175 - The biology of aging, rapamycin, and other interventions that target the aging process

1. 0:00 – 0:10

   intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. [upbeat music] Hey, Matt.

2. 0:10 – 14:08

   The various definitions of aging

   1. PAPeter Attia0:10

      Awesome to, uh, to have you back on the show. It's been a while because you were one of the, uh, very, very initial and, uh, original guests on this podcast, so, uh, I've been looking forward to having you back from almost the moment we finished our first discussion.

   2. MKMatt Kaeberlein0:24

      Yeah. Thanks, Peter. It, it's, uh, it's great to be back. Um, unfortunately, we can't see each other in person, but, uh, but this is the next best thing.

   3. PAPeter Attia0:31

      Yeah. Yeah, I know. [clears throat] I mean, we, we, we, we, we certainly will and, uh, uh, get together in person soon, I'm sure. Um, there are so many things I wanted to talk about and, and, um, you know, I think last time we spoke, we focused mostly on our mutual favorite drug, rapamycin, and our favorite pathway, the mTOR pathway, and, and, you know, certainly for those listening, uh, I don't want them to think we're not going to touch on that today. We absolutely are. But I wanna start even broader than that because [clears throat] so often you and I are having these discussions about all things that pertain to aging, and, uh, uh, you know, I, I find you to be one of the most thoughtful people across the topic. So I, I sort of wanna start with these broader questions about aging. Um, a lot of people have different definitions of aging, and truthfully, I'm not sure I even know how to define aging sometimes. I... It depends, I guess, on the context in which I'm asked, right? I think if my five-year-old asks me about aging, I would come up with one answer, and if I'm giving a keynote talk and somebody asks me about aging, I'd have to give a different one. Um, so what are some of the ways that you really describe aging?

   4. MKMatt Kaeberlein1:39

      Yeah. So that's, um, that's a really good question, and I think, uh, you know, I would probably say the same thing that you just said, which is that I'm not sure I have a great answer, and it changes depending on the situation. I think, um, in the past, I often gravitated towards sort of a molecular definition of aging. So, you know, what are the types of damage that occur during aging? What are the consequences of that damage? Um, sort of a, you know, in some ways, a hallmarks of aging framework view, right? Where we, we know that things like mitochondrial dysfunction, telomere shortening, uh, uh, cellular senescence, things like that happen during aging at the cellular and molecular level and contribute to many of the functional declines in diseases that go along with aging. And it... And so, you know, given my training in, in biochemistry and molecular biology, that, that sort of is the natural place where I, where I go when I think about, you know, what is aging. Um, I would say, you know, over the last several years, I have developed, uh, I, I think, a greater appreciation for a functional definition of aging. And so I, you know, as I start to think more and more about translation of interventions that seem to affect the biological aging process, um, in laboratory animals outside of, uh, the laboratory into the clinic, you know, uh, I spend a lot of time thinking about, well, what are some of the functional changes that go along with, with aging? And, and we know that across every organ system in the body, we see functional declines that go along with aging. And so I've started to think more about, you know, things like frailty, uh, uh, as an important component of defining aging from a biological perspective, you know, when we're, when we're talking about having an impact on health and longevity. Um, so I think it really depends on the, the context. I guess the other thing I would say is both of those definitions and the way I almost exclusively think about aging, unless somebody sort of forces me out of, out of my box, is from a biological perspective. There are other aspects of aging that intersect with biological aging, right? That are probably as, as important as what I think of as fundamental biology of aging to quality of life. So social aspects of aging, for example, are extremely important in people especially, right? For quality of life as you get older. I don't tend to gravitate towards, you know, that kind of a definition of aging, but I do recognize that it's important. So, you know, I think I just... I'm naturally always thinking about the, the biology of aging and, and as I already said, I tend to focus on the molecular mechanisms that drive the biological changes that go along with aging.

   5. PAPeter Attia4:29

      So l- let's look at the sort of [clears throat] two extreme views within the biologic and then kind of try to figure out where disease fits in. So on the one hand, you referred to the hallmarks of aging, and there's a very famous set of papers that have laid these out, and if the day comes that I can actually recite all of them, I'll be very impressed.

   6. MKMatt Kaeberlein4:47

      [laughs]

   7. PAPeter Attia4:48

      But I can... I always have to look it up, right? But it's-

   8. MKMatt Kaeberlein4:49

      I think I can probably get seven.

   9. PAPeter Attia4:51

      Yeah, yeah, yeah. It's like, so, so you, you mentioned a bunch.

   10. MKMatt Kaeberlein4:53

       We, we could do like who can, who can name the most hallmarks of aging?

   11. PAPeter Attia4:55

       Right, right. So, so-

   12. MKMatt Kaeberlein4:55

       Matt or Peter

   13. PAPeter Attia4:55

       ... d- DNA damage is, is one of them. Uh, you know, cellular senescence is another. Stem cell fatigue is another. Uh, uh, protein misfolding is another. Uh-

   14. MKMatt Kaeberlein5:07

       That's four

   15. PAPeter Attia5:07

       ... telomere shortening, uh, is another. Um, mitochondrial dysfunction is another.

   16. MKMatt Kaeberlein5:14

       My favorite. Yep.

   17. PAPeter Attia5:15

       Uh, let's see. Did I mention nutrient sensing issues?

   18. MKMatt Kaeberlein5:20

       Nope. Disper- deregulated nutrient sensing.

   19. PAPeter Attia5:21

       Deregulated nutrient sensing.

   20. MKMatt Kaeberlein5:23

       Yep. Yep.

   21. PAPeter Attia5:23

       So, uh, that's my seven. What am, what am I forgetting?

   22. MKMatt Kaeberlein5:25

       There's in- intracellular communication.

   23. PAPeter Attia5:28

       Bingo.

   24. MKMatt Kaeberlein5:29

       Uh, and what are we missing here? I'm gonna be really ashamed if it's, if it's something, uh, that I study.

   25. PAPeter Attia5:35

       Yeah.

   26. MKMatt Kaeberlein5:35

       But yeah. So we got eight out of nine.

   27. PAPeter Attia5:37

       So you've got the-

   28. MKMatt Kaeberlein5:37

       That's not bad [laughs]

   29. PAPeter Attia5:37

       ... you've got those. And then at the other side, you talked about, okay, let's talk phenotype. Let's talk about the outward expression within the organism, and frailty's-

   30. MKMatt Kaeberlein5:45

       Yeah
3. 14:08 – 20:55

   The relationship between disease and the biology of aging

   1. MKMatt Kaeberlein14:08

      think about it. I do wanna come back to one point though, which I, I also think is often, um, underappreciated be- in this relationship between disease and the biology of aging. I think, you know, sometimes, um, people get into this debate about whether or not the biology of aging causes diseases of aging, right? So does the biology of aging cause Alzheimer's disease, cancer, cardiovascular disease, right? Um, people get in debates about that, and I personally think the data are pretty good that these, that what I think of as the biology of aging, the molecular mechanisms, the hallmarks, whatever you wanna call them, contribute in a causal way to your risk of developing diseases. But I also think it doesn't matter. It does-- And this I think is really important. From the perspective of what is the best strategy to keep people healthier longer, it just doesn't matter whether aging causes disease or it creates a permissive physiological state for disease. You can't argue that biological age is the single greatest risk factor for every major cause of death and disability in developed countries. That is just a fact. And whether or not biological age causes those diseases or creates a physiological state that allows those diseases to manifest themself doesn't matter from the perspective of how, what is the most effective way to prevent those diseases. And I think that's where this debate is counterproductive, right? Should we call aging a disease? Does aging cause disease? I, I think that those are, those are not the right questions to be asking in, in my view.

   2. PAPeter Attia15:52

      Yeah. Let, let me see if you would agree with my assessment. I think you would, but, uh, it, it, I'll tell you how I think about this problem clinically, right? So, um, let's use atherosclerosis as an example. Um, and I wanna highlight what you just said in case the, the, the person watching this or listening to this missed it in any way, shape, or form. There is no gr- And, and this is one of the questions I, when I used to give talks, this is, I'd always lead with a question like this. What is the greatest risk factor for atherosclerosis? Hand will go up. Yes. Smoking. Nope. Hand will go up. High blood pressure. Nope. Hand will go up if it's in an especially, you know, erudite audience, uh, ApoB or LDL-C. Nope. And, and they'll just keep rattling o- Inflammation. Nope. Nope. Nope. Nope. Nope. Nope. Nope. The number one thing is age, hands down.

   3. MKMatt Kaeberlein16:43

      Yeah.

   4. PAPeter Attia16:44

      Right? You take a 70-year-old person who has everything perfect about them, and you compare them to a 20-year-old train wreck who has not a single thing that is in their favor, there is no comparison about their 10-year mortality prediction. The 70-year-old is in, hands down, a worse shape. So yeah, you can't, you can't undo that. Now, here's how I think about this problem clinically. Atherosclerosis is a great example because it's the disease that we understand the most of the big three, right? Which is not to say we understand it completely, but we have a far better understanding of what its drivers are and how to prevent it than we do cancer and Alzheimer's disease. Lowering ApoB pharmacologically, nutritionally, et cetera, is arguably the most important strategy you have to reduce it, along with probably improving metabolic health. So those two things, right? So regulating glucose, insulin, lowering ApoB, all of these things can be done through lifestyle, through drugs, et cetera, can dramatically reduce a person's risk of atherosclerosis. None of those things are necessarily directly t- directly targeting the nine hallmarks of aging. I think indirectly they certainly do, but when you give somebody a PCSK9 inhibitor, which specifically targets a protein that allows the body to clear more ApoB particles out of circulation, it is by no means targeting one of those nine pillars, but it's having a measurable impact on reducing their risk of disease. And in the end, that's the part that I think is hard for some people to understand within the aging community, is that you can still target metrics of a disease specifically without going after a hallmark?

   5. MKMatt Kaeberlein18:28

      Sure. And I, I mean, I think, um, I, I, I don't disagree with you that, that I think that is a, it's a concept that sometimes is, is, uh, underappreciated, right? Especially within the aging community. Um, I also think it, you know, it's not... It makes sense, right? So even if the hallmarks or, uh, you know, I hesit- uh, we focus so much on the hallmarks because it's easy, right? I think there are some reasons why the hallmarks are incomplete, but, but let's just keep using that, that term, uh, sort of as a surrogate for the molecular mechanisms of aging, right? If we accept that, that the hallmarks are at some level, you know, preceding the damage, whatever that is that's causing the disease, it makes sense that you could intervene, sort of if we think about it in an upstream/downstream perspective, right, the hallmarks being upstream, the disease being ultimately downstream, it makes sense that you could intervene at the level of the hallmarks. It also makes sense that you could intervene, you know, in whatever the bridge is that's connecting the hallmarks to the disease. You wouldn't necessarily impact the biology of aging at all. And this gets back to what I was talking about before, which in, for many diseases of aging, there comes a point where the pathology of the disease is not normative aging anymore. And so you can, you, you can quite successfully treat or cure a disease of aging in an individual, uh, without impacting the biology of aging. In fact, I would argue that's almost exclusively what is done clinically, right?

   6. PAPeter Attia19:52

      Yep.

   7. MKMatt Kaeberlein19:52

      Is, is to, to try to, to, to either alleviate the symptoms of the disease, uh, or cure the disease. Uh, there's starting to be more on the preventative side, but I still think that lags far behind, you know, waiting until people are sick and then trying to do something about their disease. But, but you don't have to impact the biology of aging to be successful at, at, at any of those things. I would just argue that impacting the biology of aging is going to be a much more effective and efficient approach from sort of the overall health perspective. I think the other point that's obvi- obvious but is important to make is if you don't target the biology of aging, that you're really only impacting that one disease. Say it's cancer. You can cure somebody's cancer. You can take the tumor out, right, and, and they can go on and live a, a normal life, but you haven't done anything to the biology of aging. Um, if you, if you don't confront the biology of aging, right, you still have all of these other functional declines and diseases of aging that are, that are increasing, you know, essentially exponentially as you're getting older,

4. 20:55 – 31:30

   Potential for lifespan extension when targeting diseases compared to targeting biological aging

   1. MKMatt Kaeberlein20:55

      and so the effect on health and longevity is quite small. In fact, um, I think Jay Olshansky was the person who originally kind of did the math here, right? And it's really very striking. So if you consider a typical 50-year-old woman in the United States and you say, you know, what would happen if we had a cure to all cancers, right? Every type of cancer, we had a cure today, and we, we implemented that. Life expectancy for a typical 50-year-old woman in the, in the United States would go up about three years. That's it. So we've won the war on cancer. We get a plus three on life expectancy. It's about the same for curing heart disease. If you cure both of those diseases, it's roughly additive. It's, I think, about seven years. So the impact on life expectancy is actually from, from curing disease is actually quite small. If you compare that to the impact of targeting biological aging, which, which again, I think we have to be honest, right? This is hypothetical in humans at this point, so all we can really do is extrapolate from what is done in laboratory animals, but it's pretty routine now. There are, I don't know, maybe a dozen, 15 different interventions that can increase lifespan, slow aging in mice by between 15% and 30%. If we com- if we just extrapolate that to the human condition, the impact on life expectancy is about 20 years with the added value that because you've sort of slowed all of the functional declines of aging simultaneously, those extra couple of decades are spent in relatively good health, right? So I think, I think it's just important to appreciate the, um, the, the, the potential difference in health and life expectancy from targeting aging as opposed to what we, what we do right now, which is, you know, trying to cure individual diseases. And I've sort of adopted the, the term... You know, I think of that as 20th century medicine, the, the disease first approach, or I would even say 19th century medicine. We've been doing this for a long time, right? Um, and I, and I contrast that to what I think of as 21st century medicine, which is, which is approaching health and longevity from the perspective of the biology of aging. And I-- we're not there yet, right, but I do believe that, that this is happening. There is a, there is a transition occurring, a slow appreciation among the broader clinical community of the potential of this kind of approach. Um, and I do believe that we will get there in this century. So, so it is my hope and expectation that 21st century medicine will really become targeting the biology of aging to enhance health and longevity, hopefully by much, much greater amount than, than we're currently able to do.

   2. PAPeter Attia23:39

      Yeah. So I, I agree with a lot of that. The one thing I would, I would throw, throw a little bit of, um, a question at is... And, and I'd love to have Jay on the podcast because I don't know that I fully agree with his analysis. Um, I agree with the spirit of his analysis. So I completely agree that disease-based Whac-A-Mole is not as go-- is not going to be nearly as effective as targeting the basic biology of aging.

   3. MKMatt Kaeberlein24:04

      Yeah.

   4. PAPeter Attia24:04

      Uh, so completely agree with, with your points. I don't know that I agree with the magnitude, right, the de minimis magnitude of it because I, I really think that Jay's analysis is focused on an independent look at each disease, whereas in reality, if you eliminated cardiovascular disease By definition, you have reduced inflammation significantly. You've reduced the burden of microvascular disease significantly. Those are going to play into other diseases. So-

   5. MKMatt Kaeberlein24:37

      Yeah

   6. PAPeter Attia24:37

      ... you know, the an- uh, his analysis is very actuarial, but it's not actually very biological. That's my opinion. Now, again, I should have-

   7. MKMatt Kaeberlein24:44

      I, I think that's fair

   8. PAPeter Attia24:44

      ... yeah, yeah.

