333 ‒ Longevity roundtable—the science of aging, geroprotective molecules, & lifestyle interventions

1. 0:00 – 1:07

   Intro

   1. PAPeter Attia0:00

      Is aging a disease? Is that even a relevant question? [laughs]

   2. RMRichard Miller0:03

      Call on me, call on me, call on me, call on me. So calling aging a disease is a fundamental error.

   3. PAPeter Attia0:08

      The question itself is incorrect.

   4. MKMatt Kaeberlein0:09

      Yeah, I agree completely. I think it's the wrong question.

   5. SASteven Austad0:11

      I, I, I agree, but-

   6. PAPeter Attia0:13

      How do we define healthspan?

   7. MKMatt Kaeberlein0:14

      I haven't seen anything to make me believe that you can separate healthspan and lifespan.

   8. RMRichard Miller0:18

      My own personal answer to that is it's a useless term.

   9. SASteven Austad0:21

      [laughs] A state of your physical being that you can do the things you like to do.

   10. PAPeter Attia0:25

       The United States has the lowest life expectancy. That's because the United States has by far the greatest rate of death in middle age.

   11. MKMatt Kaeberlein0:32

       And I mean, the reality is the research flows from where the dollars are going. This has been seen over and over and over at NIH.

   12. PAPeter Attia0:38

       Maybe it's because the public doesn't understand this.

   13. RMRichard Miller0:41

       Yes. Yes.

   14. PAPeter Attia0:41

       But those people answer to the public. 'Cause I'm in the mood to see you get spicy, can we just talk about senescence for a minute?

   15. MKMatt Kaeberlein0:46

       [laughs]

   16. RMRichard Miller0:46

       There's no evidence, as far as I know, that it either has an anti-aging effect or removes senescent cells.

   17. PAPeter Attia0:52

       Let's do the closest thing that a group like this could do in terms of a speed round. [upbeat music] Hey, everyone, welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 1:07 – 10:54

   The recent rise in public interest in longevity, misconceptions, and the link between healthspan and lifespan

   1. PAPeter Attia1:07

      Gentlemen, this is a lot of fun. I am excited to be sitting down with, with you guys today. Um, where do we wanna begin? I mean, I, uh, let me start by saying the following. Uh, the, the term longevity, someone sent me something the other day that was, like, list of, you know, I don't know, met- whether it was how many times you- the word longevity was searched on Google or something like that, but it, it literally looks like Bitcoin if you... Y- I, I mean, it's-

   2. MKMatt Kaeberlein1:34

      Yeah

   3. PAPeter Attia1:34

      ... so we are clearly at peak longevity in terms of public interest, which, um, for all of you who have kind of devoted, uh, decades plural to this, um, I just wanna kinda get a reaction from you, each of you on, on what that means, w- why you think it's happening, and, uh, uh, m- maybe even extending the metaphor a little bit. Is, is there a bubble going on? Uh, so we'll start with you, Steve.

   4. SASteven Austad1:59

      Yeah, well, I, it's a surprise to me that longevity has become so big because [chuckles] for a long time, we sort of tried to move away from that in the aging field because we were worried that people were thinking of longevity as, well, we're gonna keep frail, feeble old people alive longer. That's what longevity meant, when really what we were trying to do is extend health. And so I'm kind of surprised, but I think it's because, uh, there are certain people of a certain age who've started to think about their own longevity. And then I think there's a whole new generation of, of, of tech entrepreneurs that really feel like this is a problem that will allow them to live healthily for, mm, several decades at least longer than they are now. So I think it's a combination. It's a multi-generational thing. That, that kinda surprises me.

   5. PAPeter Attia2:47

      And you haven't seen this before, to be clear. So t-

   6. SASteven Austad2:49

      Have, have not

   7. PAPeter Attia2:49

      ... 30 years ago, you didn't see glimmers of this?

   8. SASteven Austad2:51

      No. The s-- 30 years ago, I would've said, "Let's not even say the word longevity. Let's say healthspan." Um, but, um, that's changed quite clearly as more and more people have been, you know, from the outside, they're sort of peeking in at the field. I don't think the people in the field itself have changed the way they talk that much, but the people eavesdropping on the field certainly have.

   9. PAPeter Attia3:14

      Rich, is that your experience?

   10. RMRichard Miller3:15

       Well, I think there are two aspects that, that I would want to emphasize in response both to your question and to what Steve said. Um, in response to the question, I think the reason that people are now-- People have always been fascinated for millennia on things they could do to stay alive and healthy as long as possible. But there were actually scientific discoveries in the '90s, uh, that showed that it could be done, and then in the last 20 years, there's evidence that it can be done at least in mice with pills. So that naturally should lead to speculation that there could be pills you could give to people that would postpone poor health for a substantial amount of time. Uh, 20 to 30% is what we're seeing in mice, and 20 to 30% would be very important for people. So I think that is a, a part of it. The other part is that, um, there are now people who, uh, are making a lot of money by selling stuff that is untested, to be polite about it, or is useless, to be less polite about it, to gullible customers. And so, uh, people who wanna make a lot of money have finally found that there's a impetus that will allow them to sell stuff even if there's no evidence that it works, that they control an enormous amount of advertising dollars, both formal and informal. Uh, uh, that's a, a big part of the difference. The one comment I wanted to make with regard to, to something Steve said has to do with the alleged balance between healthspan and lifespan. The, it's become fashionable for the last 20 or 30 years to imagine that you get one or the other, that you have to make a choice. It's a decision, uh, and that if you give up on lifespan, that allows you to extend healthspan. I think that's ridiculous and controverted by all the available evidence. That is all of the drugs, at least, that extend lifespan in mice and could potentially do so in people do so by postponing diseases, both the diseases that will kill you, that's why they extend lifespan, and the diseases that won't kill you but which will annoy you and make you very unhappy to be old. So I think-

   11. PAPeter Attia5:30

       Which is true, by the way, of non-molecular tools as well.

   12. RMRichard Miller5:33

       Yes, absolutely.

   13. PAPeter Attia5:33

       That's true of exercise and-

   14. RMRichard Miller5:35

       Yeah, absolutely. That's a good point

   15. PAPeter Attia5:36

       ... not being insulin resistant.

   16. RMRichard Miller5:37

       I agree with you.

   17. PAPeter Attia5:38

       Yeah.

   18. RMRichard Miller5:38

       So the notion, it's time to put behind us and to make fun of the notion that I'm not interested in lifespan. Don't put me on that boat. I am interested in healthspan because they are linked together, and they go up and down together. Getting people disabused of that false metaphor, the seesaw metaphor, is probably a, an important goal for sort of the public interface between longevity scientists, aging scientists.

   19. PAPeter Attia6:03

       Now, I just wanna push on one thing, though. Um, c- You, you talked about obviously the discoveries of molecules. You've been personally central to that work. Um, but there was still a lag, Rich, right? I mean, it was 16, 15 years ago, the first ITP was published showing the overwhelmingly surprising and positive results of rapamycin.

   20. RMRichard Miller6:30

       Yes.

   21. PAPeter Attia6:30

       Those results were repeated.

   22. RMRichard Miller6:32

       Yeah.

   23. PAPeter Attia6:32

       So why, why, why a decade, c- let's be generous and, and charitable and call it a still decade-long lag from that. And by the way, I'll throw one more thing in there. If you go back to Cynthia Kenyon's work-

   24. RMRichard Miller6:44

       Yeah, '93

   25. PAPeter Attia6:44

       ... which may have been the thin end of the wedge into the idea that lifespan was malleable-

   26. RMRichard Miller6:49

       Yeah

   27. PAPeter Attia6:49

       ... albeit through a genetic manipulation in a less relevant model.

   28. RMRichard Miller6:53

       Yeah.

   29. PAPeter Attia6:53

       There's still a lag. It, it-

   30. RMRichard Miller6:55

       Yeah.
3. 10:54 – 20:48

   Redefining healthspan, the US healthcare paradox, and separating longevity science from commercial hype

   1. PAPeter Attia10:54

      in a recent podcast that I did with Som Sutaria talking about healthcare costs. And in that discussion, one of the things that emerged, um, which I think most people are sadly familiar with this statistic today, is that among the OECD nations, the United States has the lowest life expectancy, which is ironic given that we are spending on average about 80% more, and in some cases double what most other developed nations spend on healthcare. So how do you reconcile this? Well, Som made a very interesting point, which is that's aggregate life expectancy. But why is that the case? That's because the United States has by far the greatest rate of death in middle age, right? So when you look at maternal and infant mortality, we're horrible. When you look at gun violence and suicide and homicide, we're horrible. And most of all, when you look at overdoses, we're horrible, right? So when you kill a whole bunch of people in their 40s and 50s, you cannot have a very high life expectancy. Understood. But what Som pointed out was once an American reaches the age of, and I forget the exact age, I think it was about 65, all of a sudden they jump to the top of the list. That was very interesting to me. In other words, if you look at the blended Life expectancy, we're, we're not doing very well. But if you look at life expectancy just in measured as years alive, once you escape those big causes of death in middle age, we actually do quite well, and it comes down to what you're saying, which is we get very good at delaying death in chronic disease. That's, that's the, what I call the Medicine 2.0 machine at its absolute finest. We are gonna keep you along an extra six months once you have cancer. We are going to get you through that third revascularization procedure. And so now the question is, does that-- 'Cause my intuition is where yours is, Steve. I don't think we're getting any healthier, even if we're incrementally figuring out ways to extend life in the face of chronic disease. I don't see it being a quality of life. Now, part of this might be how do we define healthspan?

