

        Nir said that, yep

    27. MKDr. Matt Kaeberlein2:25:47

        ... and, uh, Hasi Cohen, yeah, where they treated mice with this antibody late in life.

    28. PAPeter Attia2:25:52

        Late in life, yeah.

    29. MKDr. Matt Kaeberlein2:25:52

        And they got, you know, a reasonably sized lifespan extension. I, I think it was, I don't know, 14, 15% median lifespan. So-

    30. PAPeter Attia2:26:00

        Was that als- and that, that was an antibody that did not penetrate the CNS, if I recall.

Episode duration: 2:43:49