   9. MKMatt Kaeberlein24:45

      Yeah, I, I think that's fair. I think you could make the case at least for, for cancer that it may be closer to-

   10. PAPeter Attia24:51

       I agree

   11. MKMatt Kaeberlein24:52

       ... you know, just what the straight-

   12. PAPeter Attia24:53

       Yeah

   13. MKMatt Kaeberlein24:53

       ... math would suggest.

   14. PAPeter Attia24:54

       Yeah.

   15. MKMatt Kaeberlein24:55

       Yeah.

   16. PAPeter Attia24:55

       Yeah. Now, with all of that said, I couldn't agree more with the macro point here, which is delaying chronic disease, um, is probably not going to be as effective as targeting-

   17. MKMatt Kaeberlein25:09

       Yeah

   18. PAPeter Attia25:09

       ... something at the foundation. Now, that said, let's, let's, let's take a look at Nir's data, right? So when you look at, at Nir Barzilai's work with centenarians, the overwhelming statement here is they get chronic diseases later. They don't live longer with them. Um, and I, I remember, you know, really being, um, struck by that. It was not my, necessarily my, you know, that would not have been my null hypothesis going into Nir's, you know, a study of Nir's work and Tom Pearl's as well. Between Nir and Tom, you really have the greatest assessment of, of the centenarians and their siblings.

   19. MKMatt Kaeberlein25:46

       Yeah.

   20. PAPeter Attia25:46

       And you realize that, like, they don't seem to have magical protection from a disease once they get it. When they get cancer, they're just as hosed as the rest of us. When they get heart disease, they're just, they're just as bad off as the rest of us.

   21. MKMatt Kaeberlein25:59

       Yeah.

   22. PAPeter Attia25:59

       But they get a phase shift. They get a 20-year, 20, sometimes 30-year phase shift in when they're going to get the disease. And so how does that factor into my thinking clinically? My f- factoring into that clinically is the sooner you begin prevention, the more you can mimic the centenarian. What we don't fully understand is molecularly why is that the case, right?

   23. MKMatt Kaeberlein26:23

       Yeah.

   24. PAPeter Attia26:23

       We've identified some of their genes, right? We know that, you know, they're gonna be more likely to, you know, have APOE2 versus APOE3 or APOE4. Um, they're gonna be, you know, more, less likely to have APOC3, uh, high regulation versus low. I mean, there's y- you know, y- you have a lot of genes that produce phenotypes that are favorable, but when you bring it back to our nine hallmarks, by the way, the ninth hallmark is epigenetic, uh, modu-

   25. MKMatt Kaeberlein26:52

       Of course.

   26. PAPeter Attia26:52

       Yes, it's the-

   27. MKMatt Kaeberlein26:53

       Oh, my God

   28. PAPeter Attia26:53

       ... it's epigenetic modulation.

   29. MKMatt Kaeberlein26:54

       [laughs]

   30. PAPeter Attia26:54

       Yeah. Now, the, the other point I guess that we're both well aware of, but maybe for the listener, is how difficult it is to study aging in humans targeting the basic biology because you don't get to do what our clinical trials apparatus is set up to do, which is pick a-
5. 31:30 – 38:56

   Rapamycin as a longevity agent and the challenges of targeting the biology of aging with molecules

   1. MKMatt Kaeberlein31:30

      that's, that's at least a consistent explanation for why we don't see these, these, these, um, what we would think of as slower aging variants pop up in, in people. Um, the other point that's, that's important to make as well, though, is that that doesn't mean that we can't intervene in these pathways to have an impact on health and longevity. And for me, this has been, you know, probably the most, uh, exciting aspect, uh, uh, and development in the field over the last probably 15 years. You know, if you asked me 15 years ago, um, whether I thought that, that it would be easy to slow aging in an old mouse, I would've said no. I would've said you probably have to start, you know, at six months of age and treat them all the way through life to get, to get the benefits. And that was honestly largely based on caloric restriction, right? Which that seems to be the case for caloric restriction. You know, what has emerged now is there are five or six or seven or maybe even more different interventions that can be initiated in middle age or even in, in late age in mice, and you actually go be- it's not only that you slow down the declines, you actually reverse the declines, right? And again, I come back to rapamycin 'cause in pretty much every tissue where this has been looked at, you take an old mouse, you give it rapamycin, functionally it's younger in that tissue or that organ, um, and lifespan is extended.

   2. PAPeter Attia32:49

      And, and by the way, to your point, Matt, I was having dinner with a friend last night who asked me, "Why don't we start giving rapamycin to children?" And I said, "Look, I think-

   3. MKMatt Kaeberlein32:58

      [laughs]

   4. PAPeter Attia32:58

      ... I think rapamycin is-

   5. MKMatt Kaeberlein32:59

      Sorry, I couldn't laugh

   6. PAPeter Attia32:59

      ... is the most important, you know, geroprotective agent out there today, but you wouldn't want to give it to a developing, uh, child, right? You, y- i- so he said, "If you had to guess, when would be the right age to start?" I said, "I have no honest clue, but it wouldn't be before 25."

   7. MKMatt Kaeberlein33:14

      Yeah.

   8. PAPeter Attia33:15

      Right? It just wouldn't be before about the age of 25, which speaks to your point. Any genetic, uh, mani- manipulation or in this case-

   9. MKMatt Kaeberlein33:23

      Right

   10. PAPeter Attia33:23

       ... naturally acquired genetic variation that mimicked rapamycin would probably not be selective because you wouldn't be able to turn it on and off the way you would need to-

   11. MKMatt Kaeberlein33:33

       Exactly

   12. PAPeter Attia33:33

       ... with the drug.

   13. MKMatt Kaeberlein33:34

       That's right. Yeah, that's right. And I, I mean, I think that's a really interesting question about rapamycin and, and other interventions. As, as, as more and more interventions start to, you know, get to the same sort of level of confidence that we have about rapamycin, um, when is the optimal sort of treatment period, right, f- to get the, the biggest benefits? And I think, again, this is a, it's, it's, it, it, it's not something that often gets, I think, talked about in that conversation, but it's really a, it's a balancing act, right? There, a- any intervention is gonna have some risk associated with it, right? The risk can be low, the risk can be high, but there's always some risk of side effects. And, um, and so the, the o- the question of optimal treatment, right, um, is a balance between the beneficial effects that you get and the risk of detrimental effects, side effects. Um, and so I think we still don't, even with rapamycin, we still don't have a great, uh, feel for what that risk looks like, right? And that's in part because, you know, we haven't had long-term controlled clinical trials at multiple doses, multiple strategies of, of, you know, intermittent versus continuous treatment, things like that. Um, so we just don't know, right? And it's in- it's interesting in the case of rapamycin 'cause my impression is that, you know, there are a group of people, um, I think you and I both know some of them, uh, we might even be among them, who, [laughs] uh, who ha- you know, have self-experimented, right? And my impression is that the, the, the, the, um, there has been a movement towards the idea that, you know, once a week dosing with rapamycin, uh, is probably better than daily dosing with rapamycin for, for aging effects in people and that, you know, you might wanna do it for three months, and then you stop for six months, uh, and you do it again for three months, right? I think that's where, that's where people are starting to coalesce around this idea. There's not a lot of data to support that, right? It's a guess. And, and so, um, so it's just interesting to sort of see how that, you know, is evolving in the absence of long-term, large-scale controlled clinical trials. And this is getting to the point that you raised earlier, which is it's really hard and expensive to do long-term controlled clinical trials for aging in people. We really, I think, still as a field don't have a great strategy for how to, for how to address that challenge of, of, of actually trying to answer some of these questions in the way that, you know, at least traditionally we would want to see them answered in a clinical setting.

   14. PAPeter Attia36:16

       I mean, I think there's an even bigger problem, Matt, which is I don't think there's a regulatory appetite to even do what, what, what would be necessary because-

   15. MKMatt Kaeberlein36:24

       I agree, yeah

   16. PAPeter Attia36:24

       ... we, we have the regulatory appetite to say you take an individual who is either at very high risk for a disease or already has said disease, and we will go ahead and accept the risk of a clinical trial to assess it. But by definition, if you truly want to understand how geroprotective metformin or rapamycin or canagliflozin or pick your favorite molecule is, you really need to be testing it in people before they have a disease.

   17. MKMatt Kaeberlein36:51

       Yeah.

   18. PAPeter Attia36:51

       So even if you... So there's really two fundamental problems. This is one We do not have a regulatory environment that accepts that risk. So I, I, I would love to see the IRB submission that says, "We're gonna test rapamycin in healthy 50-year-olds who are, you know, whose 10-year risk of death is less than 1%."

   19. MKMatt Kaeberlein37:10

       Yeah.

   20. PAPeter Attia37:10

       And then secondly, because we can't logistically follow those people for the next 50 years, which is what would be necessary to understand its true magnitude of geroprotection, we would need really good biomarkers of aging, of which I will posit, and you may disagree, we have somewhere between zero and epsilon of those.

   21. MKMatt Kaeberlein37:31

       [laughs]

   22. PAPeter Attia37:31

       I mean, we don't have diddly squat in the way of meaningful biomarkers of aging. By the way, I wanna go back to your point on rapa. So, so, you know, as, as you do know, and I'm very happy to talk about, I mean, I've been taking rapamycin for two and a half years now, and I am one of those people who has coalesced around once-weekly dosing. I have fiddled a little bit with my dose. I've varied it from as little as five to as many as eight milligrams once a week. I've also done-

   23. MKMatt Kaeberlein37:55

       Yeah

   24. PAPeter Attia37:55

       ... the cycling on and the cycling off, but I am completely flying bli- blind. Um, most of my dosing and frequency data comes from Joan Mannick and Lloyd Klickstein's 2014 paper-

   25. MKMatt Kaeberlein38:09

       Yeah

   26. PAPeter Attia38:09

       ... with everolimus, which of course is not the same as rapamycin, but it's a pretty reasonable hand-drawn facsimile of it, and it was from that study that I concluded that, uh, you know, 20 milligrams versus five milligrams versus one milligram, your sweet spot was at about five rele- and from a side effect standpoint and an efficacy standpoint, and the daily dose of one milligram didn't seem to produce as good an effect as the five milligrams once a week. But how does that stand in comparison to what we learned from all of the ITP studies where it's continuous administration of rapamycin? And to your point, 'cause we'll come back to these and talk about them, remarkable results regardless of when it's initiated.

   27. MKMatt Kaeberlein38:54

       Right.

   28. PAPeter Attia38:55

       I don't know what to make to that.

   29. MKMatt Kaeberlein38:55

       Yeah.

6. 38:56 – 51:22

   Human studies using rapalogs for enhanced immune function

   1. MKMatt Kaeberlein38:56

      I, I mean, yeah, I, and, and, you know, I, I, I kind of agree with everything you said about, about why, you know, if you're gonna pick one regimen for rapamycin, that makes sense. And, and, and like you said, it's really based on two clinical trials, right? I mean, really.

   2. PAPeter Attia39:13

      Yep.

   3. MKMatt Kaeberlein39:13

      Uh, a- and so it's a limited data set, but at least for immune function in people, um, you know, it seemed to work. And, and that's actually... I mean, you know, we could, we could spend hours talking about this, 'cause that's a whole nother, I think, uh, interesting and informative sort of experience was, was the, the failure of the phase three clinical trial at Restore Bio, right? Uh, uh, and what happened there, and I don't think we actually... It's at least not in the... It's not published yet.

   4. PAPeter Attia39:39

      Well, let's talk about this, 'cause it is really interesting. So let's back up for a moment and give people the context. So, um, when Joan was at Novartis in, and, and both Joan and Lloyd, Lloyd were at Novartis in 2014, the everolimus study was done, and, um, do you wanna just tell people really briefly what that study looked at?

   5. MKMatt Kaeberlein39:57

      Right. So, so that study, so everolimus is a derivative of rapamycin and, and biochemically it has e- exactly the same mechanism. So it's... I, I, at least I conceptually think about them as essentially the same molecule. So, so anything that we see with everolimus we would expect to see with rapamycin. And so that was a, a phase two clinical trial in healthy older adults to look at whether or not a six-week, uh, treatment with everolimus could boost a vaccine response, so, so the ability of older adults to respond to an influenza vaccine. And that actually was based on o- one of my favorite papers from Pan Zheng's lab at the University of Michigan, who showed that in mice, uh, I think it was, I think it was four weeks of rapamycin. It was either four weeks or six weeks of rapamycin in old mice boosted the ability of a flu vaccine to, to protect those mice against a lethal dose of influenza. That, if anybody hasn't, hasn't looked at that paper, I, I would just encourage you to go check it out. I think it was a 2009 Science Signaling paper from Pan Zheng's lab. Uh, something of... The title has something about hematopoietic stem cells and rapamycin. Um-

   6. PAPeter Attia41:07

      We'll, we'll link to it in the show notes for sure.

   7. MKMatt Kaeberlein41:09

      Okay. Yeah. It's an amazing study, but, but the, my favorite experiment there was this experiment where they took young and old mice and they gave them a, a influenza vaccine, and then they waited, uh, two weeks, and then they gave them a leth- what would be a lethal dose of influenza if they hadn't got the vaccine. And in the old group, half the mice either got rapamycin or they got a control, right? So the first thing that struck me about that experiment was if you look at just the difference between young and old mice who got the vaccine, all of the young mice were protected, 100% vaccine response. I think it was about 65%, so two-thirds of the old mice did not have a sufficient response to the vaccine that they were protected against influenza, right? And I don't know if the numbers are... I don't think the numbers are, are exactly the same in people, but there is definitely that same trend where older adults tend to not respond to vaccines as effect- a- as robustly as, as younger adults. Um, unless those old mice got rapamycin. If they got six weeks of rapamycin, uh, they were 100% effective at responding to the vaccine. So at least for that measure of immune function, rapamycin fully restored the immune system back to that of a youthful immune system. So that was the mouse data that sort of served as, um, support for testing this in humans in this clinical trial that, that we're about to get to.

   8. PAPeter Attia42:36

      And, and, and by the way, Matt, do you recall if the immune response th- in, in question, i.e. the immune response that was better in the rapa group versus the non-rapa group of older mice, was this a B cell response, a memory B cell response, or was it a T cell response?

   9. MKMatt Kaeberlein42:53

      I, you know, I, I, I don't recall the data. I know they have a lot of data in there looking at, uh, at, at, at the, the antibody titers and different, uh, types of im- uh, immune cell types and, and how they responded. Um, as I said, the title of that paper and the The model that they proposed was that rapamycin was acting at the level of hematopoietic stem cells to rejuvenate hematopoietic stem cell function in some way. I, I don't recall the details of the immunology and, you know, I've, I've tried multiple times throughout my career to become fluent in, um, immunologist speak and have failed miserably every time. So that's a weakness of mine that will likely never be, uh, never be ad- addressed adequately.

   10. PAPeter Attia43:35

       It's just got such amazing implications for what we're seeing with, with COVID vaccination because we are still in-

   11. MKMatt Kaeberlein43:41

       Yeah

   12. PAPeter Attia43:41

       ... such a nascent stage of truly understanding. I mean, you know, we're seeing people who, you know, naturally acquired COVID, who within six months have no more circulating IgG.

   13. MKMatt Kaeberlein43:53

       Right.