   2. MKMatt Kaeberlein12:53

      [laughs] Yeah. So let me-- I agree with you, and, and, um, I think it's even worse, though, than, than the way you laid it out. So if you look at the statistics, if you accept that 60% of Americans have at least one chronic disease, and the median age in the United States is 38-point-something, and then you think about how long are people living on average, that would suggest if you say that, and again, this is what you're getting at with the definition of healthspan, I would not define healthspan as ending once you have your first chronic disease-

   3. PAPeter Attia13:20

      Yeah

   4. MKMatt Kaeberlein13:20

      ... but that's the definition most people would use. If you use that definition, most people are spending three decades or more in the absence of healthspan, right? Or in sickspan. So I mean, the situation is even in the United States where life expectancy is relatively short compared to other nations, a big chunk of that life expectancy is not spent in good health, and it's exactly for this reason.

   5. RMRichard Miller13:43

      But the, the two different issues that are being confused here in the discussion. O-o-one is the issue of whether you can help middle-aged people live longer, and everybody's agreed that we're getting better at that. We're pretty good at it, and that certainly contributes to whatever you think healthspan might mean. That's an issue, however, that is quite different from would a concoction that slows aging-

   6. PAPeter Attia14:16

      Sure

   7. RMRichard Miller14:17

      ... do so by extending healthspan. Those both have the word healthspan in them-

   8. PAPeter Attia14:23

      Mm-hmm

   9. RMRichard Miller14:23

      ... but they're different and shouldn't ever be confused with one another. The other point in this question you asked was what is the, is healthspan? My own personal answer to that is it's a useless term.

   10. MKMatt Kaeberlein14:34

       [laughs]

   11. RMRichard Miller14:35

       That, that is because no one can define it. It's not because no one is smart. It's because the term itself is vacuous and nebulous. If you have somebody that gets a certain chronic disease here and then another one, and then they fall down and bump their head, and by the way, they go to the hospital and with COVID, et cetera, et cetera, defining when in that broad s- over that f- 20 to 30-year period they flicked the switch, now they have gotten to the end of the healthspan, is impossible and of no interest. The general notion that people are interested in is whether that you can do stuff to keep people healthy for a long time, either without changing their life expectancy or by changing their life ex- with changing their life ex- Those are interesting, but you don't have to assign a number-

   12. PAPeter Attia15:23

       But couldn't we get away, 'cause I agree with you completely, Rich-

   13. RMRichard Miller15:25

       ... a healthspan digit

   14. PAPeter Attia15:26

       I, I don't like the medical definition of healthspan, which I believe is, quote, "The period of time in which an individual is free of disability and disease." I find that to be a very unhelpful definition.

   15. RMRichard Miller15:35

       It's awful. Yeah.

   16. PAPeter Attia15:36

       Because it be- but part of the reason it's awful is it's binary.

   17. RMRichard Miller15:39

       Yeah.

   18. MKMatt Kaeberlein15:39

       Exactly.

   19. PAPeter Attia15:39

       And that's quite silly.

   20. RMRichard Miller15:41

       You got it.

   21. PAPeter Attia15:41

       But if we made it analog instead of digital-

   22. MKMatt Kaeberlein15:44

       Right

   23. PAPeter Attia15:44

       ... a- I'm not saying that makes it easy. It's still very challenging, but now it allows us to start talking about things, right? As a person-

   24. MKMatt Kaeberlein15:52

       Or except it's a concept. It's a qualitative concept, right? I mean, I agr- I, I think we should try to make it to where we can actually come up with a way to measure some, whether we call it healthspan or not.

   25. PAPeter Attia16:01

       Yeah.

   26. MKMatt Kaeberlein16:01

       That doesn't really matter. But I, I, I, I kind of agree with Rich. Like, I agree with, I agree with what you're saying, except I think it's a really useful term as a concept. I think it's a really useful way to communicate to a broader audience what the, what one of the goals is, right, which is to increase the healthy period of life.

   27. RMRichard Miller16:19

       Yeah, I, I kind of like the term health for that. [laughs] I have a way that helps you out with your health, and you don't have to-

   28. PAPeter Attia16:27

       See, maybe it's function

   29. RMRichard Miller16:29

       ... pretend you can define it as a number.

   30. MKMatt Kaeberlein16:30

       But there is a period of, I think we all could agree, there's a period of life where you are in relatively good health.
4. 20:48 – 30:19

   The need to redirect medical research from disease-specific models to aging-focused approaches

   1. PAPeter Attia20:48

      that point, Matt, what is the collective wisdom of the group on, um, the funding appetite for that? Because I agree with you completely. Like, if we could channel this exuberance away from kind of the highly commercial, uh, speculative grifting towards the budget increasing legitimate investigative-

   2. MKMatt Kaeberlein21:12

      Yeah

   3. PAPeter Attia21:12

      ... that would be awesome. What is the appetite right now of NIA with respect to this?

   4. MKMatt Kaeberlein21:17

      [laughs] I think it's hard to say it, and I mean, NIA, NIH is a moving target, and as we all know that there's gonna be a lot of change coming in the near future. So, um, cautiously optimistic, I would say. If you look historically, it's been really pretty terrible, right? The, the percent of NIH budget that goes to biology of aging, I think is still probably around half of 1%, even though biology of aging is the greatest-

   5. PAPeter Attia21:41

      Sorry, just to put numbers in perspective, I don't-- Do you know these, uh, NIA gets how, what percent of NIH-

   6. MKMatt Kaeberlein21:46

      Not NIA.

   7. PAPeter Attia21:47

      No, no, I understand. Yeah.

   8. MKMatt Kaeberlein21:47

      So within NIA-

   9. PAPeter Attia21:48

      Yes, yes, yes

   10. MKMatt Kaeberlein21:48

       ... there's a subfraction that goes to biology of aging, right?

   11. PAPeter Attia21:51

       Yes, yes, yes.

   12. MKMatt Kaeberlein21:51

       So, yeah.

   13. PAPeter Attia21:51

       But I'm saying how, there are 17 groups of NIH-

   14. MKMatt Kaeberlein21:54

       Yeah

   15. PAPeter Attia21:54

       ... NIA being one of them, gets what fraction of NIH budget roughly?

   16. RMRichard Miller21:58

       I think it's roughly 3%.

   17. PAPeter Attia22:00

       3% of NIH budget is NIA.

   18. RMRichard Miller22:01

       I think so, yeah.

   19. PAPeter Attia22:02

       Within NIA, how much goes to this type of research?

   20. MKMatt Kaeberlein22:05

       It was about three hundred and fifty million a few years ago. It might be a little higher than that, but I don't think it's ticked up any more proportional to the increase in NIH budget since then. So that it, it reaches about half of 1%.

   21. PAPeter Attia22:17

       Wow. Um, what's your level of optimism, Rich? You're obviously very close to this.

   22. RMRichard Miller22:22

       That NIH will wake up and start to pay attention to aging research the way they should? It's near zero. Uh, it's been near zero for tw- 30 years now.

   23. PAPeter Attia22:31

       Even with this-

   24. RMRichard Miller22:32

       And the reason is-

   25. PAPeter Attia22:33

       I mean, as outside attention

   26. RMRichard Miller22:35

       Well, it's gone up. I mean, they funded the ITP, the Inventments Testing Program, 20 years ago, and they liked it, and they doubled our budget about, uh, 15 years ago. So that's something. Uh, uh, and I'm very, very grateful to them for that. But there, there's still an enormous, uh, untapped potential for making progress in the basic biology of aging. And the reason is, again, um, a matter of, of defending turf. If you are a cardiologist researcher or an oncologist researcher or an AIDS researcher or an Alzheimer's researcher, anytime somebody says, "You know, you, the smart play is to reduce your budget by 10% or your institute's budget by 10%. We're gonna go there faster if we spend money on aging and its relationship to the disease you care about," you, y-you get, uh, the porcupine defense. "You don't take any of my money because Alzheimer's is important. Little kids with leukemia are important. Breast cancer is important. You go away." And that is the predominant feeling. Most of the people making those decisions were not trained in aging research. They view it as, uh, s- something interesting. I read something about that in Time Magazine the other day. But they don't understand that to actually conquer or slow down or affect or protect against the disease they care about, the smart play is to do aging research. And so they view your suggestion, which I of course agree with 100%, as a, a, an imposition, an invasion to be repelled at any cost. No one in a position of power, um, has had whatever it takes to reverse that. And if he or she tried to do that, Congress would, even a good Congress, uh, would smack them down. They always-- The Alzheimer's A group has 100 lobbyists. The cancer group has 100 lobbyists. The AIDS group has 100 lobbyists. The aging group has two lobbyists, one who's a lawyer and one who takes the calls, and it's not enough to do it.

   27. MKMatt Kaeberlein24:36

       Can I just add something real quick to that too?

   28. RMRichard Miller24:37

       Hmm.

   29. MKMatt Kaeberlein24:37

       'Cause I, I agree completely, and I think as well the reputation of the field has hindered-

   30. RMRichard Miller24:44

       Yes
5. 30:19 – 35:36

   Proactive healthcare: rethinking health, disease, and the role of aging

   1. SASteven Austad30:19

      I, I think this is because we're, we think about health all wrong. We think, "Well, let's wait till you get cancer and see what we can do about it." That's what cancer biologists do. You have cancer, okay, how can we better treat that, or could we have diagnosed it earlier? What Rich is saying and what we can know how to do in lots of model organisms, it prevents you from getting cancer, delay it for a considerable amount of time. That's a little bit harder to study if you're a cancer biologist, um, 'cause you wanna see the cancer before you can study it. I think that's why we need aging biologists rather than people focused on certain disease to come and try to use what we do to prev- You know, if we prevented the cancers, uh, they wouldn't have-- they'd be out of a job.

   2. RMRichard Miller31:02

      I guarantee these people or mice will get cancer. They'll just have-

   3. SASteven Austad31:05

      [laughs]

   4. RMRichard Miller31:06

      ... 10 extra years of life if they're a person, or 10 extra months of life if they're-- They'll get cancer. They'll need specialists. It'll be all right.

