357 ‒ A new era of longevity science: models of aging, rapamycin trials, biological clocks, & more

1. 0:00 – 1:15

   Intro

   1. PAPeter Attia0:00

      What do we think is actually causing aging?

   2. BKBrian Kennedy0:03

      Can we stop aging? Can we reverse aging? Maybe the most important question in biology. All of the interventions that extend lifespan reduce chronic inflammation.

   3. PAPeter Attia0:11

      But if we fundamentally want to get to a point where maximal human lifespan is changed and healthspan is fundamentally altered, we have to bend the slope of that line.

   4. BKBrian Kennedy0:21

      Yeah.

   5. PAPeter Attia0:21

      What is the probability in your mind that rapamycin is doing that?

   6. BKBrian Kennedy0:25

      We're doing a study like this in, in Singapore on humans.

   7. PAPeter Attia0:29

      Okay.

   8. BKBrian Kennedy0:29

      A six-month intervention with rapamycin.

   9. PAPeter Attia0:31

      I'd like to just quit my job and-

   10. BKBrian Kennedy0:33

       [laughs]

   11. PAPeter Attia0:33

       ... do nothing other than these experiments. Did you guys do a study on urolithin A as well?

   12. BKBrian Kennedy0:40

       We haven't published it yet, but I am happy to talk a little bit about it. We don't have human data, but the mouse data's really good on urolithin A. I think a lot of these supplements are impacting exercise, and so it's kind of a, a, a win-win.

   13. PAPeter Attia0:51

       There's so many ways to just help a person find another five years of life and dramatically improve healthspan. Do you think that immortality is impossible? [upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia. Brian,

2. 1:15 – 9:12

   Brian’s journey from the Buck Institute to Singapore, & the global evolution of aging research

   1. PAPeter Attia1:15

      thank you so much for being here. Uh, you might actually hold the record for longest journey taken to come to this podcast.

   2. BKBrian Kennedy1:22

      [laughs]

   3. PAPeter Attia1:22

      In fact, I don't know if anybody could travel a greater distance than from Singapore to come out here, so thank you very much.

   4. BKBrian Kennedy1:30

      Oh, it's my pleasure to be here, and, uh, yeah, I don't think you can get further from here from to Singapore. [laughs]

   5. PAPeter Attia1:34

      So let's, let's tell folks a little bit about how you wound up in Singapore. Um, I, I guess just I'll speed things through a bit, but by way of background, obviously you used to run an institute called the Buck Institute.

   6. BKBrian Kennedy1:45

      Mm-hmm.

   7. PAPeter Attia1:45

      Tell, tell folks a little bit about what the Buck is and what you did there.

   8. BKBrian Kennedy1:49

      Yeah. It's a, it's a fascinating institute 'cause it was really the first institute solely devoted to understanding aging and longevity, and it started in the, in the, around 2000, um, with some money that was donated by a woman who died in Marin County, north of San Francisco. Uh, and I was the second CEO there in 2010. Uh, there were about 20 faculty at the time, all devoted to either aging or aspects of aging, very basic science. And as you can imagine, you know, in the 2000s and around 2010, that was a significant component of the aging research field. It was still a very small field. And so the goal was really to help that institute grow, and it was tough times in the twenty-teens 'cause the funding levels were low, and it was right before the real interest in aging and longevity happened around 2017, 2018. So, you know, we were really struggling to keep the doors open, and I think the Buck's doing a lot better now and as well as the rest of the aging field.

   9. PAPeter Attia2:48

      At the time that you were there, how much of the funding came from NIH, and how much came from either donations or industry?

   10. BKBrian Kennedy2:56

       Yeah, it was very heavily oriented to NIH, and our goal was to get more industry funding. We started seven companies when I was there, some of which are still hanging around. And, uh, also really tried to ramp up the philanthropy. But, you know, philanthropy for aging wasn't really happening until around 2017, 2018, when people started really getting the idea that you could slow aging and prevent all these diseases and stay healthy and functional. And so that, that revolution happened around that time.

   11. PAPeter Attia3:26

       The, the faculty there are... It, it's, it's quite the star-studded cast, right? I mean-

   12. BKBrian Kennedy3:31

       Yeah

   13. PAPeter Attia3:31

       ... Eric Verdin's there.

   14. BKBrian Kennedy3:32

       Yeah.

   15. PAPeter Attia3:32

       Judith Campisi was there until she passed away.

   16. BKBrian Kennedy3:34

       Yeah. Yeah, that's unfortunate.

   17. PAPeter Attia3:35

       Um, so, so I mean, you really had a collection of, of, um, of, of people doing great work, right?