   14. PAPeter Attia43:53

       And we have no clue if they still have immune function. For example, do they still have memory B cells in their bone marrow that when challenged will make antibodies? Do they still produce-

   15. MKMatt Kaeberlein44:06

       Right

   16. PAPeter Attia44:06

       ... uh, do they still have memory T cells that will show up and immediately respond? And, and, you know, so we're actually involved in a study that's looking at that. But my, my intuition is you can probably still have an immune response, uh, or, or an immune response that's ready to go absent circulating IgG.

   17. MKMatt Kaeberlein44:24

       Yeah. The one thing I will say about rapamycin and, and everolimus is that it, it, it seems like it's not one simple mechanism at play. So Joan, for example, has, has published data that one of the effects of everolimus and another drug called RTB101, which is also an mTOR inhibitor, um, is to boost antiviral gene expression, right? So, so a- a- and we know also that, that rapamycin, at least in mice and almost certainly in people, tamps down on the sort of, you know, chronic sterile inflammation that goes along with aging through mechanisms that still are being worked out. So I think it's probably multiple things that are going on that can, um, impact immune function in different ways, right? Uh, when you, when you treat with rapamycin, especially in the context of an old animal or an old person. Um, so it's, it's probably not gonna be one, one mechanism is, is my guess.

   18. PAPeter Attia45:18

       So based on this study, so Joan and colleagues take a group of, I believe, 65-year-olds. I think there are, you know, 80... 320 of them, so divided into four groups of 80. You've got a placebo group, a one milligram a week group, a 20 milligrams once a week, and five milligrams once a week, yeah?

   19. MKMatt Kaeberlein45:38

       That's right. Yeah. And so they did a six... I think it was a six-week treatment period. Uh, and then they also waited, I think, two weeks, and then they gave them a flu vaccine. And, and what they showed... I mean, obviously it's people, so you can't do the mouse experiment and then give those people a lethal dose of influenza. So they were sort of, you know, stuck with looking at things like antibody titers and to, to, to try to get an assessment of, you know, did the people who got, um, everolimus respond better to the vaccine than the people who got the vehicle control? And, and it looked like they did. And it was, you know, you can argue about the, the strength of the data. I think it was pretty clear that they had, um, at least at the, the, the five mg once a week, and I think the one mg daily, I can't remember, maybe it was the 20 mg once a week. But the five mg once a week looked pretty convincing that they had a better response to the, to the vaccine. I think the other thing that's really important about that paper is that the incidence of side effects was really hardly different at all between the, the different everolimus groups and the, the placebo, and particularly the five mg once a week. There really was no significant increase in, in adverse events in that group, which gets back to how we kind of started on this, this tangent, which is that that's part of the reason why, you know, I think people are moving towards the idea that you can still get efficacy from once weekly dosing and that the side effects are reduced at once weekly dosing to essentially zero or close to zero. Um, so that was the first phase two trial, and then they went on and did a second-

   20. PAPeter Attia47:10

       And, and before we leave this trial, Matt, I, I think-

   21. MKMatt Kaeberlein47:13

       Sure

   22. PAPeter Attia47:13

       ... it is important for someone listening to understand why people like you and I and Dave Sabatini and all the people who live in mTOR land, I'm not putting myself in the same category as you guys, but you know what I mean, I'm an mTOR fanboy. Um, why was that such an interesting and landmark paper? Well, I think it's because up until that point, the only human application for rapamycin was immune suppression, right?

   23. MKMatt Kaeberlein47:38

       That's right.

   24. PAPeter Attia47:38

       Rapamycin is a drug I have known about forever because as a surgical resident, I was giving rapamycin to kidney transplant patients, heart transplant patients, and liver transplant patients, along with a cocktail of cyclosporine, you know, uh, prednisone, MMF, all of these other really nasty drugs, and it was one part of that in their ability to suppress the immune system. So I think prior to that paper, you have, you have the ITP that, the first ITP that came out in '09 suggesting this is a remarkable tool for longevity, at least in the ITP mice. But then on the other hand, you're saying, "Well, but it can't really work in humans 'cause it's gonna be really horrible to the immune system." So-

   25. MKMatt Kaeberlein48:23

       Yeah

   26. PAPeter Attia48:23

       ... you had this sort of dialectical dilemma, which all of a sudden it became, well, maybe that's not the case. So, so how do you reconcile the, the, the data that we saw in Joan's paper with the fact that rapamycin is, um, at least in theory, an immune suppressor, uh, as it pertains to organ transplantation?

   27. MKMatt Kaeberlein48:46

       Yeah. And I think, you know, you're absolutely right. That was one important aspect of that, that paper. Um, and I unfortunately think that, that the, the old view, which in my room is the wrong view, that rapamycin is an immunosuppressant, um, still is prevalent in the clinical community. I think most clinicians still think of rapamycin and rapalogs as, as, as immune suppressants because that's often how they're used clinically to prevent organ transplant rejection. My, um, so, so I think the simple answer is it's all about dose, dummy. I mean, we, we know every drug has a dose response, right? And that you can get different effects, different outcomes, different side effects depending on the dose. And so You know, when you back off on the dose of rapamycin or everolimus, um, in the context of an aged physiology. So there's, there's, you know, there's multiple things going on here in that study. They used lower doses, they tested once-weekly dosing, and these are old people who show a functional decline. You're not gonna see a functional improvement in vaccine response if you did this experiment in young people, right? You're only gonna see it in the context of, of older people, where they already have a, a functional deficit, and that's... Again, it's an important conceptual point that I think often gets lost in these discussions. Um, the other thing to appreciate about how rapamycin has been used, you know, traditionally and how it was first approved, is these are people who had an organ transplant, right, taking high doses of the drug and also, I think always, I'm not an organ transplant physician, but my impression is these people are always taking other immune suppressants in combination with mTOR inhibitors. So in that context, yes, it does seem to be the case that mTOR inhibitors can help reduce the chance of, of organ rejection in transplant patients. I don't kn- I, I could be wrong. I think there's, I think there's preclinical data. I don't know of any strong clinical data that by itself rapamycin, even at higher doses, has substantial immune suppressing effects. It might. It wouldn't shock me if it does at high doses, but I don't know that that's really ever been, um, been shown clearly in healthy people, you know, taking higher doses of the drug.

   28. PAPeter Attia51:01

       Yeah. That's interesting. I don't think I've ever gone back and looked at the FDA approval process in '99 because obviously it was approved, a- a- approved for that use, and I think that's the only use that it's been approved for. Um-

   29. MKMatt Kaeberlein51:14

       Yeah

   30. PAPeter Attia51:15

       ... so I wonder what trials led to that approval. Uh, you know, whatever trials would've taken place in the mid-'90s.
7. 51:22 – 56:56

   The role of inflammation in functional declines and diseases of aging

   1. MKMatt Kaeberlein51:22

      I, I don't, I don't recall. Uh, uh, uh, another point that I think is worth making is, you know, we use... And I, I'm as guilty of this as anybody else. We use, um, sort of broad terms when we're talking about the immune system, suppression, you know, lower function. We say the immune system, you know, doesn't function as well in older people as compared to, to younger people. Which is true, but I think when we say doesn't function as well, we tend to think of as it's functioning at a lower level, right? It-- There's just less activation, which actually isn't necessarily the case. In old mice, in old people, there's a lot of immune activation that shouldn't be happening, right? There's a lot of sterile inflammation that's occurring. So it's not necessarily that the immune system is, is functioning less, it's functioning inappropriately. And, and I think there's a ton of evidence that, that many of the benefits that we see in mice from rapamycin occur because it tamps down on that sort of sterile inflammation that goes along with aging, right? The inappropriate activation of the immune system. So in that sense, you could think of it as an immune suppressant, but, but through mechanisms that I don't understand at all, and I don't think anybody really understands, um, it seems to be more effective at targeting the, the bad, the bad part of the aberrant immune response in an aged physiology, which might be the reason why you're able to then have more of the good part. And here I'm, you know, clearly showing my ignorance of immunology because I'm referring to it as bad and good, right? But I think in some ways that's an-- it's, it's useful to kind of think about it at that level because it's easier to, to appreciate that it's not, you know, not-- immune function isn't intrinsically good or bad, right? It, it is, and there are different types of immune responses, and if you get the, the wrong type of the immune, immune response at the wrong time, that's bad. If you get the right type of immune response when you need it, that's good, right? And, and, and I think in, in the context of aging, we just see a lot more of the bad and probably a decline in function of the good. And, and I don't know if rapamycin is affecting both of those, but I think it's definitely affecting the bad and bringing it back down, which might just be enough to allow the good to come back up where it's supposed to.

   2. PAPeter Attia53:37

      Yeah. Which, you know, look, I think that's a great point to make, and it's, it's very similar with reactive oxygen species, right? I mean, you have to have them. They are vital signaling molecules.

   3. MKMatt Kaeberlein53:46

      Right.

   4. PAPeter Attia53:46

      And yet if they run amok, they cause damage. And so-

   5. MKMatt Kaeberlein53:49

      Yeah

   6. PAPeter Attia53:50

      ... yeah, a lot of biology is, is in the Goldilocks framework of not too much, not too little.

   7. MKMatt Kaeberlein53:54

      Yeah. Can I just throw one more thing a- a- out there as well, which is... And this is, this is-- Again, I'll admit, if you'd asked me 15 years ago, like, how important did I think that, you know, chronic inflammation and immune function would be in aging, I probably would've said, you know, "I don't know, but my guess is it's not gonna be the major player," right? Because, you know, my background came from working in yeast and worms, which, you know, worms sort of have an immune system, but not really, right? Uh, where I would've pointed to things like translation and autophagy and mitochondria, all of which are clearly important for affecting inflammation and immune function. But I, I wasn't a big-- I wasn't really bullish on inflammaging at that point, and I have become very bullish on inflammaging as, you know, critically important for many of the, the functional declines and diseases of, of aging that we see in people. The, the point that I wanna make here is that maybe, maybe I shouldn't say every, all of the interventions that I know about that, that I'm enthusiastic about translationally seem to hit inflammation in mice, and they seem to tamp down on, you know, the, the chronic sterile inflammatory signaling that we see go along with aging. Which makes sense. It's encouraging, right? That, that, that, that they all seem to have this shared mechanism. But the other-- the flip side of that is I'm, I'm-- You know, people talk a lot about... They're-- People are very excited now about, you know, senolytics or reprogramming now is the new, the new senolytics, right? It's the thing everybody's excited about. I'm not sure that those are fundamentally different from rapamycin in terms of the way that they're working. And, and I think we n- obviously we need to find out because, you know, it would be nice to know whether combinations of these interventions are gonna do better than one alone. But, but to me, the, the underlying theme that seems to be similar about all of these things that work in mice is if you look in tissues of aged mice at You know, inflammatory cytokines, p16, p21, markers of senescence, they seem to be tamped down by all of these, these interventions, which might explain the functional improvements that we see, uh, from, from using these interventions in aged mice.

   8. PAPeter Attia56:04

      Yeah, I, I, I think that's actually a really interesting point, and I, I'm, I would kind of say I'm in the same boat. I have become probably more convinced at the importance of inflammation, um, certainly in Alzheimer's disease and certainly in atherosclerosis.

   9. MKMatt Kaeberlein56:22

      Yeah.

   10. PAPeter Attia56:22

       Because I've seen enough people who, um, either develop these conditions without otherwise clear reasons for it, and vice versa, right? People who do have-

   11. MKMatt Kaeberlein56:35

       Yeah

   12. PAPeter Attia56:35

       ... other risk factors and don't go on to develop, um, but have, you know, at least have a demonstrably low measured amount of, of, of inflammation. Um, again, the question becomes: Do you target-- Is there a direct target of inflammation, or do you simply reduce inflammation by targeting these other mechanisms, which we'll, we'll get to?

8. 56:56 – 1:02:26

   Study showing rapalogs may improve the immune response to a vaccine

   1. PAPeter Attia56:56

      Um, let's go back to the everolimus progression.

   2. MKMatt Kaeberlein57:01

      Yeah.

   3. PAPeter Attia57:01

      You were just about to talk about RTB101. So what, what is that?

   4. MKMatt Kaeberlein57:05

      Right.

   5. PAPeter Attia57:05

      And how is that the next stage in the evolution of this rapalog?

   6. MKMatt Kaeberlein57:09

      Right. So, so there was the, the, the, the first pha- phase 2 trial was, was done. They hit their endpoint. It looked like it worked, and they didn't see any-- I mean, this was a phase 2 trial, so, so the important thing was they didn't really see any substantial adverse effects as well, right? So then for the next trial, they added in another drug called RTB101, which is, um, uh, one of these drugs that hits multiple kinases, uh, in the cell. So mTOR is a kinase, which, you know, means its biochemical activity is to, is to put phosphate groups on other proteins. But you can think of it as a signaling sort of activity, right? So it, it, mTOR senses the environment and regulates the output based on this signaling function of being a kinase. This drug, RTB101, inhibits mTOR, the catalytic activity of mTOR. It also inhibits other kinases. So, so it's talked about as sort of a dual kinase inhibitor, but in reality, it hits multiple kinases. So it's a dirtier drug. That's, that's maybe the way to-- the point to make. It's a dirtier drug than rapamycin, which has a very specific biochemical effect on mTOR and, and mTORC1 specifically, which we haven't, we haven't dove into the mTORC1 versus mTORC2 situation yet.

   7. PAPeter Attia58:25

      And was the rationale for using a dirtier drug simply to create a new drug, to have a, a molecule that is novel and therefore protectable by IP? Or was it designed to be dirtier without thinking of it as being dirtier, but thinking of, of it as being sort of, uh, pluripotent across several kinases?

   8. MKMatt Kaeberlein58:44

      Yeah. So I wasn't-- I, I obviously wasn't involved in designing this trial, so I can't, I can't answer that question as to what the, what exactly their thought process was. I think it is true that RTB101 has a, had, had and has a longer existing patent life than everolimus, so there is that component certainly to, to, to moving a drug through the approval process. And if you talk to Joan, um, uh, she will tell you that they had, uh, unpublished data that RTB101, at the doses that they were using in this trial, um, appears to be specific for mTOR complex 1, like rapamycin. So I think their thought process, it pro- I, I mean, in reality, it was probably twofold, right?

   9. PAPeter Attia59:27

      Yep.

   10. MKMatt Kaeberlein59:27

       The IP life was greater, and, and there's a biological rationale for testing RTB101 either alone or in combination with everolimus. And so that was really the design of the phase 2 trial was, um, one r- it was, i- it was, uh, structurally very similar to the, to the first phase 2 trial, right? So you have older adults, um, same sort of age range. Uh, uh, I think they had to be 65. They couldn't have a preexisting age-related condition, significant age-related condition. They had a control, uh, placebo arm, everolimus alone, RTB101 alone, and both. And, and I'll be honest with you, I don't remember the dosing on the RTB101. Um, and so they looked at vaccine response, and then they also looked at, in this study, uh, uh, upper respiratory tract infections over the next season to, to look beyond just, you know, if there's an impact of the mTOR inhibitor on immune function. Is it specific to vaccines, or does it look like it's broadly boosting im- immune function? Um, and again, I think you can, you know, you can look at the data and, um, and not be completely convinced, but certainly for the everolimus plus RTB101 and the RTB101 alone group, um, I think the everolimus alone group in this case didn't reach statistical significance. But for the combination and the RTB101 alone group, they saw improved vaccine response, and I think what was really striking was a lower risk of upper respiratory tract infection in the, the people who'd gotten the mTOR inhibitor over the next season. So that suggested that not only is it boosting vaccine response, but it's also broadly conferring protection against a variety of, of immune challenges in this, this older population. Um, and again, very, very little in the way of adverse events, which, which gets back to the point. You know, you hear people talk about how mTOR inhibitors, you know, you could never use them for aging in people 'cause the side effects are so bad, and it, you know, it just gets frustrating over and over and over again to say, "Go read the data. You know, go look at the data, right? That's just not true at the doses that, that, you know, have been tested so far." It's just, that's just blatantly false, right? There's no evidence actually for significant side effects from rapamycin monotherapy, everolimus monotherapy, uh, or RTB101, uh, at the doses that people are talking about using in this context. So, um-

   11. PAPeter Attia1:01:55

       Yeah, I mean, statins have far, far greater side effects-

   12. MKMatt Kaeberlein1:01:59

       I know

   13. PAPeter Attia1:01:59

       ... than rapamycin.