   5. MKMatt Kaeberlein31:12

      Yeah. I think that's important. I mean, I think the reactive disease care component is still gonna be there, right? Even if we're insanely successful at slowing aging, people are still gonna get sick. But I think Steve's point is really important. Like Peter, you've been a, a leader, right, in helping people recognize the need to shift the medical approach from reactive to proactive. I think what a lot of people don't realize is that mentality goes all the way back to pharmaceutical research, biomedical research, basic science. It's, it, that is ingrained all the way through, and I think one of the challenges with getting funding for aging research is the, that mentality on the basic science world and how deeply ingrained it is.

   6. PAPeter Attia31:54

      It's very interesting because you don't know which is the tail and which is the dog. Like, I've always assumed that, that the one leading the charge is the clinical side of things, right? In other words, the engine, the machine of Medicine 2.0 is built around the delivery of care. The delivery of care, as you said, Steve, is built around, "I'm gonna wait. I'm gonna sit here and hang. We're gonna wait. When you get the disease, we're ready. You had the heart attack? Fantastic. You've got chest pain, ST elevations? We got a stent for you. Now you have cancer? We're all in." Um, and then the research flows from that mindset. Of course, I don't know, not that it really matters, but it might be that it's flipped, right? It might be that the clinical engine behaves in that way because that's how the, the, the base of the pyramid has been built. Again, not that it necessarily matters, but if you could be health czar and fix one of them, you might actually start with the research side of things.

   7. MKMatt Kaeberlein32:56

      I would. And I mean, the reality is the research flows from where the dollars are going. This has been seen over and over and over at NIH. You shift resource allocation to a certain area, and the scientists will follow, and they will submit grants to get grants in the place where the funding line is the highest. So if somebody came along and said, "We're gonna go from 0.5% to 50% of NIH budget is gonna go to biology of aging," you'd have no shortage of people. I mean, it'd be kinda messy at first. [laughs] But you'd have no shortage of people applying for grants and becoming experts in the biology of aging. It would work.

   8. PAPeter Attia33:25

      And the system would work.

   9. MKMatt Kaeberlein33:26

      It would work.

   10. PAPeter Attia33:26

       You'd get the best-

   11. MKMatt Kaeberlein33:27

       Yeah

   12. PAPeter Attia33:27

       ... and the brightest that would go into that and, and, and then do that. So, so this then begs another question that is a tired question, but, but I can't help but ask it at this point. Is aging a disease? Is that even a relevant question?

   13. RMRichard Miller33:42

       Call on me. Call on me. Call on me. Call on me.

   14. PAPeter Attia33:44

       Yes, Mr. Miller.

   15. RMRichard Miller33:44

       I have an answer to that. Call on me. It's, it's important to un- to use words optimally-

   16. PAPeter Attia33:50

       Hmm

   17. RMRichard Miller33:50

       ... and to distinguish causes from effects. One of the bad things about aging is it's a risk factor for many diseases. Some things, o- other risk factors for diseases. Aging is a risk factor for disease. And so saying that aging is a disease confuses that discussion.

   18. PAPeter Attia34:08

       Hmm.

   19. RMRichard Miller34:09

       It makes it impossible to see that relationship. So calling aging a disease is a fundamental error.

   20. PAPeter Attia34:16

       The question itself is incorrect.

   21. MKMatt Kaeberlein34:17

       Yeah. I agree completely. I think it's the wrong question.

   22. SASteven Austad34:19

       I, I, I agree, but I think we have that idea for marketing purposes, not for scientific purposes. And the idea is, well, the money goes to diseases, let's call aging a disease. Because I think what we're trying to do is we're trying to treat aging as if it were a disease, even though I, I would agree with both of you. I don't think it's a disease.

   23. MKMatt Kaeberlein34:42

       Yeah.

   24. SASteven Austad34:42

       I think that destroys the word disease if we include aging in it. Uh, but I think there was a reason that suddenly this came because you thought, "Oh, maybe this will get Congress to pay attention."

   25. RMRichard Miller34:52

       You're right. It's a c- it's a, it's a marketing ploy, and if you think you can convince people of the importance of aging research only by crossing your fingers and saying, "Oh, well, it's kind of a disease, isn't it?" Uh, and you can, you think you can fool them, yes, that's what marketing is, and it's probably good for that. I just don't like lying to people.

   26. MKMatt Kaeberlein35:12

       It also creates n- a negative feeling about the field in some people as well. So, so I think that should be considered. The other point that people often raise, though, is we have to call aging a disease in order for FDA to approve a drug for aging, which I think is a fundamental misunderstanding of how FDA operates. But that is the ar- other argument you, you will often hear among proponents of the idea that aging is a disease.

6. 35:36 – 51:42

   Biologic age versus chronologic age, and the limitations and potential of epigenetic clocks

   1. PAPeter Attia35:36

      Very interesting. I... Well, yeah. Well [laughs] okay, so now let's go one step deeper on that. How do you think about biologic versus chronologic age in concept and in practice?

   2. SASteven Austad35:53

      Yeah. So, so on the ride over here, Rich and I were talking about that. I don't believe there is such a thing as bio- one thing as biological age. I think there is potentially an age of your heart, an age of your liver, an age of your lungs, an age of your brain. But I don't see why we wouldn't simply call it health. In other words, you know, I, I got one of these a- epigenetic age clocks done on me a while ago, but I didn't know what to make out of it. You know? I thought, "Is this just flattery? Am I just-- I wanna do this, so it's..." Or did it really tell me something? It told me I was-

   3. MKMatt Kaeberlein36:31

      You must've got a good result if you thought it was flattery.

   4. SASteven Austad36:33

      Huh?

   5. MKMatt Kaeberlein36:34

      You must've got a good result if you thought it was flattery.

   6. SASteven Austad36:35

      I got a good result. But, but-

   7. RMRichard Miller36:36

      He's 13 [laughs]

   8. SASteven Austad36:36

      ... but, um-

   9. RMRichard Miller36:37

      Thirteen years old

   10. SASteven Austad36:37

       ... you know, that's, uh

   11. PAPeter Attia36:39

       That may be the point-

   12. MKMatt Kaeberlein36:41

       Yeah. [laughs]

   13. PAPeter Attia36:41

       ... of, of, of the whole thing, right? So I'm, I'm, I'm dubious about some number, uh, that is different than, "I know I'm in good health. You know, for my age, I'm in very good health." So I knew that already. Now I have a number for it. I don't put much credence in that number.

   14. RMRichard Miller36:56

       Le- let me agree with, with Steve, uh, but just put it in slightly different terminology. It's a matter of taking a very rich, complex, uh, data set and trying to collapse it to a number. So if someone wants to know how healthy I am, he or she would need information. How good is my eyesight? Uh, how good is my hearing? How good is various kinds of cognitive activities, my aerobic endurance, my ability to, my joints, all of that. All of that is pertinent to how my health is, and also about projected future health. Then there's no need, once you've got that information, which is very rich, to say, "Ah, there's a number, a single number, a real number on, a point on the number line that condenses that in any useful way." The notion 40, 50 years ago that biological age was not the same as chronological age poten- for a little while was useful. It emphasized that there might well be 60-year-old people who were unusually like youthful people, and 60-year-old people who were unusually like 70-year-old people. Would my drug or my genetic mutant or whatever help to discriminate those people or change them in some way? I can slow your biological aging process. That's a discussion that was maybe of interest 40 years ago and has-- It's now time to drop the notion, let alone the silly notion that you can count that biological age, that number which some people, too many people still think is of value. You can figure out what it is by measuring something, transcriptions or epigenetic markers or something. I can do it and give you personally your personal biological age. That's a waste of everyone's time, and it also distracts attention from things that actually are important and need to be thought about.

   15. MKMatt Kaeberlein38:47

       Hmm. I, I, I gotta talk 'cause [laughs] I think, I think I disagree fundamentally, and I'm surprised, but this'll be an interesting conversation. So I agree that the idea of a kit that you can buy to measure biological age, first of all, that's, the stuff that's out there doesn't work, and we should, can and should talk about that.

   16. RMRichard Miller39:05

       I wanna-- Yeah.

   17. MKMatt Kaeberlein39:05

       But also, I sort of agree with the idea that reducing it to one number, while conceptually I think it's possible, I think in reality is gonna be really, really difficult to do. But do I believe that there is a biological aging process that is different from chronological aging? Absolutely.

   18. RMRichard Miller39:21

       Oh, yes, absolutely. I didn't-

   19. MKMatt Kaeberlein39:22

       Okay. Well, it sounded like you guys were both saying no.

   20. RMRichard Miller39:24

       No, no, no, no, no.

   21. MKMatt Kaeberlein39:24

       You didn't think it was a real thing. [laughs]

   22. RMRichard Miller39:25

       I agree with that completely. I, that's, you can agree with that and not like the idea of a number that constitutes-

   23. MKMatt Kaeberlein39:31

       Sure. Sure

   24. RMRichard Miller39:31

       ... your biological age.

   25. MKMatt Kaeberlein39:32

       Okay.

   26. RMRichard Miller39:32

       Yeah. Okay.

   27. MKMatt Kaeberlein39:33

       So there's two things I would, that, that kind of make me feel pretty confident in this idea. One is, and this is the example I use a lot among the general public, is just look at dogs compared to people, right? Everybody's familiar with the idea that one human year is about seven dog years. What does that mean? It means that dogs age about seven times faster than people do. But of course, chronological time is the same between dogs and people. It's the biological aging process. And so you can look across the animal kingdom and see this, and dogs get almost all of the same diseases and functional declines that we do at the tissue and organ level, but also at the whole body level. Um, and y- we also know now there are single genes that significantly modulate what I would call the rate of aging. Now, maybe we have a different meaning to what we mean then.

   28. RMRichard Miller40:19

       No, I agree completely. No, I agree entirely. Yeah.

   29. MKMatt Kaeberlein40:21

       Okay. So the fact that that's possible.