   18. BKBrian Kennedy3:40

       Yeah. Well, Eric came after I left. He took over as the next CEO. But yeah, Judy was there. Henry Jasper, he's gone on to Genentech. Um, but, um, Gordon Lithgoe and a bunch of other people working on aging. So it was a good, good group of people for sure.

   19. PAPeter Attia3:55

       What do you think led to this, um, interest that you've alluded to in 2017, 2018, uh, in this idea of, you know... Well, you, you describe it as you see fit, but, but something happened in 2017, 2018 that's, that, that's brought a lot more interest into the field, however one describes it.

   20. BKBrian Kennedy4:15

       I think you just reach an inflection point. It's really hard to know what triggers it. Uh, you know, Calico started a few years before that, uh, you know, where Google's, uh, Alphabet company's, that was focused on longevity. Um, you know, they've not been very open about what they're doing, but it triggered a lot of, uh, publicity for the longevity field. It got Silicon Valley interested and I think that that... You know, I've been-- Matt and I used this slide that you have aging, you know, pointing to all these different diseases. Uh, we started using that slide around 2005, and we were making the point around healthspan shortly afterwards and, you know, really this idea of preventing disease and keeping people healthy, interacting earlier. And, uh, I don't know. I'm so sick of that slide. I can't look at it anymore. [laughs] But it's, uh, finally... And, and we weren't the only ones doing it, but I think there were a few of us doing it, and it, it, it really finally, I think, helped trigger a movement hopefully, so.

   21. PAPeter Attia5:13

       Do you think the field would have... And these are sort of dumb questions as I realize as I'm asking it, but d- do you think the field would've accelerated sooner had it not been for some notable setbacks? For example, um, I don't remember exactly when GSK bought, um, resveratrol.

   22. BKBrian Kennedy5:31

       Yeah.

   23. PAPeter Attia5:31

       But I believe it was, like, around 2006, 2007.

   24. BKBrian Kennedy5:34

       Yeah.

   25. PAPeter Attia5:35

       Uh, you know, I, I... It was clear to me, I think, by about 2010 that that was not gonna work.

   26. BKBrian Kennedy5:42

       Yeah.

   27. PAPeter Attia5:42

       And, and I think it was probably clear to GSK around that time as well.

   28. BKBrian Kennedy5:45

       Sooner than that, I think. [laughs]

   29. PAPeter Attia5:46

       Yeah, maybe sooner. Um, so do you think that that type of hype with nothing to show for it was, was a kind of a negative, uh, force in that equation and, and maybe this, this ge- you know, inflection point could have happened sooner, i.e. during your earlier tenure there? Could it have been easier to, uh, to have raised funds if there had been less-

   30. BKBrian Kennedy6:05

       Yeah
3. 9:12 – 14:13

   Rethinking the biology of aging

   1. PAPeter Attia9:12

      So let's kind of start with a question that I think we'll end up coming back to because it's so fundamental. Um, I enjoy, you know, I, I, I enjoy going down the rabbit hole of fundamental questions in physics. Um-

   2. BKBrian Kennedy9:24

      Yeah. Sounds good [laughs] .

   3. PAPeter Attia9:25

      And, and we're not gonna do that, but, but I think the fundamental questions in biology, I think some of them center around aging. And, and so what do we think is actually causing aging?

   4. BKBrian Kennedy9:37

      Oh, okay. So I'm gonna force you into physics since you asked that question.

   5. PAPeter Attia9:40

      All right. Very well.

   6. BKBrian Kennedy9:41

      'Cause we just, um, had the first ever international conference on gerophysics in Singapore.

   7. PAPeter Attia9:46

      Hmm.

   8. BKBrian Kennedy9:47

      And it-- I was one of the organizers, and the reason I got behind it is the very question you just asked. You know, we've been debating what aging is, um, uh, for the longest time. And, uh, you know, I think we would argue for two hours in some conference s-room somewhere in the world, and at the end of it, we would come up with the definition, "Shit happens and then you die." [both laugh] You know? It's, it's really just, it's frustrating. I don't even want to talk about it now. And, you know, Vadim Gladyshev has, uh, has, has been on like a evangelical rant about how do we define aging? We don't know how to define it. He asks that question at every conference, and I, I think it's a fair question. Uh, and we all throw our hands up in the air. And so the idea was we have a lot of data now, a lot of human data, um, and aging researchers are beginning to try to model that data. Uh, but they're not modelers. You know, I think, uh, most aging biologists, or at least myself, if I have a skill, it's intuition. It's not writing equations and code, you know? And, but the physics people, the theoretical physicists as, es- especially, they know how to model things, and they model things based on physical principles that are-

   9. PAPeter Attia10:55

      Yes

   10. BKBrian Kennedy10:55

       ... that are proven, right? And so we, we've been trying to bring these groups together, uh, because I believe maybe the only answer to your question is that we have to write it in equations. And so, uh, early days on that, but I'm excited about where that's going.