   14. MKMatt Kaeberlein1:02:00

       I, I know.

   15. PAPeter Attia1:02:00

       I mean, and, and it's not even close. And it, you know, I, I think statins are a very important type of drug, but, you know, I mean, to think that, to think how ubiquitous they are and that we accept-

   16. MKMatt Kaeberlein1:02:12

       Yeah

   17. PAPeter Attia1:02:12

       ... hey, 10% of people, I mean, I think the literature says 5%, but really clinically, 10% of people have debilitating muscle aches from statins, um, that, you know, render it impossible to take them. People, some people have elevated liver function tests that are otherwise unexplained. I mean,

9. 1:02:26 – 1:14:44

   Roadblocks to studying gero-protective molecules in humans

   1. PAPeter Attia1:02:26

      um-

   2. MKMatt Kaeberlein1:02:27

      Yeah

   3. PAPeter Attia1:02:27

      ... yeah. It is, it is really frustrating for me to hear this, especially when people talk about how, well, we could never really study rapamycin because, you know, it's just too unsafe. It's like I, I'm not sure what data you're pointing to, but when, when you have it, let me know.

   4. MKMatt Kaeberlein1:02:42

      Yeah. Yeah, I agree. Um, so anyways, uh, so that, so that was the second phase two trial which was successful. Um, so then they went on to a phase three trial to, uh, to hopefully get FDA approval for improving a vaccine response and immune function in, in elderly people. Um, and in that phase three trial, um, I'm trying to remember what they called that-

   5. PAPeter Attia1:03:04

      They think they called it-

   6. MKMatt Kaeberlein1:03:05

      ... that drug. I don't, I-

   7. PAPeter Attia1:03:05

      I don't remember the trial, but, uh, now what was RAD001? What was that agent?

   8. MKMatt Kaeberlein1:03:10

      That's everolimus. That's the same drug.

   9. PAPeter Attia1:03:11

      That's what they were calling everolimus?

   10. MKMatt Kaeberlein1:03:12

       Right.

   11. PAPeter Attia1:03:12

       Okay.

   12. MKMatt Kaeberlein1:03:14

       Yes.

   13. PAPeter Attia1:03:14

       Okay.

   14. MKMatt Kaeberlein1:03:14

       Yeah. And they had a name for the t- all clinical trials have names.

   15. PAPeter Attia1:03:17

       Yeah.

   16. MKMatt Kaeberlein1:03:17

       So they had a name. I, I don't remember what it was.

   17. PAPeter Attia1:03:19

       Yeah.

   18. MKMatt Kaeberlein1:03:19

       But, but in that phase three clinical trial, um, they only tested RTB101. So they, they took out the rapalog, everolimus, and only tested RTB101.

   19. PAPeter Attia1:03:30

       So there was no RAD001 plus RT-

   20. MKMatt Kaeberlein1:03:33

       Right

   21. PAPeter Attia1:03:33

       ... B101. Okay.

   22. MKMatt Kaeberlein1:03:35

       That's right. No combination, no individual, uh, rapalog. That's right. And that clinical trial failed to hit the endpoint, and it was, it was terminated halfway through. So they... This is my understanding. Um, they, they were going to do, uh, uh, one group in the, the fall season and one group in the spring season or something like that, and they got halfway through. They weren't hitting their endpoint, so they terminated the trial early. And, um, and then RTB101, or sorry, Restore Bio was the company that was doing this clinical trial to try to, to move RTB101 through to approval. Um, they, the board basically, um, merged them with a, with a CAR T cell therapy cancer company, and they gave up on, um, RTB101 because of the failed clinical trial. So, you know, why that clinical trial failed, I think still the data has not seen the light of day yet. Um, I don't think, uh, there, yeah, I don't think it's come out yet. So, so we don't know for sure what happened. Um, I think, you know, we can observe that the rapalog wasn't in there anymore, right? That is one difference between the two successful trials and the one that failed. And I believe Joan has talked about this publicly that, that, that they also in conversations with the FDA were required to change the endpoint, um, uh, from laboratory-confirmed infections, right? That, that was the prior, that was the, that was the endpoint, one of the endpoints in the phase two trial, um, to, uh, something else which involved owner-reported symp- or not owner, sorry. Thinking about dog trials here.

   23. PAPeter Attia1:05:12

       [laughs]

   24. MKMatt Kaeberlein1:05:12

       Patient-reported symptoms as the endpoint, and they didn't hit it. And so I think that... I think my understanding from talking to Joan is that data will come out at some point, and, you know, we'll be able to really take a look and, and see, you know, what the drug was doing and, and what it, what it wasn't doing in that third clinical trial. M- my intuition is that it probably worked, and they probably got screwed, um, by being forced to change the, the endpoint of that clinical trial. And if that's the case, then I think, you know, we really do need to have a conversation around the way that FDA... I mean, we need to have this conversation anyway, but the, the way that FDA is approaching clinical trials, um, uh, in the, the, the aging space, right? Um, what, what needs to be shown for a, an appropriate endpoint, and what is the acceptable level of risk when the, uh, the goal of the trial is to test whether or not an intervention is affecting a functional decline that goes along with aging or aging itself, right? And that's a, that's a bigger question. I certainly have plenty of thoughts around that. I know there are lots of people in the field who are thinking about this and working on it, and some have talked to FDA. Um, it's a, it's a real challenge, and I think it, I think that, um, and I don't want to blame anything on FDA, right? I think that they are... The people at FDA want to do their jobs to the best of their ability. I think there are constraints around the way that FDA is required to work, um, and the culture that, um, does not in my view appropriately evaluate risk/reward, right? I think that there is a culture of, you know, the risk has to be extremely low in people who are of normal health status for their age. I actually am trying very hard, I still slip, but I'm trying very hard not to use the word healthy when we talk about aging or older people. I'm relatively healthy for my age. I would say I'm probably in the top 10% health-wise for my age group. I am not as healthy as I was 20 years ago. We already talked about this, right? So I'm of, you know, normal to upper health status for my age. But I would not call a 65-year-old, a typical 65 or 70-year-old healthy. They're not. They're functionally impaired, and we really need, we being, you know, the, the regulators, society, policymakers, you know, really need, I think, to start taking a realistic look at What normal aging is, right? It is a progressive, chronic decline in function that at some point will lead to overt disease and with 100% probability will lead to death, right? And so if, if we can, if we can intervene in that process to slow it down or reverse it, there should be some level of risk that is acceptable for that potential outcome. And I think that because we tend to think of 65, 70-year-olds as healthy as opposed to functionally impaired, it makes it really hard to have a rational discussion around what the appropriate level of risk is.

   25. PAPeter Attia1:08:35

       Matt, I think, I think that is so astonishingly well said, and I've, I've had so many discussions with Nir, um, and to a lesser extent Steve Austad about the choice of metformin over rapamycin in TAME, and it always comes back to this point, which is the regulators will absolutely, positively not consider rapamycin, which of course comes back to this question, which is what are, what are we, what are we claiming to be studying and in whom?

   26. MKMatt Kaeberlein1:09:05

       Yeah.

   27. PAPeter Attia1:09:05

       The other thing is, you know, the studies are being designed around disease, right? Progression of disease or outcomes of disease. So this really comes back to a broader theme, which is where are we on the spectrum of understanding aging in the way that you're defining it and getting it further away from the discrete definition that involves a disease? Because until we really get people to center around that, your very eloquent explanation of there being no such thing as a healthy 70-year-old, um, u-until we realize that at the regulatory level, right, at the policy level-

   28. MKMatt Kaeberlein1:09:49

       Yeah

   29. PAPeter Attia1:09:49

       ... even at the scientific level, it's going to be very difficult to study the things that will have an opportunity to give step function changes in longevity.

   30. MKMatt Kaeberlein1:09:58

       Yeah. So let me, let me start by pushing back on, on what you said about TAME and metformin versus rapamycin, because I, I think that's a myth that regulators would not allow you to do a clinical trial with rapamycin, right? Uh, we just talked about three clinical trials that were done, you know, with mTOR inhibitors, two of which w-with, were with everolimus, right, um, which is essentially rapamycin. So I think that is, um, talked about-
10. 1:14:44 – 1:24:40

    Potential benefits of rapamycin for age-related diseases—periodontal, reproductive function, and more

    1. MKMatt Kaeberlein1:14:44

       improved it. So Restorbio went with immune function, and they, they went with vaccine response initially, and then ultimately, I think in the phase III trial, they were also looking at, um, respiratory tract infections, right, over the next season. That was their endpoint. It's quantitative. The problem is it's really hard, right? It's a really noisy endpoint, and I'm, I'm not at all criticizing them. In fact, I think, you know, a- as you know, Joan Mannick is one of my favorite people. She's a good friend. I have an amazing amount of respect for her. I think they went for it, and for reasons that were probably beyond their control, you know, that clinical trial failed. But I have so much respect for what they tried to do. I'm just saying it's a tough clinical trial. It's a tough endpoint. It's noisy. I, I think there are other endpoints that you could consider that, um, that might not be as noisy, right? That you could consider doing a clinical trial for. So my-- one of my favorites at this, at this moment is, um, periodontal disease, and that's because, you know, my lab has published that in-- that aged mice get periodontal disease, that, um, uh, eight weeks of treatment with rapamycin reverses the clinically defining features of periodontal disease in mice. We know that something like two-thirds of older adults have periodontal disease or will get it, and those who have periodontal disease are at higher risk for dementia, cardiovascular disease, diabetes. So it's connected in some way to other age-related diseases.

    2. PAPeter Attia1:16:10

       A- and, and by the way, uh, in a recent, a recent podcast of mine explored this topic, and, and it, it may in fact be causally related through that inflammatory axis, right? I mean, I think that-

    3. MKMatt Kaeberlein1:16:20

       Absolutely

    4. PAPeter Attia1:16:21

       ... that's probably the strongest line of evidence connecting oral disease with-

    5. MKMatt Kaeberlein1:16:27

       Yeah

    6. PAPeter Attia1:16:27

       ... systemic disease. It's through this immune inflammatory pathway. So I, I think that's actually an elegant, uh, approach.

    7. MKMatt Kaeberlein1:16:34

       So the reason why I like periodontal disease, right, is the endpoints are extremely quantitative, right? So what we looked at in the mice are gingival inflammation, bone around the teeth, which can be measured, you know, crudely by pocket depth, more quantitatively by X-ray, um, and microbiome. That's, that's really the, at least in my understanding... I'm not a dentist, but I've learned a lot about, uh, oral health over the last few years. That's my understanding of, you know, if you have gingival inflammation, you've lost enough bone around the teeth, you don't even have to have the dysregulation of the oral microbiome, but it always goes along with it. You've got periodontal disease, right? So there are nice quantitative endpoints that can be looked at in people, and it's extremely non-invasive, right? The, the way that you do this clinical trial is you have people come in for a, for a dental exam, right? Before and after treatment. So you've got, you've got a shot at seeing quant- changes in quantitative endpoints that we can not just delay, but actually reverse the declines in mice, in people, you know, in a reasonable timeframe. So you could easily imagine something similar to the, the structure of the Restorbio trial with rapamycin or everolimus or RTB 101 or, you know, pick your favorite intervention, where you treat people for eight weeks, three months. You know, they have a dental exam before, a dental exam after, a dental exam six months later, and you just look and see what was the, what was the impact of the, the intervention. Um, so it's a pretty straightforward clinical trial. And I, you know, I think we're gonna... I, I hope we will get this off the ground. We're actually trying to get some funding to do a clinical trial now. Um, this is, this is, I should say-

    8. PAPeter Attia1:18:11

       In, in humans-

    9. MKMatt Kaeberlein1:18:12

       This is, uh-

    10. PAPeter Attia1:18:12

        ... or in dogs?

    11. MKMatt Kaeberlein1:18:13

        In people. Yeah.

    12. PAPeter Attia1:18:14

        Okay.

    13. MKMatt Kaeberlein1:18:14

        In people. And this is, this is really... The person who deserves all the credit for, for m- this crystallizing in my mind is a, a, a, a gentleman named Jonathan Ahn, who was a, a DDS PhD student. So, so he had already got his dental degree. He did his PhD with me. And he, you know, before he came to my lab, he came to me one, one day, um, I vividly remember this conversation because I had never thought about oral health. And he goes, "You know, people get periodontal disease when they get older in much the same way that people get Alzheimer's disease or heart disease. If you look at the risk profile as a function of age, it looks strikingly similar to these other age-related diseases. You know, what do you think? Maybe the biology of aging is contributing." And, you know, in hindsight, it's like, oh yeah, that makes a lot of sense, but I had never thought about that before. And so he came to my lab and showed that we could do this in mice. We could, we could see age-related periodontal disease. We could see bone loss around the teeth. We could see inflammation of the gums, and that we could reverse that with rapamycin. And so he's actually now a faculty member, um, at the University of Washington, and he's really the one who's trying to push this clinical trial forward. So, so I'm sort of peripherally involved, but Jon is really the guy in this space. He's gonna be a rock star.

    14. PAPeter Attia1:19:26

        And this would be a phase II?

    15. MKMatt Kaeberlein1:19:28

        Yes. Right.

    16. PAPeter Attia1:19:29

        What's the approximate budget for this study?

    17. MKMatt Kaeberlein1:19:31

        If it gets funded. I mean, we're, we're, we're just submitting the grant now, so I don't know. You know, it's very early, right?

    18. PAPeter Attia1:19:35

        What, what would be the budget for this study?

    19. MKMatt Kaeberlein1:19:37

        Uh, so it's gonna be a three-year grant. I, you know, I don't know. It's, I think it's R01 size, couple hundred thousand a year, uh, over three years.

    20. PAPeter Attia1:19:45

        Okay. If money were no object, what secondary endpoints would you add to that study? In other words, if you could power this study to hit that as your primary, but also go after multiple secondaries, let's just throw in immune function. There'd be no reason not to repeat what was done with, uh, RAD001. What else would you add to that?

    21. MKMatt Kaeberlein1:20:06

        Right. So if you look at the mouse data, I mean, I think, I think the mouse data is, uh, uh, it's a reasonable place to start. Again, obviously mice aren't people, but it's a reasonable place to start. So where does rapamycin reverse functional declines associated with aging?

    22. PAPeter Attia1:20:22

        Hearing, right? Wasn't there that study-

    23. MKMatt Kaeberlein1:20:25

        Yes. Right

    24. PAPeter Attia1:20:25

        ... that just came out?