   30. RMRichard Miller40:22

       Right.
7. 51:42 – 59:22

   The utility and drawbacks of the “hallmarks of aging” as a framework for research and funding

   1. PAPeter Attia51:42

      so much in what you just said, Matt, that I'm gonna, I'm gonna lay out a broad question, and then we can start attacking it in different ways. So one of the things I want to address is, do we believe that it's possible that of the hallmarks of aging, epigenetic change is the most important? Another topic I want to address, do we believe that the epigenetic changes that we observe over time, which are undeniable, are causal in the arrival of other states? Everything from the arrival of senescent cells, the increase in inflammation, the reduced function of the organs, which really is the hallmark of aging. And if so, does that mean that reversing the epigenetic phenotype will undo the phenotype of interest? And Rich, where I'm going that you and I left off was, what about the proteome? What about the metabolome?

   2. RMRichard Miller52:29

      So you made three statements there.

   3. PAPeter Attia52:31

      [laughs]

   4. RMRichard Miller52:32

      Broad general statements, and I think each of the three deserves careful amendment-

   5. PAPeter Attia52:39

      Let's do it

   6. RMRichard Miller52:39

      ... to, to be polite about it. Um, the first has to do with hallmarks of aging, which I think set the field back dramatically.

   7. PAPeter Attia52:47

      Mm.

   8. RMRichard Miller52:47

      Um, I, I think when you are officially branded a hallmark of aging by two people sitting alone at their computers and writing a review article, a hallmark of aging-

   9. PAPeter Attia52:58

      Wait, they weren't, I thought they were walking around a pond when they came up with this.

   10. RMRichard Miller53:01

       Walking around a pond.

   11. PAPeter Attia53:01

       All right. Okay, okay.

   12. RMRichard Miller53:02

       Um, means that somebody once said, "You know, I, I'm interested in aging. That's kind of important, isn't it? Let's put it on our list." You can't tell if someone is a hallmark, something is a hallmark of aging. Does that mean it goes up with age? It goes down with age? You can change it in a way that will extend lifespan. You can kill a mouse or a worm by removing it. Um, basically, it's something that somebody once thought might be of interest to aging. And the downside of that is once you're officially branded as a hallmark of aging, anyone who wants to write a, a, a grant on that doesn't have to prove that their fundamental cause and effect model has any merit. Because it's a hallmark of aging. I don't have to prove it anymore. Someone, I don't know who or on what grounds, has decided it's important. My reviewers know it's important 'cause they've read the hallmark of aging paper, so I don't have to think about whether it's important. The negative side of that coin is that there are lots of things that didn't make it into the hallmark list, and I really think it's premature to close thought off-

   13. PAPeter Attia54:07

       Mm

   14. RMRichard Miller54:07

       ... on some of those. It's easy to come up with a dozen things that ought to be investigated, but if you want to investigate it and it's not on the hallmarks list, what are you wasting? So deciding which of the hallmarks is the big daddy hallmark-

   15. PAPeter Attia54:21

       [laughs]

   16. RMRichard Miller54:21

       ... or whatever strikes me as not the correct thing to talk about in the hallmarks arena. The second question-

   17. MKMatt Kaeberlein54:29

       So maybe we should talk about that before we go through all the rest.

   18. PAPeter Attia54:31

       Yeah, yeah, yeah.

   19. MKMatt Kaeberlein54:32

       There's, there's a lot to unpack there.

   20. PAPeter Attia54:33

       You'll remember the other ones too, I bet.

   21. RMRichard Miller54:34

       If you guys could afford to give me a little piece of paper and a pen-

   22. MKMatt Kaeberlein54:37

       [laughs]

   23. RMRichard Miller54:38

       ... then I'd be able to write down my-

   24. SASteven Austad54:39

       I think the hallmarks as a list, a kind of arbitrary list, not completely arbitrary, 'cause they had some reasons for being there, and I don't think any of us would say that those 12 things are not involved in aging. But that's of very little interest of itself.

   25. PAPeter Attia54:53

       Do any of us want to rattle them off, being that I'm the only one that's got the list sitting in front of me?

   26. MKMatt Kaeberlein54:56

       We could, we could do a game where we each name one and see who, who, who can't-

   27. SASteven Austad55:00

       See, see if we get to all 12.

   28. MKMatt Kaeberlein55:01

       Yeah. [laughs]

   29. PAPeter Attia55:01

       Yeah.

   30. SASteven Austad55:03

       But certainly in that list, I, I would not, I would not consider epigenetics as the, the key hallmark. A-assuming there are such things, I consider it to be an interesting list. It became biblically sacrosanct almost immediately, and I've never understood why, but for some reason it did. So I'd agree with Rich that-
8. 59:22 – 1:07:08

   The role of epigenetic changes in aging and the challenges of proving causality

   1. PAPeter Attia59:22

      Hmm. So what's your sec-

   2. RMRichard Miller59:25

      So I can, I wrote them down.

   3. PAPeter Attia59:26

      Yes. I want you-

   4. RMRichard Miller59:26

      I cheated.

   5. PAPeter Attia59:26

      Let's go back. [laughs]

   6. RMRichard Miller59:27

      I wrote them down. So the second of your, of your, uh, multipartite question was does epigenetic change, what, what are the r- results of-

   7. PAPeter Attia59:36

      Is it causal?

   8. RMRichard Miller59:36

      C-causal effect.

   9. PAPeter Attia59:37

      Yeah.

   10. RMRichard Miller59:37

       And the third, which we may get to, is can you reverse it, and would that be a good thing? So let's talk about the second element here. Is it causal? And the, here the definite, the problem is what it means. There are some changes that occur in this particular set of 40 cells in the pineal, and there are other changes that occur in these cells in the bone marrow, and there are other cells that change in the gut and villus lining cells and the crypt cells. So they are all epigenetic in some. They are caused by some things, and we don't really know which, if any of these, count for aging. If someone says, "I'm gonna prove that an epigenetic change is responsible for aging," they haven't begun to come to grips with the nitty-gritty. Uh, people always ask, just as you hinted, "Does your drug change epigenetic things?" And unfortunately, that's where they stop thinking. If-- We're always willing to give people tissues from our drug-treated mice if they are keen on epigenetic changes that affect neuron regeneration. Excellent. Their experts will send them the brains, and they can do that stuff. It's important. I'm not making fun of it. But the general notion that it's aging vaguely thought of is due to epigenetic change more vaguely thought of doesn't really get you anywhere. That's my sort of skeptical view.

   11. PAPeter Attia1:01:04

       Is, is part of the issue that you're saying, "Well, what's causing the cause?"

   12. RMRichard Miller1:01:07

       No, it's just that the, the concept of epigenetic change encompasses thousands of changes in hundreds of cell types under hundreds of influences. Of course, some of that causes other stuff. Agreeing to that, assenting to that notion that epigenetic change is causal for all sorts of age-related pathologies, everyone can agree to that, but it does- it's meaningless because what counts is to say this specific change is really important in this disease and-

   13. PAPeter Attia1:01:37

       But let's go back to the example I used

   14. RMRichard Miller1:01:39

       ... here's an epigenetic alteration, or this specific broad spectrum change in multiple tissues causes something good or bad. You have to define what it is before you can test it.

   15. PAPeter Attia1:01:50

       But, but let, so let's use a specific example. When you look at a patient with Type 1 diabetes-

   16. RMRichard Miller1:01:55

       Mm-hmm

   17. PAPeter Attia1:01:56

       ... and you look at their beta cells in their pancreas-

   18. RMRichard Miller1:01:59

       Yeah

   19. PAPeter Attia1:01:59

       ... they look different-

   20. RMRichard Miller1:02:01

       Yeah

   21. PAPeter Attia1:02:01

       ... epigenetically than the beta cells of an age-matched person without Type 1 diabetes.

   22. RMRichard Miller1:02:06

       Okay.

   23. PAPeter Attia1:02:07

       And we also know that their beta cells don't function, so they're, they-

   24. RMRichard Miller1:02:09

       Yeah

   25. PAPeter Attia1:02:09

       ... so they've, they've lost function.

   26. RMRichard Miller1:02:11

       Yeah.

   27. PAPeter Attia1:02:11

       So the, so let's ask that question as a specific example. What do you believe or what confidence would, would you assign to the notion that the epigenetic change on the beta cells of the Type 1 diabetic are indeed causal to the loss of function of the beta cell?

   28. RMRichard Miller1:02:26

       Right. So my, my last, uh, exposure to the causes of Type 1 diabetes was when I was in medical school, which is more than five years ago. Uh, but if I-

   29. PAPeter Attia1:02:35

       [laughs]

   30. RMRichard Miller1:02:35

       I vaguely remember it was an autoimmune disease.
9. 1:07:08 – 1:22:23

   The translational challenges of moving aging research from preclinical studies to human applications

   1. MKMatt Kaeberlein1:07:08

      And one way I think about this, and again, this, this may be completely wrong, but it, but it's a useful way for me to think about it, is I think about age-related disease as the sort of downstream effect of biological aging. And then y- in for most diseases, there becomes a point where the pathology of that disease mechanistically is no longer the same as biological aging, in which case-

   2. SASteven Austad1:07:31

      He, he's very good. You should listen to him

   3. MKMatt Kaeberlein1:07:32

      [laughs] In which- and one of the implications of that is the interventions that slow biological aging may not work once you get past that point, but things that do work for that disease may have nothing to do with biological aging. Does that make sense?

   4. PAPeter Attia1:07:44

      Yeah, go, go deeper on that idea, though. Let's use, let's use the example.

   5. MKMatt Kaeberlein1:07:48

      Yeah, well, I think, um, so let's just, I mean, what's your favorite disease?

   6. PAPeter Attia1:07:53

      My favorite disease.

   7. MKMatt Kaeberlein1:07:54

      [laughs]

   8. PAPeter Attia1:07:54

      Let's talk about cancer.

   9. MKMatt Kaeberlein1:07:55

      Cancer, cancer's an easy one, right?

   10. PAPeter Attia1:07:56

       Yeah. Let's talk about cancer.

   11. MKMatt Kaeberlein1:07:57

       We know with cancer, in many cancers, the process is you have one or more mutations, which then often lead to additional mutations. You get genome instability. Eventually, you get an oncogene that gets activated, and that leads to uncontrolled cell division. There are multiple steps that have to happen.