   11. PAPeter Attia11:10

       And do you think that these will be explainable through equations, or do you think that this exceeds our level of intelligence to understand and it's really going to be up to a black box that contains a neural network to understand this? And maybe we take a step back, actually. So for the listeners, they've heard us on this podcast talk about, quote-unquote, "hallmarks of aging."

   12. BKBrian Kennedy11:33

       Mm-hmm.

   13. PAPeter Attia11:34

       Um, maybe explain to people what the hallmarks of aging are, which I d- I don't mean like list them all.

   14. BKBrian Kennedy11:42

       Yeah. Yeah. No, don't worry.

   15. PAPeter Attia11:42

       But the concept of them. [both laughing] Yeah. Don't worry. I won't, I wouldn't put you on the spot for that. Um, but the idea that has been proposed is that there are hallmarks of aging, and why is stating those not the same as answering the question that you, me, and everybody else is struggling with?

   16. BKBrian Kennedy11:58

       Yeah. Well, this is kind of an existential crisis with me because the hallmarks of aging came out in twenty fourteen or twenty thirteen, and then I wrote another paper right after that called "The Pillars of Aging," which is kind of the poor stepchild of the hallmarks of aging.

   17. PAPeter Attia12:12

       [laughs]

   18. BKBrian Kennedy12:12

       And that was, um, because there was an NIH conference and there were seven topics discussed, and they asked me to write a review on calling them the pillars of aging, so I did. But even in that review, I had the seven pillars of aging, but I connected them all with lines because I don't really think that these hallmarks and pillars, which are like the pathways in the cell that are thought to be driving the aging process, you know, inflammation, uh- You know, epigenetic changes-

   19. PAPeter Attia12:39

       Epigenetics, yeah

   20. BKBrian Kennedy12:39

       ... these kinds of things. Uh, they're all interesting to aging, and you can modify them, or they get modified if you slow the aging process. But I, what strikes me is how entrained everything is. So if you take an intervention like rapamycin that slows aging, it can impact all of the hallmarks [chuckles] . Um, and so I don't really... I think those are like outputs or ways you can look at aging, but they're not the... Nobody has really just targeted... The idea that you can target each hallmark and then you'll live to li- live forever, uh, is, is not gonna work because it's really the network that connects the hallmarks together. And to me, aging is a, healthy aging is about maintaining homeostasis. It's about, you know, maintaining a responsive network in your body that sort of keeps you in equilibrium, responds to the events that are happening during aging, the stochastic events, the damage that's happening, and it keeps you functional. And, and that network is highly malleable. You can influence that network by drugs or behavior. Uh, and if you do, you get derived benefit from it, and you can read it out as an improvement of all the hallmarks. It's not like one thing of exercise affects only this hallmark. Um, so I think it's-- the hallmarks was good because it, it, it drove interest in the field. It's part of the reason a lot of investment came, uh, in the biotech sector. But, uh, it also is misleading because, uh, I think the idea that aging is 12 different things and you just need to fix all 12 of them is, is completely wrong. It's really about maint- Your body knows how to function in a healthy way. It's about trying to maintain that and maybe improve upon it,

4. 14:13 – 18:00

   How inflammation & mTOR signaling may play a central, causal role in aging

   1. BKBrian Kennedy14:13

      so.

   2. PAPeter Attia14:13

      Do you look at the hallmarks, which I believe have been modified since the original-

   3. BKBrian Kennedy14:17

      Yeah

   4. PAPeter Attia14:17

      ... paper and a few others have been added, do you see an, an, a rank order or a seniority of them in terms of causality? So for example, one of the hallmarks is mitochondrial dysfunction.

   5. BKBrian Kennedy14:30

      Yeah.

   6. PAPeter Attia14:30

      Now, one could say that mitochondrial dysfunction occurs independent of another hallmark of aging, which you've listed, epigenetic change. Alternatively, you could say, actually, it's the epigenetic change that occurs stochastically-

   7. BKBrian Kennedy14:46

      Mm-hmm

   8. PAPeter Attia14:46

      ... and that that is driving mitochondrial dysfunction.

   9. BKBrian Kennedy14:49

      Mm-hmm.