    25. MKMatt Kaeberlein1:20:25

        There's a, there's a paper... Right.

    26. PAPeter Attia1:20:26

        Yeah, just came out two weeks ago.

    27. MKMatt Kaeberlein1:20:28

        Yeah, yeah. Absolutely. Right

    28. PAPeter Attia1:20:28

        It reversed age-related hearing loss, which I, I... That was, that got me very excited.

    29. MKMatt Kaeberlein1:20:33

        Yeah, I agree. So that, and that's again a very easy and quantitative endpoint, right?

    30. PAPeter Attia1:20:38

        Yep.
11. 1:24:40 – 1:32:38

    Debating the ideal length and frequency of rapamycin treatment for various indications like inflammation and longevity

    1. MKMatt Kaeberlein1:24:40

       Look and see whether or not you get, you get an improvement, uh, in outcome using that functional measure. I, I, I would... I mean, it, you know-

    2. PAPeter Attia1:24:49

       Now, why the eight weeks?

    3. MKMatt Kaeberlein1:24:49

       I think that's the way I would say-

    4. PAPeter Attia1:24:50

       Do we, do we really believe that that would be a sufficient amount of time? I mean, we're... Are we just coming up with eight weeks because that's where we saw the vaccine response, uh, on, in the everolimus trial? Like, uh, or do we think we... You know, if you were-

    5. MKMatt Kaeberlein1:25:02

       Yeah

    6. PAPeter Attia1:25:02

       ... if you were shooting for the moon-

    7. MKMatt Kaeberlein1:25:03

       Yeah

    8. PAPeter Attia1:25:03

       ... and cost were not an issue, what would be the downside of longer treatment?

    9. MKMatt Kaeberlein1:25:07

       Well, a, a couple things, right? So, so one is, uh, increased risk of side effects, right? I mean, I think that's, that's, that's one... The, the longer you go with any treatment, the more risk there is for, for an adverse event, even though I think the risks are pretty low. Um, and the other is I think... So, so with the... Here's a, here's a really interesting piece of data that we don't have with the immune function studies in, in mice or people. In all of those studies, the treatment was stopped.

    10. PAPeter Attia1:25:33

        That's right.

    11. MKMatt Kaeberlein1:25:34

        And then there was a two-week or so period before the, the vaccine was given.

    12. PAPeter Attia1:25:38

        So what was the rationale for that washout?

    13. MKMatt Kaeberlein1:25:40

        I think it's because people think and thought about rapamycin as an immu- immune suppressant, right? So that you might, if it... So and this is where I was going with that. What we don't know is if they were still taking the drug, would you have gotten the same effects for immune function? I, I don't know. So, so it's an important question that I think we just don't know the answer to, but the other risk is that for, at least for some of your f- your functional measures, if it requires, let's say, hyperactivation of mTOR to get the, the response Um, you might impair that by doing continued treatment with rapamycin. And at least all of the data that I've seen, limited in people, extensive in mice, uh, eight weeks is enough to give you essentially that full benefit for whatever the functional out- output is that you're looking at. Maybe not for lifespan, right? Maybe you, maybe, maybe multiple eight-week, you know, transient interventions would be better than one. On- only thing that I know of for data there is our study where we did three months, right, of rapamycin treatment between 20 and 23 months of age, and then let them go to the end of life. The magnitude of effect was pretty similar to what the ITP saw. So it was, it was reasonably close to continuing, um, treatment, but we don't know.

    14. PAPeter Attia1:26:53

        But eight weeks in mice is, you know, what would that be in humans, right?

    15. MKMatt Kaeberlein1:26:57

        Yeah, I know where you're going with that, right? If, yeah, if you were to linearly extrapolate that, that would be a few years, right, in people.

    16. PAPeter Attia1:27:01

        Yeah.

    17. MKMatt Kaeberlein1:27:02

        Um, and I agree with that. I think that the, the, the immune, uh, phys- the immune trials, uh, that we've talked about suggest that that might be long enough, um, but I agree. We don't know, we don't know is the answer. I, I'll just say, so I haven't talked about, you know, my experience with rapamycin, and I, and I really don't talk about this publicly, but I'll do it here. Um, so, uh, so I've, I've tried, uh, eight to 10-week courses of rapamycin a couple of times. Um, the most recent time, it was because this was probably spring of 2019. So I, I'm pretty active. I play softball in the spring. Um, and I noticed I had a lot of shoulder pain, and, and by the end of the season, it was to the point where I, I couldn't throw a football. Like, I couldn't go play catch with my son. Actually, that's one of the hardest, uh, uh, personal sort of aging experiences I had, was when we went across the street to the park, and I was gonna, gonna, gonna play catch with my son, and I couldn't do it 'cause my shoulder hurt so much. It was my right shoulder. And I thought, "I must have a rotator cuff tear." I, I went in to see the specialist. Finally got diagnosed, uh, uh, with, uh, frozen shoulder, which is inflammation of the shoulder capsule, which happens to people as they, some people as they get older. Extremely painful, completely limited my range of motion, and the, the doctor was like, "Well, I could give you a shot of cortisol, but I don't really recommend it. That can, that can degrade the cartilage. Really, there's not a lot you can do. Some people, it goes away after a year. Some people just, you just learn to live with it." And I was pretty depressed by [laughs] that diagnosis, right? I was like, at least if it was a rotator cuff tear, I could get surgery, get it fixed. So I go home, and I'm sitting there, and I'm think- and so I'm looking on the internet, and I see, okay, it's an inflammation of the shoulder capsule. I'm thinking to myself, "What do I know that has anti-inflammatory effects, you know, in the context of aging," right? Rapamycin. So I, so I got some rapamycin, and I did eight weeks. And, and I mean, again, placebo effect is real, but this was so painful, I don't believe it was placebo effect. Within two weeks, I had probably half my range of motion back. Within eight weeks, uh, I was back a hundred, 95%.

    18. PAPeter Attia1:29:06

        And were you just taking, were you just dosing once a week?

    19. MKMatt Kaeberlein1:29:09

        Once a week. Eight mgs once a week, yeah. I mean, I, I, I, I couldn't do this two years ago, right? 'Cause it hurt so much, right?

    20. PAPeter Attia1:29:17

        Mm-hmm.

    21. MKMatt Kaeberlein1:29:17

        Um, and now it doesn't hurt at all. Within eight weeks of... And I, and I, and I wanna be careful 'cause I wanna say I'm not encouraging other people to go do this, but I am a true believer after that experience, right? I don't think it's placebo effect. I don't see how it could be with how painful it was, how real the limitations were on range of motion. So that goes to this eight-week question. At least for that indication, which I believe this was a real effect, eight weeks was plenty, and it hasn't come back, right? Which actually kinda makes sense with frozen shoulder. I think when, when people recover from it, it doesn't-

    22. PAPeter Attia1:29:49

        Mm-hmm

    23. MKMatt Kaeberlein1:29:50

        ... always come back. So I think that, again, a lot of these age-related conditions that are inflammatory driven, you can kind of reset that with, uh, an eight-week treatment, and, and rapamycin. I suspect senolytics, if we had good senolytics, would do pretty much the same thing.

    24. PAPeter Attia1:30:09

        Do you think that rapamycin is itself a senolytic?

    25. MKMatt Kaeberlein1:30:12

        I don't think it's a senolytic in the sense that it, that it, uh, at least the classical way people have thought about senolytics, where it kills the senescent cell.

    26. PAPeter Attia1:30:19

        Right.

    27. MKMatt Kaeberlein1:30:20

        I absolutely think it turns down the chronic inflammatory signaling that is driven by p16, p21, NF-kappa B. Yes, we see that in mice, multiple tissues, no question about it. I also, you know, I still think the senescence field is a little bit messy in the terminology. I think a lot of what people call senescence isn't truly being derived from senescent cells the way that we think about them. It's p16, p21 mediated inflammatory cytokines, right? Doesn't necessarily have to come from senescent cells. No question, rapamycin shuts that off, and it shuts it off within eight weeks, at least in mice, in a lot of tissues.

    28. PAPeter Attia1:31:01

        And do you think it's doing that independent of what it's doing at the mTOR, or, uh, do you think that it's doing that through mTOR?

    29. MKMatt Kaeberlein1:31:09

        I would be shocked if it's not doing that through mTOR. I don't know of any good evidence that rapamycin has off-target effects that aren't through mTOR.

    30. PAPeter Attia1:31:16

        Yeah, okay. And so, so really, it's these SASPs getting whacked that is how it would act through, uh, via the senescent pathway, as opposed to targeting a senescent cell directly. But that's, by the way, that's been my reading of the literature.
12. 1:32:38 – 1:41:05

    Biomarkers of aging and epigenetic clocks

    1. PAPeter Attia1:32:38

       I, I, you know, I think two and a half years ago when I started, I was very strict about eight on, six off, eight on, six off, eight on, six off. And I don't know, a little while ago, I just sort of said, "Yeah, I'm just not coming off."

    2. MKMatt Kaeberlein1:32:52

       [laughs]

    3. PAPeter Attia1:32:53

       And I wish I had a biomarker to point to. I wish I had some-

    4. MKMatt Kaeberlein1:32:58

       Yeah

    5. PAPeter Attia1:32:58

       ... way of measuring whether this is the right thing to do or if there's a, or if, you know, eight, four, eight, four, eight, four.

    6. MKMatt Kaeberlein1:33:06

       Right.

    7. PAPeter Attia1:33:06

       Um, there's a symmetry to eight, five 'cause you'll get through exactly four cycles a year. Maybe I do eight, five, eight, five, eight, five, eight, five. Um, but it really frustrates me that we don't have a biomarker for this.

    8. MKMatt Kaeberlein1:33:18

       Yeah, or, or aging in general. Yeah, I mean-

    9. PAPeter Attia1:33:20

       Or for aging in general. So let, let's talk a little bit about that.

    10. MKMatt Kaeberlein1:33:22

        Yeah.

    11. PAPeter Attia1:33:22

        So what does, what does that look like? I mean, when I had Eileen White on the podcast, uh, gosh, it's been, phew, maybe a year and a half now. We had a really interesting discussion about why we don't even have biomarkers for autophagy. I mean, something that is so important-

    12. MKMatt Kaeberlein1:33:37

        Yeah

    13. PAPeter Attia1:33:38

        ... and we can't measure it. And this was important in the context of people who choose to calorically restrict or fast. Um-

    14. MKMatt Kaeberlein1:33:45

        Right

    15. PAPeter Attia1:33:46

        ... you know, is fasting for a day long enough to generate a meaningful amount of autophagy in a human? In a mouse it clearly is, but in a human, is it? No idea. Is-

    16. MKMatt Kaeberlein1:33:57

        Right

    17. PAPeter Attia1:33:57

        ... two days, three days, seven days? You know, seven days is almost assuredly enough. There's a big difference between fasting for a day and fasting for seven days.

    18. MKMatt Kaeberlein1:34:05

        Yeah.

    19. PAPeter Attia1:34:05

        Why don't we have biomarkers for that? Why don't we have a biomarker that can assess nutrient sensing better? Why don't we have a... You know, I mean, you could argue we have some biomarkers. We can measure telomere length, but, you know, you know my feelings on this, Matt. I'm in the camp that thinks measuring telomere length is not helpful at all for aging. And I think there's plenty of data to suggest that while telomere length is a very important marker of cellular division, it really speaks very little about the orgas- the organism's state of aging, um, despite the popularity of that, that biomarker.

    20. MKMatt Kaeberlein1:34:36

        Right.

    21. PAPeter Attia1:34:37

        Um, even the epigenetic clocks I don't find to be helpful. I find them to be far too... And I'd like you to push back on this if, if you feel as much. Um, but I, I've seen how easily they can be manipulated by short-term interventions that don't seem biologically relevant.

    22. MKMatt Kaeberlein1:34:51

        Yeah. So I, I think I'll start with the epigenetic clock 'cause everybody... That, that's a big-

    23. PAPeter Attia1:34:56

        Yeah. Let's-

    24. MKMatt Kaeberlein1:34:56

        ... you know-

    25. PAPeter Attia1:34:56

        Let's explain to people what that is

    26. MKMatt Kaeberlein1:34:57

        ... uh, area of interest in the field. But-

    27. PAPeter Attia1:34:58

        Let's, let's, let's start from the beginning. Assume people don't know what an epigenetic clock is.

    28. MKMatt Kaeberlein1:35:01

        Right. So, so the epigenetic clock refers to, um, typically chemical marks on DNA that regulate, uh, gene expression, whether or not, you know, the gene that is located at specific points in your genome gets turned on or, or off. And what has been observed is that those marks change with age in pretty much every organism where it's been studied, and that you can identify patterns of change at specific locations in the genome, so specific changes in these chemical marks with age that correlate very, uh, strongly with chronological age. And, and so that has led to the idea that you can create clocks that look at specific changes in chemical marks in the, the DNA, the genome, that are, um, telling you something about how long that, that organism has been alive. Um, and then what sort of has emerged from that is that there may be... You've... There are two things that have emerged from that. One is you may be able to use that chronological aging clock to find individuals whose marks don't fall on the line that you would expect it to fall on based on their chronological age. In other words, you know, they have marks that make them look older or younger than their chronological age says that they are. And so you might, you would hypothesize that those individuals biologically, if those marks are really reflecting biological age, might be aging more slowly or more quickly. And what's been shown is that indeed, those individuals who tend to be off the line, depending on whether they seem to be aging more slowly or more quickly, are at lower or higher risk for specific diseases. So that adds some level of confidence that this epigenetic clock, chronological epigenetic aging clock, is actually reflecting biological age. And so the idea is maybe we can use that information to develop epigenetic clocks that will, that will, in a predictive way, tell you how old you are biologically, right? So you can get tests now. There are plenty of companies now that are selling these things where you can go buy your epigenetic blood test. Mostly this has been done in blood cells. That's one limitation to think about, is almost all of the literature in humans is developed on epigenetic clocks from blood, and it's, and it's still I think a little bit of a question, you know, what... If the, even if this is reflecting biological age, it's the biological age of your blood, which may or may not reflect the biological age of your entire body. Um, but you can buy tests now that based on your, you give them some of your blood, they will tell you your epigenetic biological age or some number.

    29. PAPeter Attia1:37:42

        So they're, they're looking at, uh, PBMC, I assume?

    30. MKMatt Kaeberlein1:37:45

        I don't know, honestly. I'm not, I'm not involved in any of this stuff.
13. 1:41:05 – 1:47:28

    Prospects of a test that could calculate biological age

    1. MKMatt Kaeberlein1:41:05

       I also think, though, this gets to the fundamental challenge with biomarkers, and I think this is where you're dissatisfied. Um, we have a lot of biomarkers of aging. We just don't have any validated biomarkers [laughs] of aging, right? And it's, and it's a, it's a real... This has been a problem, you know, since I was a graduate student. Um, everybody's wanted biomarkers of aging. The, the NIA had a huge program where they f- they did all this funding to identify biomarkers of aging. I think it was back in the '80s.

    2. PAPeter Attia1:41:33

       Right, right.