   12. PAPeter Attia1:08:13

       Or a tumor suppressor gene that gets deactivated.

   13. MKMatt Kaeberlein1:08:15

       Right. Yeah, right. So at, and if we accept that immune surveillance is one important anti-cancer mechanism, we know that immune surveillance declines with age. So early on, we're clearing a lot of our cancers. As our immune system declines, these cancers are gonna escape immune surveillance. They're gonna accumulate all these mutations. They're eventually going to go into uncontrolled cell division. That uncontrolled cell division, at that point, you can treat the cancer, right? But uncontrolled cell division is not biological aging, right? It's not a normal part, it's not a part of the normative aging process.

   14. PAPeter Attia1:08:51

       That's right. Yep.

   15. MKMatt Kaeberlein1:08:51

       Right? So the treatment there, so the mechanism now is fundamentally different from normative aging.

   16. PAPeter Attia1:08:57

       Yep.

   17. MKMatt Kaeberlein1:08:57

       And the treatment, let's just say the treatment in this case is chemotherapy, might benefit the cancer.

   18. PAPeter Attia1:09:04

       Has nothing to do with normal aging.

   19. MKMatt Kaeberlein1:09:04

       It's not gonna slow target aging, right?

   20. PAPeter Attia1:09:05

       Yeah, yeah, yeah.

   21. MKMatt Kaeberlein1:09:05

       And I think rapamycin's a good example here where we, I think we all believe that rapamycin and inhibiting mTOR slows biological aging, at least in up to mice. Hopefully in dogs.

   22. PAPeter Attia1:09:16

       Hopefully dogs.

   23. MKMatt Kaeberlein1:09:16

       Hopefully in people.

   24. PAPeter Attia1:09:17

       Yeah.

   25. MKMatt Kaeberlein1:09:18

       Yeah. So it's a fundamental node in the network. That's the way I think about the hallmarks of aging. It's a node in the network that underlies the hallmarks of aging. So we can manipulate mTOR with rapamycin, slow aging. Rapamycin's a pretty good anti-cancer drug until the cancers have evolved to ignore the mTOR break, and then rapamycin doesn't work anymore. And we know rapamycin doesn't work for most cancers. That's an example-

   26. PAPeter Attia1:09:41

       That's been tested. We know that.

   27. MKMatt Kaeberlein1:09:42

       Yeah, absolutely.

   28. PAPeter Attia1:09:43

       Yep, yep.

   29. MKMatt Kaeberlein1:09:43

       Um, and it's because the cancers evolve to bypass the mTOR break or to bypass the ability of rapamycin to inhibit mTOR. So that's a case where the intervention-

   30. PAPeter Attia1:09:51

       Right. Important, that's a, that's a, that's a really good point that we all take for granted that I think is worth noting. Rapamycin can be unsuccessful as a chemotherapeutic agent and can yet be very successful as a cancer preventive agent.
10. 1:22:23 – 1:26:32

    Distinguishing between a biomarker of aging and aging rate indicators

    1. PAPeter Attia1:22:23

       I wanted to go next, and I'm gonna let Rich decide 'cause he's gonna have the strongest point of view. Can we talk about senescence, or can we talk about what biomarkers would be necessary to help us study aging in humans as we translate from your work and Matt's work?

    2. RMRichard Miller1:22:42

       I know what I wanna talk about, and it's the second of those two.

    3. PAPeter Attia1:22:45

       Okay.

    4. RMRichard Miller1:22:45

       Um, I don't wanna spend the next three or four hours explaining why s- senescence is silly and anti-senolytics are untested at best. So let's talk con-

    5. PAPeter Attia1:22:53

       There's no way we're not talking about that

    6. RMRichard Miller1:22:55

       ... concerning about any of that.

    7. PAPeter Attia1:22:55

       Let's go on to item number two.

    8. RMRichard Miller1:22:57

       Um, and I think the clear, the, the most important thing is to make a clear distinction between biomarkers and aging rate indicators. So a bio-

    9. PAPeter Attia1:23:06

       Please explain the difference to people, please.

    10. RMRichard Miller1:23:08

        Okay. I, I'll do my best. So a biomarker allegedly and in real life, uh, is something that changes with age. So if you have some drug that slows aging, the biomarkers, many of them in the different cell types and in the blood will change more slowly. They are a good way of looking at whether you're slowing, it'll work in the dogs. Long, long-lived dogs and short-lived dogs will have differences in the rate of change of biomarkers. Very established part of the literature and valuable. But you have to wait till somebody's old, whether it's a dog or a mouse or a person, because only when they're old has the biomarker of aging, the surrogate marker for biological aging changed very much. So in a clinical trial, certainly in a, a human situation, no one wants to wait 20 years to see whether the biomarkers have changed. And, uh, one year is such a tiny fraction of a human lifespan that you don't really anticipate detectable change with a appropriately powered study. Age, it's like aging rate indicators, which are much less well-studied and much less well-established in principle, are things you can measure that tell you whether you're in a slow aging state or a normal state.

    11. PAPeter Attia1:24:20

        Can I just make some, make a point for the listeners so they understand kind of the challenge of what we're talking about?

    12. RMRichard Miller1:24:25

        Yeah.

    13. PAPeter Attia1:24:25

        When we study blood pressure drugs or cholesterol drugs, the biomarkers change so rapidly, and we know the relationship between the biomarker and the disease state.

    14. RMRichard Miller1:24:38

        Mm-hmm.

    15. PAPeter Attia1:24:38

        So if your blood pressure is 145 over 90 on average before I give you this ACE inhibitor, and three months later, six months later, nine months later, a year later, your blood pressure is averaging 119 over 74, I know I've done something well. Now, I will still probably in the phase three, in fact, I will in the phase three have to make sure that I also reduce some event in you.

    16. RMRichard Miller1:25:02

        Yeah.

    17. PAPeter Attia1:25:03

        But generally by the phase two, I know that this drug is not toxic and that it's predictably lowering your blood pressure. That's, that's really, really valuable.

    18. RMRichard Miller1:25:10

        A biomarker generically is something that's easy to measure that you, i- is informative about something that's hard to measure. A, a classical example, famous example is you wanna know how many cigarettes somebody smokes a day. They'll lie to you. But if you measure cotinine in their blood, that's a, a byproduct of nicotine. You don't have to ask them. You can find out how many cigarettes they had in the last couple of days by measuring blood co- That's a biomarker of, of cigarette consumption.

    19. PAPeter Attia1:25:36

        Is it a marker of nicotine or carbon monoxide?

    20. RMRichard Miller1:25:37

        I don't know the answer to that.

    21. PAPeter Attia1:25:38

        Okay, okay. I just, yeah, I wasn't sure.

    22. RMRichard Miller1:25:41

        So in principle, a biomarker of aging is measuring, there are many of them, and they are measuring biological aging processes, and they're useful in that regard. But they don't tell you how fast you're aging. And, and the analogy I love to use is an odometer is like a biomarker of aging of your car. It tells you how many miles your car has gone, but it doesn't tell you how fast the car is going. The speedometer tells you how fast your car is going. And so what we need and what I think we're just beginning now to, to document is things like the speedometer, aging rate indicators that reliably discriminate slow aging mice or people from regular old mice or people. We have now a, a dozen or so things that change in the fat, in the blood, in the liver, in the brain, and in the muscle that are always changed in any slow aging mouse, whether it's drug A, drug B, drug

11. 1:26:32 – 1:42:45

    The difficulties of translating longevity research in mice to humans, and the difficulties of testing interventions in humans

    1. RMRichard Miller1:26:32

       C, calorie restriction diet, or single gene mutations. We've looked now at five different single gene mutations, and this whole set of 12, or roughly 12 aging rate indicators always changes in every slow aging mouse. And it does so in youth, which is the key point. So if it does so quickly after an anti-aging drug is administered, that's the transition, that's the bridge you need for clinical studies in people. If you want to know whether metformin or canagliflozin or something slows aging in people and you don't want to wait 20 years, but you've got things that tell you whether they're in a slow aging state, how fast they are aging versus normal, and that's a big if. We don't yet have evidence we can do that. We just have hope we can do that. Then that allows you quickly to, with, quickly being within six months to a year, to know whether your anti-aging manipulat- alleged anti-aging manipulation has moved them to a physiological status which is associated with slower aging. That allows, that can be done, a lot of that can be done in mice with drugs, with mutants.

    2. PAPeter Attia1:27:39

       And are these all proteins, Rich?

    3. RMRichard Miller1:27:41

       No. No, some of them are changes in the, the fat of different classes of macrophages. The pro-inflammatory macrophages, the bad ones go away. The anti-inflammatory macrophages, the good ones go up. Uh, I'm not-

    4. PAPeter Attia1:27:55

       UCP1, I recall from our discussion.

    5. RMRichard Miller1:27:57

       UCP1, uh, goes up in every one of our 10 different kinds, 11 now, of slow aging mice.

    6. PAPeter Attia1:28:02

       Does it go up in any of the mice that did not receive a successful drug?

    7. RMRichard Miller1:28:08

       Well, we compare them to controls.

    8. PAPeter Attia1:28:10

       Oh.

    9. RMRichard Miller1:28:10

       And the question you're asking is really important. That's what we're doing in the next five years.

    10. PAPeter Attia1:28:15

        Okay.

    11. RMRichard Miller1:28:15

        We just got a grant to do that. We're going to take mice and give them either a good drug or a different drug that doesn't work.

    12. PAPeter Attia1:28:21

        Yep.

    13. RMRichard Miller1:28:22

        And then make those comparisons.

    14. PAPeter Attia1:28:23

        Okay.

    15. RMRichard Miller1:28:23

        A really important thing to prove. So far, our only control has been untreated mice.

    16. SASteven Austad1:28:29

        At s- at some point in this, I have, I had to bring this up, but let's imagine that Rich is incredibly successful at finding these things. That is a very, very long way from assuming that it's gonna be the same in people. Most things that clinically work in mice do not work in people. It might be, and that would be wonderful, but I think ultimately we're gonna have to find this for people. And my thought is the kind of a, the kind of evaluation that you do routinely of your patients, if we took a group of 65-year-olds and we gave them a drug that we thought was an anti-aging drug and followed them the next five or six years doing these evaluations, I think you could probably safely say this is slowing aging or slowing not, or, or not slowing aging. So I don't think that it's gonna be that easy to jump from mice to people in this.

    17. PAPeter Attia1:29:29

        I've always wondered if in people the, the easiest way to do it would be to take the most obvious thing that we know is gonna reduce the rate of aging. So it'd be an interesting experiment, but you find someone who is overweight, diabetic, and smokes, and has hypertension. You get hundreds of these folks. You put half of them on a sort of, to be ethical, a, a plan where you try to get them to stop, and presumably many don't, right? But on the o- in the other group, you pull out all the stops. And you don't care because you're interested not in testing the hypothesis, does this thing help you? You're interested in getting them to lose weight, not have diabetes, stop smoking, exercise like crazy. So y- you with the greatest division between two groups of individuals where we would, I think, be able to agree that this group is now aging slower, the group that we've reconciled their diabetes, quit the smoking, et cetera, et cetera. And then I'd love to see Rich's 12 line up in that, in that population.

    18. SASteven Austad1:30:33

        That would be great. Uh, uh, let me just say that I think that people that study animals, myself included, always underestimate how well we can evaluate health in people with a very, very thorough evaluation, 'cause we don't do that in our experimental animal.

    19. PAPeter Attia1:30:50

        Why do you think that is, Steve? Why is it that... 'Cause I was gonna ask about parabiosis later on in the discussion. We might as well talk about it now, right? Parabiosis seems to actually kind of work in certain mouse models. Do we have any reason to believe it's gonna work in humans? And if not, why not? Why are mice so different from people?

    20. MKMatt Kaeberlein1:31:09

        Well, wait a minute. I wouldn't say that just because we don't have evidence that it works in humans means mice are different from people, first of all, when it comes to parabiosis, right?

    21. PAPeter Attia1:31:16

        Yeah, yeah.

    22. MKMatt Kaeberlein1:31:16

        I mean, that's a different-

    23. PAPeter Attia1:31:17

        Okay

    24. MKMatt Kaeberlein1:31:17

        ... discussion. But I, I actually have a little bit, I agree that most, if you look at the attempts to cure cancer or other diseases in mice and translation to people, most have failed. I actually think that's because those are artificial mouse models where they tried to give young mice an age-related disease. I'm more optimistic-

    25. PAPeter Attia1:31:36

        But Rich's are not

    26. MKMatt Kaeberlein1:31:37

        ... and I don't, I don't know this. Hmm? No, I know that.

    27. PAPeter Attia1:31:38

        Rich doesn't have those mice. Yeah.

    28. MKMatt Kaeberlein1:31:39

        I know. I'm, I'm more optimistic that biological aging or normative aging is gonna be much more likely to translate to people both interventions and biomarkers than the specific disease interventions. I might be wrong. I don't know the answer. I'm just more opt- I-

    29. SASteven Austad1:31:55

        We would hope that's the case.

    30. MKMatt Kaeberlein1:31:56

        Yeah. So I, I don't, I don't-
12. 1:42:45 – 1:48:26

    Exercise, aging, and healthspan: does exercise slow aging?

    1. PAPeter Attia1:42:45

       point.

    2. RMRichard Miller1:42:45

       I agree.

    3. MKMatt Kaeberlein1:42:45

       It's not clear, but I, it's an interesting question. Like, do you believe exercise slows aging? Exercise, healthy diet, sleep?

    4. PAPeter Attia1:42:51

       I, I have no idea. I think so. That would be my, my intuition is I think so.

    5. MKMatt Kaeberlein1:42:54

       Yeah.

    6. PAPeter Attia1:42:55

       But I can't point to the evidence that tells me so.

    7. MKMatt Kaeberlein1:42:58

       Well, there's evidence to support it, but it's not, the question is does it rise to the level of evidence that would convince Rich? I don't know. I, like, I, I believe it probably does too, but I'm not gonna, you know, say it with 100% certainty.

    8. SASteven Austad1:43:07

       I, so I think here's where we get back into healthspan versus lifespan. The effect of exercise on longevity is pretty small. Its effect on quality of life is enormous. You know?

    9. MKMatt Kaeberlein1:43:20

       Somewhat depends on where you start.

    10. PAPeter Attia1:43:21

        And it also depends on the-

    11. MKMatt Kaeberlein1:43:22

        Sure

    12. PAPeter Attia1:43:22

        ... I, I've always found these to be a little bit problematic because I don't think that defining it by the input is as valuable as defining it by the output. In other words, to say you exercise this many minutes a week versus that many minutes a week is a little dirty-

    13. MKMatt Kaeberlein1:43:38

        Mm-hmm

    14. PAPeter Attia1:43:38

        ... because intensity matters. What you do matters. Sometimes the output is what matters more. How strong you are, how high your VO2 max is, those tend to be more predictive, uh, because that's the integral of the work that's been done. But, but your point is I, uh, it, it's well taken. Like, the impact on healthspan is what I tell my patients. If this, if this amount of exercise didn't make you live one day longer, the quality in which your life would improve would justify it

    15. RMRichard Miller1:44:04

        Now fortunately, we can move past this sort of semantic, uh, discussions, uh, because there's now molecular ways of checking this. Exercise, as I'll bet all of you know, increases an enzyme called GPLD1 in the blood of exercised people and in mice. And Saul Villeda's lab has shown that if you elevate GPLD1, it does great things to your brain, more neurogenesis and more brain-derived protective factors, brain-derived neurotropic factors. Irisin also goes up-

    16. PAPeter Attia1:44:33

        Yep

    17. RMRichard Miller1:44:33

        ... in humans and in mice after exercise. It does great things for your fat. At least-

    18. PAPeter Attia1:44:37

        As does clotho?

    19. RMRichard Miller1:44:39

        Uh, let's leave that out for a moment.

    20. PAPeter Attia1:44:40

        Oh, boy.

    21. RMRichard Miller1:44:41

        So-

    22. PAPeter Attia1:44:41

        Oh, boy. I'm striking all the nerves here today.

    23. RMRichard Miller1:44:43

        Well-

    24. PAPeter Attia1:44:43

        All right

    25. RMRichard Miller1:44:44

        ... you may be quite right. I just don't... I wanted to stick with the GPLD1 and irisin-

    26. PAPeter Attia1:44:49

        Okay. All right

    27. RMRichard Miller1:44:49

        ... to make the point that they also go up in all of the slow-aging mice.

    28. PAPeter Attia1:44:55

        I see. Okay.

    29. RMRichard Miller1:44:55

        That is all the anti-aging drugs, the calorie-restricted diet, the isoleucine-restricted diet, and five different single gene mutants that extend lifespan in mice, they all elevate GPLD1. And they-

    30. PAPeter Attia1:45:07

        17 alpha estradiol?
13. 1:48:26 – 1:54:15

    Are GLP-1 receptor agonists geroprotective beyond caloric restriction effects?

    1. PAPeter Attia1:48:26

       Do any of you believe that GLP-1 agonists are geroprotective?

    2. MKMatt Kaeberlein1:48:30

       Oh, it's, I'm super interested in that question.

    3. RMRichard Miller1:48:32

       Yeah.

    4. MKMatt Kaeberlein1:48:32

       I don't know.

    5. RMRichard Miller1:48:33

       I think it's, we need to find that out. It's, it's, they look good from-

    6. MKMatt Kaeberlein1:48:36

       I think there's two parts, though.

    7. RMRichard Miller1:48:38

       Yeah.

    8. MKMatt Kaeberlein1:48:38

       Are they geroprotective from a caloric restriction effect?

    9. RMRichard Miller1:48:43

       Hmm.

    10. MKMatt Kaeberlein1:48:43

        Or are there caloric independent effects that could potentially be geroprotective?

    11. PAPeter Attia1:48:46

        I'm actually asking the second question.

    12. MKMatt Kaeberlein1:48:48

        Okay.

    13. PAPeter Attia1:48:48

        I'm taking the first as a given.

    14. MKMatt Kaeberlein1:48:49

        Okay. Well, I... Yeah. That's a different question is, is chronic caloric restriction beneficial in normal weight people? But most people taking GLP-1 agonists aren't normal weight to begin with.

    15. PAPeter Attia1:48:59

        Yes, yes, yes.

    16. MKMatt Kaeberlein1:49:00

        Yeah.

    17. PAPeter Attia1:49:00

        And, and I think it's impossible at this point because the studies are all done in obese and type, and patients with type 2 diabetes-

    18. MKMatt Kaeberlein1:49:06

        Right

    19. PAPeter Attia1:49:06

        ... that we can't disentangle them. So we will just say that for that patient population, the caloric restriction appears to be geroprotective. But yes, you're right. I'm technically asking the second question, which is in an individual who is metabolically healthy but overweight, where there's actually no evidence that weight loss per se is necessary-

    20. MKMatt Kaeberlein1:49:26

        Yeah

    21. PAPeter Attia1:49:26

        ... outside of maybe some edge cases in orthopedic stuff, um, is there, is there a geroprotective nature to this? And where it's most talked about is in dementia prevention right now.

    22. MKMatt Kaeberlein1:49:36

        Hmm.

    23. RMRichard Miller1:49:36

        Mm-hmm.

    24. PAPeter Attia1:49:37

        That's where it's at least most complicated to tease that out. So what do you guys think?

    25. MKMatt Kaeberlein1:49:40

        And it clearly has neurological effects. There's effects on addiction, right? So the-

    26. PAPeter Attia1:49:44

        Yes

    27. MKMatt Kaeberlein1:49:44

        ... dementia connection is not-

    28. PAPeter Attia1:49:46

        It's crossing the blood-brain barrier

    29. MKMatt Kaeberlein1:49:48

        ... inconceivable. Right. That's right.