    3. MKMatt Kaeberlein1:41:34

       Maybe. Um, before my time. '90s maybe. Um, the, you can identify all sorts of things that correlate with age. How do you get to the point of convincing yourself first, and other people second, that these things are actually telling you something about biological aging that can then be used to understand whether an intervention is working, first of all, at the population level, but ultimately where we want to get to is at the individual level, right? So what we all want is a test that you can take, and you can fast, you can do your fasting regimen, you can do your rapamycin, you can take metformin, whatever, and you can come back and find out is it working from this set of biomarkers? And, and that's where we want to get to, and, and we're not there yet, I think everyone would agree. Uh, I'm not sure when we're gonna get there. Um-

    4. PAPeter Attia1:42:27

       So who's the natural owner of getting there? 'Cause, you know, I had this discussion with Steve-

    5. MKMatt Kaeberlein1:42:31

       Yeah

    6. PAPeter Attia1:42:31

       ... Austad recently, and, and he, he made the same point you did, which is, look, the NIA tried to do this a long time ago and, and, and tried, you know, validly, right? They put a lot of money into it. You could make the case that the technology simply wasn't mature enough to do this. 30, 30 years later, we have a lot more tools at our disposal, right? It's, it's-

    7. MKMatt Kaeberlein1:42:52

       Yeah

    8. PAPeter Attia1:42:52

       ... you've got, you've got the entire world of omics at your disposable, plus you've got machine learning, plus, plus-

    9. MKMatt Kaeberlein1:42:58

       Yep

    10. PAPeter Attia1:42:59

        ... plus. Um, is there any reason this couldn't be done today? And if so, is this... This strikes me as a project that's almost too big for, for academics, right? 'Cause it's too disjointed. But at the same time, it's not a particularly interesting, um, commercial problem to solve because it's far too big an investment before you could get to why you would care about it, right? A commercial problem is, "Give me a drug."

    11. MKMatt Kaeberlein1:43:24

        Yeah.

    12. PAPeter Attia1:43:25

        But I'm arguing you can't develop a drug really well without this. So who's... Like, there's a bit of a, a, a cart and a horse thing, which is someone's got to pony up a lot of money to develop the foundation of a pyramid that will ultimately become a great tool for drug discovery and, um, a much more streamlined manner in which we could do clinical trials around this.

    13. MKMatt Kaeberlein1:43:49

        Yeah. So, so I think it, I think the answer to your question is it depends on whether you're talking about doing this preclinically or clinically, right? I, I actually think this is a problem that is-

    14. PAPeter Attia1:43:59

        Don't you think it has to be done both?

    15. MKMatt Kaeberlein1:44:02

        Uh, well, eventually, yes. It's, it's, it's a problem that can be solved today preclinically. Like, there is no real barrier to doing what you just said. So multi-omic analysis of aging in mice-

    16. PAPeter Attia1:44:14

        Right

    17. MKMatt Kaeberlein1:44:14

        ... with interventions, applying machine learning to identify patterns that predict the effect of interventions and individual outcomes for longevity. You obviously have to think a little bit about, you know, what, what can you measure? Um, if you want to do this longitudinally, right, you can't kill the, the animals, right? [laughs] Uh, um, so you could, you're sort of restricted to blood. But, but so there are some practical aspects, but there's no, there's no technical barrier to, to doing that now. Who should do it? Who might be doing it, right? Um, I mean, I think this would fall maybe in the realm of what Calico could do. Right? They've got the resources, they've got the expertise

    18. PAPeter Attia1:44:55

        Is there any evidence that Calico is interested in this type of a problem?

    19. MKMatt Kaeberlein1:44:59

        Um, I think so. I, I don't, I don't know. I don't, honestly don't know anything about the inner workings of, of Calico these days. Um, I think conceptually they are interested in, in multi-omics signatures of different aging processes. I don't know if they've done this particular ex- experiment. They certainly have the resources and expertise to do it. Um, they're not the only ones, but they're the first ones who come to mind, and they sort of fit this space between true academia and industry, right?

    20. PAPeter Attia1:45:27

        Yeah.

    21. MKMatt Kaeberlein1:45:27

        Where they're kind of, they're kind of this interesting beast in the middle. Um, so I think it could be done preclinically and you could actually then, once you... Let's just say you have this test, right? You get to the end of day, you say, "Okay, these are the most predictive," I don't know, whatever, "24 things that, that give you, you know, 95% confidence on remaining life," right? Or whatever.

    22. PAPeter Attia1:45:49

        Yep.

    23. MKMatt Kaeberlein1:45:49

        Whatever your endpoint is. Um, then you, you get that test, and then you show whether it works or not in an independent study. And if it does, I'd be pretty convinced, right? If you can show me that you create this test, and then you go do a separate experiment, and you can predict when the mice are six months old how long they're gonna live at an individual level, I'm impressed. And if you can show that this intervention, when you treat them, makes the signature go in the way that you think it should go, and you can predict they're gonna live 30% longer, I'm even more impressed. I'll believe it at that point. That's not easy, but I think it's doable. I think we know enough now, and we've got enough things that we could measure that, that you could certainly, you could certainly build the test, and then whether it would work in the validation step or not, I don't know. But I wouldn't... I, I, I think you could probably get it to work. Um, you can't take exactly that same approach to people.

    24. PAPeter Attia1:46:38

        Right.

    25. MKMatt Kaeberlein1:46:38

        And this gets back to that, that, [chuckles] you know, the same issue that we talked about with clinical trials, right? Takes a long time to do the validation step and know that you have actually changed somebody's biological state so that as they get older, they are at lower risk for disease and are likely to live some X percent longer. So you're almost obligated to have some level... You, you have to have some level of faith in the test at that point, right? And I don't know. It's gonna be different for everybody, and I honestly don't know what the regulatory step has to be, right, before you could convince regulators that you can actually, you know, go out and tell the general public that this test works. Although, I will say, there are already people doing that, and the regulators aren't doing anything about it as far as I can tell. So,

14. 1:47:28 – 2:05:00

    The Dog Aging Project testing rapamycin in pet dogs

    1. MKMatt Kaeberlein1:47:28

       you know, there you are.

    2. PAPeter Attia1:47:29

       Let's come back to your dogs. We spoke about them at length, um, three years ago when we sat down to, to talk about rapamycin. But again, let's assume a clean slate, and folks might not be familiar with some of your work specifically around dogs and how-

    3. MKMatt Kaeberlein1:47:46

       Sure

    4. PAPeter Attia1:47:46

       ... working with companion dogs, uh, offers many advantages over working in mice, beginning with some of the obvious, like they're far more genetically similar to us. They live in our environment. Um-

    5. MKMatt Kaeberlein1:47:58

       Right

    6. PAPeter Attia1:47:59

       ... and, you know, they also seem to, to die of things that more closely replicate how we die. They die of heart failure. They die of cancer, but not the same type of cancer that a mouse gets that's almost genetically predetermined.

    7. MKMatt Kaeberlein1:48:13

       Yeah. So, um, so just to start from ground zero, uh, we, um, at the University of Washington and Texas A&M and at, and at several other institutions have a large project called the Dog Aging Project. And so the, the goal of the Dog Aging Project, um, is really to understand the biology of aging in companion dogs or pet dogs. Some people... When I say companion, some people think I mean, you know, like, like-

    8. PAPeter Attia1:48:41

       Seeing eye dogs

    9. MKMatt Kaeberlein1:48:41

       ... seeing eye dogs or things like that.

    10. PAPeter Attia1:48:42

        Yeah, yeah.

    11. MKMatt Kaeberlein1:48:42

        Yeah, no, but it's pet dogs. Um, and there are really two aspects of this project. One is a large scale longitudinal study of aging, completely observational. The goal there is really just to understand what are the most important genetic and environmental factors that influence healthy aging in dogs. And part of that, this is getting back to the conversation we just had, is to measure as much as we can about those dogs every year as they go through their lives, um, in order to be able to identify patterns, right, that are associated with health outcomes during aging, lifespan, disease incidence. Um, so it, in some respects, it's a similar approach as to what you would do if you wanted to create biomarkers of, of aging, right? Um, so that's the longitudinal study of aging. The second goal, and that, that... So one way to think about that is that's to try to understand aging in dogs. The second goal, and this is really where I'm, you know, focused, uh, uh, largely, is to do something about it. So can we slow or reverse biological aging in pet dogs to increase healthy lifespan? And so that, um, ultimately, I hope, will be a series of veterinary clinical trials to test interventions to figure out, can we slow aging, reduce disease, and increase lifespan in pet dogs? The first clinical trial is with rapamycin. Um, and so that's our first shot on goal, uh, but I hope it won't be the only one. Um, and so you talked about, so why, why dogs? Why pet dogs in particular? And I think you hit on, I think, most of the, the most important, um, reasons, right? So they've got this really interesting and powerful genetic architecture. We have a couple hundred purebred breeds of dogs, which you can almost think of as inbred strains, right? And then on top of that, we have this mixed breed population. Um, and that's coupled with, with phenotypic diversity. So for almost any trait that you think about, dogs are more diverse than people are even. Body size is a really easy one.

    12. PAPeter Attia1:50:45

        Mm-hmm.

    13. MKMatt Kaeberlein1:50:45

        Everybody can just think about the difference between a Great Dane and a Chihuahua. Um, so that combination of, of unique genetic architecture with, with phenotypic diversity is really powerful for mapping genotype onto specific traits. And lifespan is another case where you have this strong diversity, right? A, a Great Dane will grow old and die, you know, maybe in eight to 10 years, uh, whereas a Chihuahua often will live to be 16, 17 years old. So, you know, we're talking 100% difference in lifespan. Um, so that, so, so that's really powerful for mapping genotype onto lifespan. Uh, dogs share the human environment is, is another big one, right? And that's, that's for me, one of the most important because we cannot model that in the laboratory. In fact, we do exactly the opposite. We really try to limit variation in environment to extreme measures. Dogs share our environment, with the exception of diet, share almost all aspects of the, of the human environment, and so that's a, a bridge in some ways between laboratory studies and, and human studies. And as I've already alluded to, they age more rapidly than we do. Their lifespan is substantially shorter. We all are familiar with the idea of one human year is about seven dog years, right? That's just another way of saying dogs age about seven times faster than people do. Um, that's... A- and we can talk about that. It's interesting. If you actually look at the epigenetic clock, it's not a linear-

    14. PAPeter Attia1:52:13

        Yeah

    15. MKMatt Kaeberlein1:52:13

        ... seven time rate, but, but they, but I think it's close enough, right? It's close enough. Uh, and as you suggested, they age very similarly to the way that people do. They get essentially all of the same age-related diseases, and they're all age-related, and they show the same functional declines that people do. So dogs get arthritis as they get older, right? Uh, you, you know, and arthritis is, I guess it's a disease, but it's also starts as a functional decline, right? Anybody who's ever had an old dog, you will notice that your old dog doesn't move around as much, doesn't walk as fast, right? So, so, so they are going through the same changes with aging at the functional level that, that we are. Again, it just happens seven to 10 times more quickly. So they're a very powerful animal in which to understand aging and test interventions for that reason, and you can do it in a timeframe that's, that's, you know, feasible. That's ag- I think, you know, we've talked about the challenges with doing a, a clinical trial for lifespan in people. Even if we believe metformin is gonna extend lifespan in people, you're not gonna do a clinical trial to prove that. You can do that clinical trial in dogs, and so we've designed the, the rapamycin, the test of rapamycin in aging dogs or TRIAD, that's, that's what we call our clinical trial. We've designed TRIAD so that we'll be able, we'll be powered, statistically powered to detect a 15% change in, in lifespan within a three-year window, right? So we can do a three-year clinical trial, reasonable cohort sizes to see an effect on lifespan that's comparable to what rapamycin does in mice.

    16. PAPeter Attia1:53:46

        That's a pretty high bar, Matt. That's, um, are you at all worried you've underpowered that given that you only have, um... And, and, and they're being administered the drug for the entire three years?

    17. MKMatt Kaeberlein1:53:59

        No. Uh, so, so yes, uh, yes, I'm worried that the study is underpowered. Um, I will say, uh, from my experience now, we've done two safety clinical trials, and this is our big clinical trial, so this is my third veterinary clinical trial. I've learned that there are many reasons to be concerned [chuckles] when you do a clinical trial. Clinical trials are a lot of guesswork. You have to take an educated guess about a lot of different things. You can't test every dose. You can't test every duration. You're, you know, you can't test, you know, an, an infinite number of study subjects. So I'm, I'm worried about this clinical trial for many reasons. Um, I think we've done the best that we can, you know, given what we know and given the constraints that we have to work under to give ourselves a reasonable shot. 15% might be a high bar, uh, but it, you know, it's, it's consistent with the lower end of what people see in mice. So the first study at the low, low dose of rapamycin in mice from the ITP had a 14% effect, I think, in females and a 9% effect in, in males. Subsequent studies at higher doses had larger effects. So-

    18. PAPeter Attia1:55:09

        Do you expect to see a sex difference in dogs?

    19. MKMatt Kaeberlein1:55:12

        I don't know. I don't know. Um, so people still don't completely understand why female mice seems to respond to a given dose of rapamycin better than male mice. So it's correlated with blood levels, so I think the simple idea is that, that male mice, uh, either take up rapamycin less effectively or break it down more quickly. Um, there's no evidence for that in dogs. We will be measuring rapamycin levels in the dogs, so we will see if there is a difference in blood, uh, concentration in females versus males. From the limited data that we've got so far, we don't have any evidence that that's the case in dogs, and I don't know of any evidence in people that that's the, the case either. So that might be a mouse specific thing. I think there's this misperception, uh, that rapamycin, you know, works better in female mice than in male mice. That's not true. At a given dose, especially at a lower doses-

    20. PAPeter Attia1:56:07

        At a given plasma dose, we don't know if it's true, right?

    21. MKMatt Kaeberlein1:56:11

        Or, no, no, gi- given dose in the food-

    22. PAPeter Attia1:56:13

        Yeah

    23. MKMatt Kaeberlein1:56:13

        ... at lower doses, females show a bigger lifespan extension. When you go to higher doses, the males catch up, and if you push it too far, you can actually find a dose where female mice, the lifespan extension starts to go back the other direction, and male mice actually get a bigger lifespan extension. So I think it's more about effective concentration-

    24. PAPeter Attia1:56:32

        Yeah

    25. MKMatt Kaeberlein1:56:32

        ... than it is a, a male versus female, um, truly sex specific response.

    26. PAPeter Attia1:56:37

        And in the dogs, you give it daily in their food?

    27. MKMatt Kaeberlein1:56:41

        No. No. So it's once a week.

    28. PAPeter Attia1:56:43

        Okay.

    29. MKMatt Kaeberlein1:56:43

        So this is a now, now, you know- [chuckles]

    30. PAPeter Attia1:56:45

        Mm-hmm
15. 2:05:00 – 2:16:53

    The role of the mTOR complexes

    1. PAPeter Attia2:05:01

       Explain to people, um, 'cause we, we, we just mentioned it briefly and then said we'd come back to it. Now we're gonna sort of bifurcate mTOR into mTOR complex one, mTOR complex two. Give people a sense of how those function and why it, on the one hand, is leading you to do what you're doing, me to do what I'm doing, um, and why in some ways it makes it a little bit interesting why the ITP found what it did with daily dosing. Let's tie all of that together, but first with an explanation of how mTOR works.