    30. PAPeter Attia1:49:50

        Yeah. I mean, Rich, this is one for you to tackle.
14. 1:54:15 – 2:09:46

    The role of senescent cells in aging, challenges with reproducibility in studies, and differing views on the value of current research approaches

    1. PAPeter Attia1:54:15

       Um, can we just, 'cause I'm in the mood to see you get spicy, can we just talk about senescence for a minute?

    2. MKMatt Kaeberlein1:54:21

       [laughs] Senescent cells, he means, Rich. You know, the things that drive aging.

    3. RMRichard Miller1:54:27

       Oh, tell me more. What do you mean? [laughs] You want, you want me to, to talk about senescent cells? Okay, yes, I'll be glad to do that. It's a, it's a terrible historical accident. Um, Leonard Hayflick way back found that human cells would only divide fifty times, then stop. One of his colleagues, a, a guy named Vittorio Defendi, made a joke at lunch and said to him, "Hey, Len, maybe they're getting old. Ha ha ha ha ha." And Len did not understand it was a joke. Uh, he thought it was a serious scientific hypothesis. It's clearly nuts because we don't, uh, get old in a way that it is modeled by having lung, embryonic lung fibroblasts stop growing. But at, at the time, the hottest technique in modern medicine was you could grow cells in culture. That was really so cool. You could do stuff with them. So all the cell biologists who really wanted to use the coolest new toys wanted to have a way of studying aging without all these messy mice and rats and having to wait and stuff. They could do it in vitro because this was in vitro aging. This is in vitro senescence. And the field, to skip thirty or forty years, the field, um, went ahead with this metaphor without ever questioning it. It's now such an industry that the people who review these grants and papers, uh, and advise billionaires, um, and advise startup companies, they all were trained in labs that just do senescence for a living, so they never stop to question. One of the most famous and best scientists in this area is a woman named Judy Campisi, who just-

    4. PAPeter Attia1:56:00

       Who recently passed away. Mm-hmm

    5. RMRichard Miller1:56:01

       ... who just died last year. She and I were assistant professors together at Boston University, and I-- she and I were gonna send in a program project with a third person, Barbara Gilchrist. Uh, I was gonna study immu-immunity and aging. Barbara was gonna study skin cells. We talked, "Judy, you wanna study cell senescence?" So she read the literature. She sing- came back to us and she said, "It has nothing to do with aging. [chuckles] I mean, it's good cell biology, it's good about cancer biology, but of course it's nothing to do with aging." And we told Judy, "Of course it has nothing to do with aging. We understand that. But the reviewers think it is aging. So if you can just keep a straight face for, uh, the three hours of the site visit, pretend you think it has to do with aging, you'll get a great score." And that's what happened. She got a great score. We got the program project. When she moved to Berkeley, she took her grant with her, and after a year or two, she had apparently convinced herself that it was aging. It was close enough to aging. So the notion that aging is due to senescent cell accumulation is bad for two reasons. It's, it's a grotesque oversimplification. The evidence for this is awful. But even worse, it again cuts off productive thinking. There almost certainly are changes that occur in some glial cells in the brain, so that as you get older they start making bad cytokines. It's bad for your brain. There probably are changes in some bone marrow cells or some cells in the lineage that leads to the beta cells in the pancreas that lose the ability to divide, and f- that's bad for you, and finding out how it happens is really important. But once you've convinced yourself that's all the same thing, this cytokine, this source of proliferation, this change in, uh, ability to make specific fibrous connective tissue, let's call that senescence. It's the same thing. You've lost what you need to think of good, careful, well-defined experiments with well-defined endpoints. If you say that senescence s- there is a thing called a senescent cell, the thing that's happening in this glia and in this marrow cell and in this pancreas, it's due to the senescent cell accumulating. You've blocked off productive generation of research hypotheses. The, the last point I'll mention in this rant has to do with, um, senolytic drugs. So the ITP was asked to test an allegedly senolytic drug called fisetin. It was given to us by someone who is using this now for clinical trials and who has a company that's interested in senolytic drugs. So we gave it to mice. It had no beneficial effect whatsoever. At the dose-

    6. PAPeter Attia1:58:46

       What's the mechanism of this drug's action?

    7. RMRichard Miller1:58:48

       Oh, it has no action. Okay, I mean-

    8. PAPeter Attia1:58:52

       It has no action or it had no effect?

    9. RMRichard Miller1:58:54

       Well, it didn't have any effect. It had no effect.

    10. PAPeter Attia1:58:56

        Okay, okay.

    11. RMRichard Miller1:58:56

        I mean, I-- what is it supposed to do? It's supposed to kill senoles- senescent cells or something.

    12. PAPeter Attia1:58:59

        Okay.

    13. RMRichard Miller1:59:00

        Um, so we told this guy, "Sorry, it had no effect." He said, "Well, let's prove that whether it had any change in senescent cells." So we gave him blind tissues from each of the treated and untreated mice, and he tried a test, and there were no changes in senescent cells by his marker. He tried six different markers. There were no changes in senescent cells. So then he said, "Well, send the brain and the liver and the muscle. Maybe the senescent cells have been changed in the brain." So we blind, sent blind samples to a colleague of his. There were no changes in senescent cells by any of the markers that these folks looked at. So this drug, which is now being marketed in clinical trials, and you can buy it, I'm sure, as an anti-

    14. PAPeter Attia1:59:45

        It's a natural product, yeah.

    15. RMRichard Miller1:59:46

        It's a natural product.

    16. SASteven Austad1:59:47

        Yeah, it's a supplement. Yeah.

    17. RMRichard Miller1:59:48

        Um, yeah, there's no evidence as far as I know that it either has an anti-aging effect or removes senescent cells. But once you've got a commercial company pushing this stuff and your whole brand, your whole lab, your whole program project, and all the people who are reviewing you are convinced senescent cells exist, there's, they're bad, and drugs can kill them, it's, it's a snowball rolling downhill, and, uh, a rant of the sort I've just delivered has no impact on the field.

    18. SASteven Austad2:00:18

        So can I give a-

    19. PAPeter Attia2:00:19

        Yeah, I wanna hear your take

    20. SASteven Austad2:00:20

        ... counter example? 'Cause there's good experimental data that there, that these things can be at least partially eliminated, and when you do that, there's an improvement in health. And this has been done both in a genetic treatment, which genetically, uh, which they prime these cells to be genetically killed, and it's also been done with, uh, you know, with, with drugs. Not with fisetin, I hasten to say. So I think there's strong evidence that getting rid of these p16-positive cells, which is really what it's all based on, can have an improvement in health and in longevity and life.

    21. RMRichard Miller2:01:00

        Is the Van Deursen paper you're talking about in which they were allegedly depleted?

    22. SASteven Austad2:01:04

        Yeah. Yeah, yeah, yeah.

    23. RMRichard Miller2:01:05

        Let me tell you about that, 'cause I was on the program project. My job in that program-

    24. SASteven Austad2:01:09

        There are two papers, okay? One was with, with, was with the short-lived mice-

    25. RMRichard Miller2:01:13

        Yes

    26. SASteven Austad2:01:13

        ... and one was-- Okay, so tell me.

    27. RMRichard Miller2:01:14

        I'm gonna talk about the one-

    28. SASteven Austad2:01:15

        Yeah

    29. RMRichard Miller2:01:16

        ... that, that is not the short-lived mice.

    30. SASteven Austad2:01:18

        Yeah.
15. 2:09:46 – 2:12:11

    How funding challenges and leadership in NIH and other institutes impact the advancement of aging-related research

    1. MKMatt Kaeberlein2:09:46

       Maybe inefficient, but the field is making, I would say, quite a bit of progress. And, and, and I think the way you learn about the complexity is you start with a simple model, you study it, and then your model get, gets more complicated. So I totally get the frustration, Rich, 'cause I get as frustrated as you are about senescent cells, about other things. But I think this is also part of the natural process here. And I think what Steve said is really important. Um, yeah, the, the, the, the fraction of the NIH budget that goes to study the biology of aging through NIA has remained tiny. But senescent cells are actually a really good example of how a bunch of people in other institutes are studying aging, and they don't even know it. They're studying, they, you know, they're studying senescence in cancer or senescence in Alzheimer's or senescence in kidney disease. Um, so it actually has had an impact in kind of broadening the appeal and scope of the field outside of NIA in ways that I don't, I certainly didn't an-anticipate.

    2. PAPeter Attia2:10:39

       Do you think that going back to the meta problem at the beginning of our discussion, do you think that's, um, a, maybe a better way to think about allocating funds? So for example, the NCI obviously receives the most funding within NIH. Maybe some of the NCI funding goes to the NCI to study cancer prevention through geroprotection, right? If, if the turf war-

    3. RMRichard Miller2:11:03

       Sure

    4. PAPeter Attia2:11:03

       ... is what matters-

    5. RMRichard Miller2:11:04

       That's a good idea

    6. PAPeter Attia2:11:04

       ... right?

    7. MKMatt Kaeberlein2:11:04

       I'm all for it.

    8. SASteven Austad2:11:05

       No, no, no. We've actually-

    9. RMRichard Miller2:11:06

       Why not?

    10. SASteven Austad2:11:06

        So a, a, a group of us who are lobbying the, the Congress have actually asked the NIH to tell us exactly this. How much work in geroscience is going on in all these other institutes?

    11. MKMatt Kaeberlein2:11:22

        Yeah.

    12. SASteven Austad2:11:22

        Of course, they're gonna have some motivation to minimize that or maximize that or something, but at least it will give us an idea. Right now, we have no idea how much of the NCI budget is g-going to this or, or NIDDK or anything else. So they already have produced a report that told us how much they were spending in the NIA, but we already knew that. We wanted to know how much they're spending in the other institutes.

    13. MKMatt Kaeberlein2:11:47

        I mean, I think that could alleviate some of the turf war issues.

    14. PAPeter Attia2:11:50

        Yeah.

    15. MKMatt Kaeberlein2:11:50

        But I think what you really need is, you know, the, the change in leadership and, and leaders who actually recognize why this is important, and that's where it starts. I mean, we can have a conversation about how much power does the NIH director have, how much power does the director of HHS have, but that's a place to start. If you can get people in those positions who get it, it's gonna have an impact.

16. 2:12:11 – 2:21:45

    Metformin: geroprotective potential, mechanisms, and unanswered questions

    1. PAPeter Attia2:12:11

       Let's talk a little bit about metformin. Um, Rich, do you think metformin is geroprotective in humans? I know it's-

    2. RMRichard Miller2:12:20

       Yeah

    3. PAPeter Attia2:12:20

       ... doesn't appear to be in your mice.

    4. RMRichard Miller2:12:24

       I, I think, uh, the evidence is uncl- certain. There's a famous paper from Bannister-

    5. PAPeter Attia2:12:31

       Yes

    6. RMRichard Miller2:12:31

       ... that alleged that, uh, diabetics on metformin had lower survival, lo-lower mortality risks than age-matched-

    7. PAPeter Attia2:12:37

       You don't listen to my podcast, do you?

    8. RMRichard Miller2:12:39

       I do occasionally when, when, uh-

    9. PAPeter Attia2:12:41

       Actually, no. You know what? It was a different, it was a different podcast. I did a very lengthy treatise in a journal club comparing the Bannister paper to the Keys paper-

    10. RMRichard Miller2:12:50

        Good

    11. PAPeter Attia2:12:50

        ... and came to the conclusion that the Bannister paper had too many methodologic flaws to be valid.

    12. RMRichard Miller2:12:56

        That's exactly what I was going to say. And in, as a matter of fact, Keys Christensen, who's the senior member of the group, and I have just written a review article which says exactly that. You've just-- That's the title of our paper.

    13. PAPeter Attia2:13:07

        Is it out yet?

    14. RMRichard Miller2:13:08

        Uh, it's under review. So yes, so you know exactly what I was going to say, and I agree completely. Uh, the question as to whether metformin would be geroprotective, that is-

    15. PAPeter Attia2:13:18

        In a non-diabetic

    16. RMRichard Miller2:13:19

        ... slow in a non-diabetic-

    17. PAPeter Attia2:13:20

        Yeah

    18. RMRichard Miller2:13:20

        ... in humans, I think is interesting, unanswered. It's not the drug I've, I would have looked at myself if I had a big d- set of dogs, for instance, and I wanted to give them a drug that, uh, modified their glucose homeostasis. I would probably start with, uh, something like canagliflozin that, uh, actually does work in mice and which is known to be safe over the long term in people. Metformin is safe over the long term in people, but I don't think there's much evidence that it's anti-aging, uh, leaving aside how great it is for diabetics and pre-diabetics.

    19. PAPeter Attia2:13:55

        What do you think, Steve?

    20. SASteven Austad2:13:57

        I think it's very promising. You know, I'm skeptical because I'm always skeptical in the absence of evidence. But the observational evidence, ignoring the Bannister paper, just the observational, the consistency of the observational data that it reduces dementia, cancer, cardiovascular disease suggests to me there's enough smoke there to look to see if there's, if there's fire or not.

    21. RMRichard Miller2:14:19

        I'll send you the, the Keys review article-

    22. PAPeter Attia2:14:21

        But, yeah

    23. RMRichard Miller2:14:21

        ... and then you can rethink that.

    24. SASteven Austad2:14:23

        Okay.

    25. RMRichard Miller2:14:23

        Yeah.

    26. PAPeter Attia2:14:23

        But, but sorry, Steve. You're saying it does all of those things in diabetics.

    27. SASteven Austad2:14:27

        In-- Well, most of the studies have been done in diabetics, absolutely.

    28. PAPeter Attia2:14:30

        Yeah.

    29. SASteven Austad2:14:30

        And, and how much of that is just because you're curing the diabetes is an open question. But I think it's-

    30. PAPeter Attia2:14:38

        And, and how much of that is a selection for people in diabetes that are progressing much less slowly 'cause they're the ones that stay on a single agent as opposed to the ones that progress into-
17. 2:21:45 – 2:35:22

    Canagliflozin and rapamycin as geroprotective molecules: mechanisms, dosing strategies, and longevity potential

    1. PAPeter Attia2:21:45

       use Canagliflozin as an example.

    2. RMRichard Miller2:21:47

       Yeah.

    3. PAPeter Attia2:21:47

       We've demonstrated, when, and I use we very liberally here.

    4. RMRichard Miller2:21:50

       Yeah.

    5. PAPeter Attia2:21:51

       Um, you've demonstrated that it reduces all-cause mortality in your mice.

    6. RMRichard Miller2:21:55

       In males.

    7. PAPeter Attia2:21:56

       In males. Do you believe-- And, and we know exactly what Canagliflozin does in the kidney.

    8. RMRichard Miller2:22:02

       Yes.

    9. PAPeter Attia2:22:02

       And we know that those mice live longer. Do you believe that the longevity benefit came through glycemic control? 'Cause there was no difference in weight, if I recall.

    10. RMRichard Miller2:22:12

        Uh, they actually lost weight. Males and females lost weight on Canagliflozin. But the question is a gene-

    11. PAPeter Attia2:22:17

        But the, oh, but was there a difference in weight between-- So was the difference in weight statistically significant between the long-lived males and the less, and the normal males?

    12. RMRichard Miller2:22:26

        The mice treated with the drug were lighter in weight-

    13. PAPeter Attia2:22:29

        Mm-hmm

    14. RMRichard Miller2:22:29

        ... than controls, and that's true of both sexes.

    15. PAPeter Attia2:22:31

        Both sexes. So the weight loss wasn't necessarily what explained-

    16. RMRichard Miller2:22:34

        Does not account. They actually lost more weight in females than in males.

    17. PAPeter Attia2:22:37

        Okay.

    18. RMRichard Miller2:22:37

        So the question is very valid and, and we do not know the answer. Uh, SGLT2 is on many other cell types. And it's quite possible, very plausible-

    19. PAPeter Attia2:22:46

        Mm

    20. RMRichard Miller2:22:47

        ... that Canagliflozin had an effect principally through controlling peak daily blood glucose, not average, but peak. And it's also possible that it had effects on cells of unknown origin in the brain. And all of these are very valid, and I don't think anyone knows the answer. It's well worth exa- evaluating. There are other inhibitors of SGLT2 and SGLT1 that have differential cell specificities and differential effects on different cell types. Uh, and looking at those would help give you glimpses into this question. We, we guessed it had to do with glucose, but we might be wrong.

    21. PAPeter Attia2:23:25

        So what is your intuition, Steve?

    22. MKMatt Kaeberlein2:23:27

        Well, I [chuckles] -

    23. PAPeter Attia2:23:28

        Going back to Metformin.

    24. MKMatt Kaeberlein2:23:30

        My intuition is that it might work. I, you know, I don't have a strong opinion. It, I, there's enough suggestive evidence that I think it's worth a trial. And I, I think that if we wait until we figure out exactly what each drug does in each cell type, it will take us forever to get any therapies. And in medicine, there have been many, many advances that came about before we understood the mechanistic underpinning. And if there's enough suggestive evidence and there's not a lot of side effects, suggests me that it's worth digging into now because the, the benefits are so enormous. You know, like we said, one year, healthy aging, thirty-eight trillion dollars. That's, you know, that makes, you know, that should talk to Congress if nothing else does.

    25. PAPeter Attia2:24:15

        Yeah. Well, and I would also say TAME could be successful independent of whether Metformin is effective at slowing biological aging, right? So th- those are not necessarily-

    26. MKMatt Kaeberlein2:24:25

        No, by, by getting others into the field, you mean?

    27. PAPeter Attia2:24:27

        No, by, by reducing its disease-

    28. MKMatt Kaeberlein2:24:28

        Well, also even just hitting the endpoint, right?

    29. PAPeter Attia2:24:29

        Yeah.

    30. MKMatt Kaeberlein2:24:29

        So the endpoint is multi- multimorbidity, right?
18. 2:35:22 – 2:43:17

    Resveratrol and NAD precursors—a lack of evidence for anti-aging effects

    1. PAPeter Attia2:35:22

       do the closest thing that a group like this could do in terms of a speed round. Gonna go through a couple of other ideas. I just wanna get the, what are you thinking about this? Can we say anything positive about resveratrol?

    2. MKMatt Kaeberlein2:35:37

       No.

    3. PAPeter Attia2:35:40

       Rich?

    4. RMRichard Miller2:35:41

       No. No.

    5. PAPeter Attia2:35:44

       Why does this thing not die? Why is there still-

    6. MKMatt Kaeberlein2:35:49

       Money

    7. PAPeter Attia2:35:49

       ... a hundred different resveratrols being sold on Amazon? Why do I still get people asking me, "Do you take resveratrol? Should I be taking resveratrol?"

    8. RMRichard Miller2:36:00

       It has a good PR team.

    9. MKMatt Kaeberlein2:36:01

       [laughs] I think it's really hard to prove something doesn't work, right? So once it gets in the consciousness as, as improving health, I mean, even in the longevity field. Jesus Christ, I was saying the resveratrol stuff was garbage for 10 years before people believed it, right? Now everybody believes it, but-

    10. PAPeter Attia2:36:19

        Apparently not [laughs]

    11. MKMatt Kaeberlein2:36:19

        ... it takes a really long time [laughs] Well, at least in the aging field. Like, I think if you went-- Like, you never see, you never see people studying resveratrol in the, the aging field anymore. I think if you went to a conference and asked scientists, "What do you think about resveratrol?" you'd get the same answer here with maybe one exception. Um, [laughs] but I think, I think it takes a really hard-

Episode duration: 2:55:00