    2. MKMatt Kaeberlein2:05:33

       Sure. So, so mTOR, of course, is a protein. It's a kinase. We already talked about that. Um, but it acts in a complex with other partner proteins. Um, and, and so, uh, the mTOR protein, um, acts in at least two, I think there's only two that we know of, uh, two different complexes called mTOR complex one, or mTORC1, and mTOR complex two, or mTORC2, and the difference between those, those complexes is that they have different partner proteins for mTOR. So there are a couple of things that are the same across both complexes, and then there are a set of partner proteins that are unique, and the two complexes do functionally different things in the cell. Um, so mTOR complex one, you know, is largely thought of as the, the mTOR complex that is most responsive to nutrient levels. So when nutrient signals, uh, are low, that leads to lower mTOR complex one activity, and mTOR complex one downstream, um, is known to regulate things like autophagy, uh, mRNA translation, effects on metabolism. Um, uh, and mTOR complex two does different things, and I think we know a lot about what mTOR complex one does. We know much less about what mTOR complex two does, although people are, are studying that and, and learning more and more about what mTOR complex two does. From the perspective of aging biology, people have focused almost exclusively on mTOR complex one. There's a little bit of data in C elegans on mTOR complex two affecting lifespan, but outside of C elegans, almost all of this, the data for rapamycin or mTOR as a regulator of aging, uh, is thought to be mediated by inhibition or reduced signaling through mTOR complex one. So that's what people almost always think about when they think about effects of mTOR on aging. And rapamycin, as a drug, biochemically is a specific inhibitor of mTOR complex one. So the way rapamycin works is it actually, it's a small molecule that binds to another protein called FKBP12 or FPR1 in yeast, and once rapamycin binds to FKBP12, that complex of rapamycin with FKBP12 goes to mTOR complex one, and you can think of it as sort of just messing it up, breaks it apart. So it inhibits mTOR complex one when rapamycin is bind to FKBP12. So biochemically, rapamycin is an extremely clean drug in that as far as I know, and, and I haven't really seen any good data otherwise, there's no direct inhibitory effect of rapamycin on anything other than m- mTOR complex one. What people have observed is that chronic long-term inhibition of mTOR complex one can have feedback effects on mTOR complex two, and it's kind of confusing, 'cause there's actually some data both directions, that, that chronic inhibition of mTOR complex one can lead to activation of mTOR complex two in some context. Mostly I think the data supports the idea that chronic inhibition of mTOR complex one with rapamycin can lead to inhibition of mTOR complex two in the long term. Um, and that's definitely true in mice at higher doses of rapamycin. At lower doses of rapamycin, it's, it's not completely clear to me how, how much, uh, effect on mTOR complex two there is. So, so the reason why that's interesting from the perspective of aging is I, I, I just said that almost all of the data for lifespan at least is that it's inhibition of mTOR complex one that leads to lifespan extension. Work from David Sabatini and Dudley Lamming when he was in David's lab, um, led to the development of a model which, which I think is still the, the sort of preferred model. I will say upfront, I, I, I think it's At least partly wrong, but it's the preferred model, which is that the side effects associated with rapamycin, particularly the metabolic side effects associated with rapamycin, are due to this chronic, uh, effect of inhibiting mTOR complex 2. So people will talk about rapamycin as if it induces a, a something like diabetes, a pseudo-diabetes. Um, and this is true in mice. There's evidence for it in humans as well, that, that chronic longterm treatment with rapamycin leads to, um, glucose intolerance. So if you give a mouse who's been on rapamycin for, you know, a year a glucose tolerance test, they will not clear that glucose as rapidly as a mouse that never saw rapamycin. Um, and the model is that that's due to the chronic effects of rapamycin on mTOR complex 2. Most of the evidence in support of that model comes from genetic experiments with, with mTOR complex 2-deficient mice, so I have yet to see a really clean experiment showing that, that that's, that that's what accounts for the rapamycin effects, uh, on glucose tolerance. I think it's a reasonable model.

    3. PAPeter Attia2:10:32

       In, in other words, the, that evidence comes from creating genetic mice where you manipulate mTORC1 and mTORC2 rather than-

    4. MKMatt Kaeberlein2:10:40

       Right

    5. PAPeter Attia2:10:40

       ... experiments where you give them, give the mice rapamycin. Uh, you know-

    6. MKMatt Kaeberlein2:10:44

       Right

    7. PAPeter Attia2:10:44

       ... I didn't ask Rich Miller this question because I'm pretty sure the answer is they didn't do it, but in all of the ITPs where the animals are getting rapamycin every single day, did they see impaired glucose tolerance?

    8. MKMatt Kaeberlein2:10:56

       So I, my recollection is-

    9. PAPeter Attia2:10:58

       Despite longer life

    10. MKMatt Kaeberlein2:10:59

        ... yeah, my recollection is they did not look, but there have been other studies, um, I think mostly in the C57 black 6J mouse strain, so that's a different strain than the-

    11. PAPeter Attia2:11:08

        Yeah

    12. MKMatt Kaeberlein2:11:08

        ... ITP, right? We don't need to get into it, but it's a different genetic background. But in, in the C57, uh, background, you do see the same changes in, in a glucose tolerance test at the, I think at the 42 part per million for sure rapamycin dose, so the higher ITP dose, uh, um, in older mice. So, so I think it's a real effect. I think you see that effect with rapamycin, and like I said, there's evidence in organ transplant patients for impaired glucose homeostasis as well. So I think it's a real effect. Um, uh, there's a couple of things that I... And I actually, my intuition is it probably is due to mTORC2. I don't, I don't, I, I don't have any reason to doubt that. I just don't think it's been shown cleanly that that's the mechanism. Where I differ a little bit, certainly from Dudley, I'm not sure what, what David's, uh, view on this is right now. Um, where I differ from Dudley's interpretation is that I am less convinced that these effects, uh, that we see for glucose homeostasis are bad, right? I, I think there's at least as, as much likelihood that what, what this really reflects is an underlying change in, in metabolism-

    13. PAPeter Attia2:12:16

        Hmm

    14. MKMatt Kaeberlein2:12:16

        ... that might actually account for part of the beneficial effects of rapamycin, where they shift away from primarily relying on, on glucose as the preferred carbon source and switch over to fat metabolism and, and maybe even ketogenesis to some extent. And when, in that context, so it's a different physiological metabolic state. In that context, when you challenge them with a non-physiological amount of glucose, they don't respond the same way. So I don't know that it's actually a defect in glucose homeostasis. I think it may reflect the, the test that's done, and in some ways it's an artifact of that test that you get a different response, which is, in the context of, you know, diabetes, would be interpreted as a bad response. It might just reflect a different underlying physiological state, and I haven't seen anybody really try to address that. And what makes me believe that's, that might be the case is, is, you know, we and others have seen that rapamycin treatment has pretty profound effects on, uh, uh, fat mobilization, fat metabolism, adipogenesis, and at higher doses, ketogenesis. And so it, it would not surprise me at all if that metabolic adaptation is ac- accounts for some of the beneficial effects of rapamycin, um, and is also leading to this apparent aberrant response to a glucose tolerance test.

    15. PAPeter Attia2:13:42

        Yeah, it's interesting. When I-- I've spoken with one other physician who uses rapamycin, although he uses it very liberally in many of his patients. I do not. Um, I think his patients are coming in much older and much more metabolically deranged, and the results that he's seeing in an uncontrolled manner, meaning you simply have no idea what the performance effect of rapamycin is-

    16. MKMatt Kaeberlein2:14:05

        Right

    17. PAPeter Attia2:14:05

        ... so when you give it to somebody who's expecting to get better, they may go and change many other behaviors.

    18. MKMatt Kaeberlein2:14:11

        Of course.

    19. PAPeter Attia2:14:11

        Um, but you know, he shared with me some of his data, and it's quite profound, right? So, you know, triglycerides falling from, you know, unhealthy levels of 200 milligrams per deciliter to 70 milligrams per deciliter. Um, you know, a- and actually, they're seeing the opposite, right? They're seeing improved glucose homeostasis. Again, these are people starting who are pre-diabetic and in some cases diabetic. Um, and I think your point's a fair one about oral glucose tolerance tests are very unnatural, and, um, you, you can see a physiologic insulin resistance when you do them on people who are either calorie restricted or carbohydrate restricted-

    20. MKMatt Kaeberlein2:14:51

        Right

    21. PAPeter Attia2:14:51

        ... because-

    22. MKMatt Kaeberlein2:14:52

        Yep

    23. PAPeter Attia2:14:52

        ... that initial form of muscle insulin resistance is actually a protective element there. So all of that said, you've decided to go with once a week rather than daily, despite all of the ani- other the, all, all of the other animal models that have shown great success with daily dosing. Is that a hedge?

    24. MKMatt Kaeberlein2:15:12

        Yeah, so there's a couple... Uh, I don't know if I would define it as a hedge. I mean, I think that, um, so the, the rationale there, uh, is both based on the human data, which again is limited, right? But we've talked about the, the daily versus, uh, weekly dosing for immune function.

    25. PAPeter Attia2:15:31

        Mm-hmm.

    26. MKMatt Kaeberlein2:15:31

        Um, and again, we've also talked about why I think that readouts of immune function are probably telling us about the underlying inflammatory state, which I think is a big part of what rapamycin is doing. So, so that is suggestive that daily do- weekly dosing is at least as good as daily dosing, and it's also suggestive that weekly dosing has fewer side effects. And because this is a, this is a challenge with human clinical trials, as we've already talked about, it's also something you have to be, you know, absolutely aware of when you're talking about doing a clinical trial in, in companion dogs, right? These are people's pets. There is an extremely, rightly so, an extremely low tolerance for significant side effects when we're talking about people's pets, right? I love my dog and, and I would be, you know, devastated if I hurt anybody else's dog in this clinical trial. So you wanna do everything you can to reduce the likelihood of side effects, and there's reason to believe that once-weekly dosing, um, is, is likely to have fewer side effects. So a- and there's also the pragmatic aspect of, you know, we're, we're asking owners to give this medication to their dog in the context of a clinical trial. We expect that there will be better compliance and fewer mistakes with once-a-week dosing versus daily dosing or three times a week.

    27. PAPeter Attia2:16:52

        So let's

16. 2:16:53 – 2:27:24

    mTor inhibitor called Torin2, mitochondrial disease and other potential pathways

    1. PAPeter Attia2:16:53

       pivot a bit from rapa to, to Torin 2. You've recently-

    2. MKMatt Kaeberlein2:16:58

       Yeah

    3. PAPeter Attia2:16:58

       ... uh, you and I have shared a couple of emails on this topic. T- tell people a little bit about what that is and why you're excited.

    4. MKMatt Kaeberlein2:17:04

       Right. So, so Torin 2 is a, a different, uh, version of an mTOR inhibitor. So, so we just talked about mTOR complex 1 and mTOR complex 2 and how rapamycin, um, at least biochemically, is a s- specific inhibitor of mTOR complex 1. Torin 2 is a, a, a, what's called a catalytic inhibitor or an ATP competitive inhibitor of mTOR, which at least in theory-

    5. PAPeter Attia2:17:28

       Versus, versus what we call allosteric

    6. MKMatt Kaeberlein2:17:29

       ... allosteric inhibitor-

    7. PAPeter Attia2:17:31

       Yeah

    8. MKMatt Kaeberlein2:17:31

       ... which is rapamycin-

    9. PAPeter Attia2:17:32

       Yeah

    10. MKMatt Kaeberlein2:17:32

        ... meaning it, it interacts not through the catalytic site.

    11. PAPeter Attia2:17:34

        Yeah.

    12. MKMatt Kaeberlein2:17:35

        Yes. Um, at least in theory, Torin 2 and Torin 1 and other catalytic inhibitors, uh, will equally inhibit both mTOR complex 1 and mTOR complex 2. And for reasons that I still, um, am not sure about, as far as I know, nobody has tested Torin 2, Torin 1, other catalytic inhibitors, uh, for effects on aging in mice. Um, it seems like an obvious-

    13. PAPeter Attia2:18:04

        Why has this not been... This, yeah, this seems like something that needs to be submitted to ITP tomorrow, right? For nex- or at least for the next cycle.

    14. MKMatt Kaeberlein2:18:12

        Yeah. Um, I don't know. I don't know why it hasn't been done, to be honest with you. Uh, and maybe it has and I just haven't seen the data. That, that certainly is possible. Um, but I don't think, I don't know of any data, not just for lifespan, but for, you know, other functional measures of aging. Um, I don't know of any data. So, uh, so I, I don't know that I would say I'm... I can tell you why I think there's a, there's additional reason to test it beyond, you know, sort of the, the rationale that seems obvious. Um, but I don't, uh, I, I don't know that I would say I'm excited about Torin 2. It seems like an obvious gap in knowledge, and would be actually a nice way to test the question we were talking about previously of TORC1 versus TORC2, good, bad, right? All of that stuff. Um, uh, it seems like an important set of experiments to do, and as far as I know, nobody's done it. So part of the reason, additional reason why I think it's an interesting set of experiments to do is, you know, in addition to studying aging, my lab also works on mitochondrial dysfunction and mitochondrial disease, and we have worked for many years in a mouse model of a childhood mitochondrial disease called Leigh syndrome. So this mouse is defective in, in complex one of the electron transport chain of the mitochondria, and it, it is very short-lived. It lives about 55, 60 days, and it develops many of the same, uh, molecular phenotypes and neurological phenotypes as kids who have Leigh syndrome, this childhood mitochondrial disease.

    15. PAPeter Attia2:19:39

        And, and these children typically live how long?

    16. MKMatt Kaeberlein2:19:42

        You know, it's, it's variable onset, but it's anywhere from infants to, you know, eight, nine years old.

    17. PAPeter Attia2:19:48

        Hmm.

    18. MKMatt Kaeberlein2:19:48

        It typically, kids with Leigh syndrome don't make it to be teenagers.

    19. PAPeter Attia2:19:52

        Wow.

    20. MKMatt Kaeberlein2:19:52

        It's a, it's a, it's a horrible, horrible disorder. Um, so we found out many years ago that rapamycin could roughly double or triple the survival of these mice and basically prevent the neurodegeneration and brain lesions that, that, that are thought to limit lifespan in both the mice and the, the kids with Leigh syndrome.

    21. PAPeter Attia2:20:11

        And presumably, Matt, that's, that's because when you knock out complex one, you're destroying oxidative phosphorylation, and, uh, presumably the neurons are gonna be the most sensitive to that.

    22. MKMatt Kaeberlein2:20:25

        Yeah.

    23. PAPeter Attia2:20:25

        Is that the thinking?

    24. MKMatt Kaeberlein2:20:25

        So it's a good, it's an interesting question. We don't really know.

    25. PAPeter Attia2:20:27

        Hmm.

    26. MKMatt Kaeberlein2:20:28

        I mean, so I'll tell you what, I'll tell you the sort of current thinking in the field. So first thing is to recognize is, is, um, this particular, uh, component of complex one, uh, is, is, uh, an accessory st- stabilizing factor. So the mice are not 100% def- deficient in complex one. They have a low level of complex one. I think you'd probably be dead if you didn't have any complex one. Uh, and the same thing's true in the, the patients. So it's a deficiency in complex one, and, um, you're right. So one, one idea, w- uh, w- there, there are actually several thing, reasons why being deficient in complex one could be a problem. One could be you just can't generate enough ATP, and, and neurons or a subset of neurons are particularly sensitive, right? Another could be that you're generating high levels of reactive oxygen species.

    27. PAPeter Attia2:21:12

        Yep.

    28. MKMatt Kaeberlein2:21:12

        We know subsets of neurons are, are especially sensitive to that, right? Um, uh, and you could come up... There's also an inflammatory component to this disease, where we see a lot of neuroinflammation in the brain regions where, uh, the lesions occur, and we don't quite understand what's causing that in- inflammation. So there are multiple ways that, that this could be causing, you know, the symptoms of the, of the disease. Um, uh- An interesting body of work from, uh, Vamsi Mootha's lab and, and Isha Jain, who was in his lab and now has her own lab, um, uh, shows that hypoxia can also rescue these mice. And, and hypoxia actually rescues these mice to a greater extent than rapamycin. So that at least is consistent with an oxidative stress model, right? So one idea would be that when you're deficient in complex I, those neurons are not using as much oxygen 'cause they've switched over to-

    29. PAPeter Attia2:22:06

        Yep

    30. MKMatt Kaeberlein2:22:06

        ... to non-oxidative glycolytic, uh, metabolism and fermentation, so you have higher oxygen levels in the brain. That leads to higher oxidative damage. When you reduce o- oxygen through hypoxia, you've suppressed that.
17. 2:27:24 – 2:36:47

    Catalytic inhibitors, sirtuins, and NAD

    1. MKMatt Kaeberlein2:27:24

       The other point that's, that's interesting to make is RTB101, the drug we talked about previously in, in the, the Restorbio Phase 3 clinical trial, is a catalytic inhibitor of mTOR as well as other kinases. So it would fall, at least biochemically, into the Torin 2 class as opposed to the, the rapamycin class.

    2. PAPeter Attia2:27:44

       Uh, how is Torin 2 discovered or synthesized? W- was it, uh, was it synthesized directly to be a catalytic inhibitor? Was it discovered and modified?

    3. MKMatt Kaeberlein2:27:53

       I, you know, David Sabatini would be the person to ask. I, I should know the answer to that. My, my recollect- so rapamycin is interesting, right?

    4. PAPeter Attia2:27:59

       Of course, we- yeah, that's-

    5. MKMatt Kaeberlein2:27:59

       It was found on Rapa Nui-

    6. PAPeter Attia2:28:00

       Yeah, yeah

    7. MKMatt Kaeberlein2:28:01

       ... made by bacteria. I think Torin 2 came out of a, a more traditional sort of chemical screening, uh, as a, as a, a mTOR inhibitor, and then was modified to be a more potent, uh, catalytic mTOR inhibitor, but I, I honestly don't, don't know that literature or recall it.

    8. PAPeter Attia2:28:16

       And does it already have an IND? Is there already a molecule that's in a pipeline, in an FDA pipeline?

    9. MKMatt Kaeberlein2:28:22

       That's a good question. I have looked a little bit, and I d- I don't know of anybody who's developing Torin 2 or Torin 1, which is another catalytic inhibitor for, uh, FDA approval. And I, I've, I've wondered about this, and honestly, I just haven't had the bandwidth to really dig into it. Is it, is it because people tried and there were side effects? I don't know. Um, but I don't know of anybody who's actively developing, uh, the Torins at least, uh, for FDA approval. RTB101, you know, again, we talked about-

    10. PAPeter Attia2:28:49

        Yep

    11. MKMatt Kaeberlein2:28:49

        ... that's being developed or has attempted to be developed for FDA approval. There are other dual kinase inhibitors that are used clinically that hit mTOR in addition to, to other, like a PI3 kinase, a different class of kinase. So there are molecules that have similar types of activity, but I don't know of anybody who's really trying hard to develop the more specific, um, mTOR catalytic inhibitors. And I'm not, again, I'm not sure why.

    12. PAPeter Attia2:29:15

        Let's change gears for a second and talk about NAD, NR-

    13. MKMatt Kaeberlein2:29:19

        Okay

    14. PAPeter Attia2:29:19

        ... NMN, all these things. Um, I've, I've had, uh, David Sinclair on the podcast a couple of times. He's very eloquently explained what sirtuins are, how they work, why they require NAD. So for, for folks who wanna get up to speed on that, um, you can do so in great depth. Do you wanna give the 30-second answer as to why sirtuins matter and why they need NAD?

    15. MKMatt Kaeberlein2:29:41

        Sure, but I would start by saying that I'm not sure that, that sirtuins are the only or most important reason why NAD is important, right?

    16. PAPeter Attia2:29:50

        Sure. Sure.

    17. MKMatt Kaeberlein2:29:51

        So sir-

    18. PAPeter Attia2:29:51

        Yeah

    19. MKMatt Kaeberlein2:29:51

        ... sirtuins are a class of NAD-dependent, mostly deacetylases. They also can do some other, um, activities, but, but basically one way to think about it is that, that sirtuins, uh, take acetyl groups off of other proteins. Uh, that's their activity, and that, that requires NAD, and it actually consumes NAD. So NAD is a cofactor for many metabolic reactions where it gets converted between NAD, which is the oxidized form of the coenzyme, and NADH, which is the reduced form. Uh, many, many different metabolic reactions use NAD in that way.

    20. PAPeter Attia2:30:27

        Including the electron transport chain. [laughs]

    21. MKMatt Kaeberlein2:30:29

        Including the electron transport chain-

    22. PAPeter Attia2:30:31

        Right

    23. MKMatt Kaeberlein2:30:31

        ... and glycolysis and fermentation, yes. Um, sirtuins are fundamentally different in that they, they use up NAD, right? Uh, um, uh, and so NAD is required for their activity. NADH, the reduced form of NAD, is actually an inhibitor of sirtuins. So the NAD to NADH ratio can be used as a proxy of, of likely sirtuin activity. Um, so sirtuins are, are important in the aging field. Um, you know, this really goes back to my work as a graduate student in yeast when I was a grad student with Lenny Guarente, w- when we first showed that you could overexpress the yeast sirtuin, which is called Sir2. That's where sirtuin comes from. So the yeast protein is called Sir2. If you overexpress Sir2, you increase lifespan in yeast, and since then, other people have shown that, that activation or overexpression of sirtuins in worms or flies or mice can have interesting effects on aging.

    24. PAPeter Attia2:31:30

        You and David must have overlapped, right? In the-- You guys must have both been in Lenny's lab at the same time.

    25. MKMatt Kaeberlein2:31:34

        David and I overlapped in Lenny's lab, yes.

    26. PAPeter Attia2:31:35

        Yeah, yeah.

    27. MKMatt Kaeberlein2:31:36

        So he was a postdoc when I was a grad student, and I gotta give David... I mean, David and I have had our scientific disagreements over the years, um, but I gotta give David a ton of credit. As, as a postdoc, you know, he, uh, uh, mentored me, um, i- in important ways and I think actually guided me to the project looking at Sir2, which is what I just talked about when we overexpressed Sir2. So, so David was a very important early, um, influence on, on my scientific career. And, and the Guarente lab at that time, you know, was full of, uh, really smart... I'm sure it's still full of really smart people, but it was just a really great environment.

    28. PAPeter Attia2:32:10

        It was a powerhouse.

    29. MKMatt Kaeberlein2:32:11

        Yeah. Uh, with, with lots of, lots of really, um, really fantastic scientists. Um, so that was the first... And it was really Lenny's lab that established sirtuins as important in aging in, in multiple model systems. So in mice, um, I, I mean, I think, you know, uh, uh, David might disagree with this a little bit, but I think if you're being honest, right, the, the evidence that sirtuins are potent regulators of lifespan in mice is mixed. It's not strong. There are a couple of studies, uh, out of probably, you know, a dozen that have been published, and there's probably two dozen that are unpublished, where people saw no effects on lifespan from manipulating or activating sirtuins. There are a couple of studies that show, in one case, a, a brain-specific activation of one of the sirtuins called SirT1 could slightly extend lifespan, and another that, that overexpression of a different sirtuin, SirT6, could slightly extend lifespan, I think only in males, but nowhere near the, the reproducibility or magnitude of effect of other things, including rapamycin. So, so the, the data on sirtuins is broad, but, um, but the absolute effects on, on lifespan at least are, in my personal view, unconvincing. Like, it hasn't been broadly replicated like rapamycin has, and they're not big. What we do see with sirtuins is abundant evidence that, that metabolic markers of health can be improved by activating sirtuins, um, and in a few other disease-specific models, pretty good evidence, heart disease in particular, some evidence for cognitive function as well, uh, uh, improvements in age-related outcomes. So there's a lot of smoke there, but I think, I think, you know- It, it, Pete, there's a lot of confusion in the field about the relative strength of data for different interventions. And at least in my view, you know, there's really no comparison between the effects you get from inhibiting mTOR and the effects, at least so far, that people have reported from, from activating sirtuins. Like, mTOR is head and shoulders above sirtuins when it comes to magnitude of effect.

    30. PAPeter Attia2:34:15

        Yeah, I'd, I, I, I think it would be impossible to dispute that. I, I don't think there could be any dispute of that. What's interesting is if I were to tally up the number of questions I get per month about NR and NMN versus rapalogs, the, the, the ratio is the exact opposite to the magnitude. So if the effect size of rapamycin and the importance of mTOR is 10X that of [laughs]
18. 2:36:47 – 2:42:34

    NAD precursors: help or hype?

    1. MKMatt Kaeberlein2:36:47

       with age. So, so those two observations, less NAD, right, bad, sirtuins good, the prediction is that, that if we could boost NAD, that would be good, because that would then restore sirtuin activity and have effects on aging. And so this led to the, the development and popularization of, of these molecules called NAD precursors or NAD boosters. The two of which get talked about the most are, are nicotinamide riboside, NR, NR. That was kind of the first to, uh, to gain popularity, and then nicotinamide mononucleotide, NMN. Both of those are precursors of NAD that within cells can be converted into NAD. And so, you know, there has, there's a, there's a large body of literature, uh, in a variety of model organisms showing that treatment with NA- NR or NMN sometimes leads to benefits that are, uh, associated with healthy aging and in one study, uh, lifespan extension in mice. I say sometimes because there's also a large body of literature that, that doesn't reproduce those results.

    2. PAPeter Attia2:37:55

       In- including the ITP.

    3. MKMatt Kaeberlein2:37:57

       Including the ITP, that's right.

    4. PAPeter Attia2:37:59

       Which is, w- I think has to be considered the gold standard for at least mice data.

    5. MKMatt Kaeberlein2:38:03

       I think that's true, although, you know, as we talked about before, it's a different genetic background than, than C57 Black 6, right? So the original publication-

    6. PAPeter Attia2:38:10

       And I would argue it's a much better genetic [laughs] background.

    7. MKMatt Kaeberlein2:38:12

       I think, I think... Well, I think you can make that argument and, um, there are good reasons to, uh, to believe that argument.

    8. PAPeter Attia2:38:19

       Yeah.

    9. MKMatt Kaeberlein2:38:20

       Um, nonetheless, I, I think, I, I think it's important to note, right?

    10. PAPeter Attia2:38:23

        Yeah.

    11. MKMatt Kaeberlein2:38:23

        That that could be why it worked in one context and didn't work in another-

    12. PAPeter Attia2:38:26

        Yeah. Yes, absolutely

    13. MKMatt Kaeberlein2:38:27

        ... context. Um, a- and we've struggled with this as well in my lab. So, you know, it's been reported in this mitochondrial disease mouse by a collaborator of ours, who I, I trust their data, right? That, that NMN could increase lifespan in that mouse model. We've tried multiple times with both NR and NMN in that mouse model and been unable to, to get these effects. So I think these drugs a- are tricky, uh, from a, from a biological efficacy perspective to there's something we don't understand about delivery or, or uptake, uh, that-

    14. PAPeter Attia2:39:00

        Do you think they're temperature stable?

    15. MKMatt Kaeberlein2:39:02

        Probab- Well, I mean, I, I don't know. Um, I- I'm sure, I'm sure there are people who know the answer to that. Um-

    16. PAPeter Attia2:39:09

        I've read conflicting things, right? I've read that... And I, I need to go back to the sources on it, but I've read that at least through the lens in which they're provided as supplements, the likelihood that by the time that thing arrives at your door, it still has the biologic activity that it would have had in a refrigerated manner is low. Now, I don't know that the companies-

    17. MKMatt Kaeberlein2:39:28

        Yeah

    18. PAPeter Attia2:39:28

        ... that sell them recommend refrigerating them, but they might not recommend refrigerating them because then it would imply that they're being shipped in an unrefrigerated manner, which sort of nullifies the whole benefit. But-

    19. MKMatt Kaeberlein2:39:38

        Right.

    20. PAPeter Attia2:39:38

        Um-

    21. MKMatt Kaeberlein2:39:38

        Right

    22. PAPeter Attia2:39:39

        ... I don't know if you, i- i- if you've looked at any of that.

    23. MKMatt Kaeberlein2:39:44

        We haven't. Um, so I thi- so definitely in our mouse studies we are careful to keep the food in the, in the refrigerator until we put it in the mouse cage. Um, I s- you know, I, I suspect that, uh, that, that there certainly is, is... might be some truth to the idea that the biological activity goes off over time at, at room temperature. Um, but I think that reflects a bigger problem with the NAD precursor field, which is that, you know, there's a lot of, um, controversy, even among the two camps. So I mean, it's sort of funny, right? 'Cause there's an NR camp of researchers who really, you know, think NR is the, the, the tool that we should use, and then there's an NMN camp, and they both, you know, say that the other camp, that their molecule doesn't work, right? Because it's not biologically available or, you know, all sorts of reasons, right? So there's a lot of, a lack of clarity around biological availability and efficacy with these molecules in the preclinical literature, right? Where, you know, in theory, people should be able to exactly reproduce the way that other people do the work and get the same results, right? There are lots of reasons why scientific results don't get replicated. It's my impression that in the NAD precursor field, that's a bigger problem than in some other areas. Um, and I don't know the reasons for that, but all I can say is we've experienced that in my lab as well. Um, so, so I, you know, I've tried to stay on the fence here because I think there's a ton of smoke, right? There's a ton of smoke with sirtuins. There's a ton of smoke with NAD precursors, that they can, if you do the experiment the right way, have positive effects that look a lot like what we would expect for something that's impacting the aging process. And as I said, I mean, it's funny because, you know, people who are in the field, I think sometimes think of me as this anti-sirtuin guy, which is absolutely not the truth. I'm the guy, I'm the guy who first showed that you could overexpress a sirtuin and increase lifespan. If anybody's gonna be pro-sirtuin, it's me. I think the problem is that I've seen a lot of data that has... that people have struggled to reproduce, right? And, and I, and I just honestly don't know how to interpret that, whereas with rapamycin, it works for everybody, right? It's robust, and everybody gets the same result over and over and over again. So I'm less enthusiastic, I would say, about sirtuins and NAD precursors as o- as opposed to some other interventions, right? In, in the field. But I think there's a lot of data, um, that suggests that, that these molecules and that sirtuins are important for aging. I think what, what we haven't done yet is figured out how to tweak the system in exactly the right way to get robust and reproducible experimental results that I personally would feel comfortable moving forward with clinically.

    24. PAPeter Attia2:42:21

        And it might be that the answer is you have to hit this system with two prongs. You have to provide more of the precursor, and you have to activate the sirtuin in the way that resveratrol attempted to do but wasn't doing, right?

Episode duration: 2:49:44