   10. PAPeter Attia14:49

       And if you reverse the epigenetic change to the previous epigenetic layout, you will correct the mitochondrial dysfunction. How do you, how do you think about the interconnectedness-

   11. BKBrian Kennedy14:58

       Yeah

   12. PAPeter Attia14:58

       ... through the lens of causality?

   13. BKBrian Kennedy15:00

       Yeah, I think the, the primacy issue is a major one. I, I like the idea that mitochondrial might have been one of the primary drivers. Uh, also, you know, every time we do an experiment, we keep coming back to inflammation. All, all of the interventions that extend lifespan reduce chronic inflammation, almost all of them. And then every time we create a new biologic aging clock, which we're doing a lot of now in my lab, you know, and we do principal components and figure out what the main driver is, it al- [chuckles] it's always related to inflammation. Uh, and so I, I think there's something-- It may not be-- Inflammation may be a response, but it's so central that, uh, a lot of the interventions I think are working by dampening inflammation.

   14. PAPeter Attia15:41

       But to your point, inflammation could easily be a readout state.

   15. BKBrian Kennedy15:44

       Yeah. It c-- Yeah. But it, it certainly, when you modify-- I think when you modify it, you get an outcome, you know? So it's not just an endpoint that you look at.

   16. PAPeter Attia15:53

       How are you measuring inflammation? And maybe walk me through how you're doing it in different model systems. So i-i-if... Are you studying inflammation in yeast?

   17. BKBrian Kennedy16:03

       Uh, not, not so much in yeast, but you can study innate inflammation in worms and flies because those pathways, the rudimentary elements of those pathways are there. And then in mice, you have both innate and adaptive, uh, immunity that you can study. And so we look at inflammatory cytokine panels and a range of other things in various tissues to see, you know, how that's changing over time and how interventions impact that. And we do that in humans too in our clinical studies.

   18. PAPeter Attia16:28

       And so what do you believe is the hallmark of maladaptive inflammation? Would you-

   19. BKBrian Kennedy16:34

       Yeah

   20. PAPeter Attia16:35

       ... do, do you think that the hallmark of that is based on immune function, i.e. deteriorated immune function and/or overaggressive immune function? Or do you think, no, the hallmark of that could simply be found in a cytokine, uh, profile that is not typical? I mean, uh, this is maybe more of a technical question, but it's, it's gonna become interesting as we move our way into humans.

   21. BKBrian Kennedy16:56

       Yeah. Well, I think it's central to mTOR. Uh, you know, one of the things we were one of the earliest people to publish was that what's happening during aging is that baseline levels of mTOR are creeping up. You can't turn the pathway off. And I think most of the interventions, w- sirtuins, mTOR, inflammation, it's not about doing anything super physiologic with the interventions. It's about restoring the dynamic range that you had when you were youthful. And mTOR is a great example of that, and I'll bring it back to inflammation. You need mTOR on when you wound your skin or you get an infection or you have a big meal in your liver, but you need it off the rest of the time. And when you're young, you're very good at maintaining that dynamic range. But what's happening with aging, at least in stem cells, is that the baseline levels of mTOR are creeping up.

   22. PAPeter Attia17:48

       People on this podcast are pretty familiar with mTOR.

   23. BKBrian Kennedy17:51

       Yeah.

   24. PAPeter Attia17:51

       We've had David Sabatini on-

   25. BKBrian Kennedy17:53

       Yeah

   26. PAPeter Attia17:53

       ... many times, Matt Kaeberlein as well.

   27. BKBrian Kennedy17:55

       Yeah.

   28. PAPeter Attia17:55

       But I just wanna make sure that for anybody who's here who's either new or forgot-

5. 18:00 – 23:32

   Biological role of mTOR in aging, & the potential of rapamycin to slow aging & enhance immune resilience

   1. BKBrian Kennedy18:00

      Yeah

   2. PAPeter Attia18:00

      ... let's take a step back. mTOR is so important to this discussion.

   3. BKBrian Kennedy18:04

      Yeah.

   4. PAPeter Attia18:04

      Let's go back as far as we need to and explain mTOR.

   5. BKBrian Kennedy18:07

      Okay.

   6. PAPeter Attia18:07

      And talk about complex one. Talk about-

   7. BKBrian Kennedy18:10

      Yeah

   8. PAPeter Attia18:10

      ... complex two. Talk about how one impacts the other. We're obviously gonna talk about rapamycin in that context, but take as much time as you need to make sure listeners really understand why mTOR is so central-

   9. BKBrian Kennedy18:23

      Sure

   10. PAPeter Attia18:23

       ... across all of life that we've kn- ever known.

   11. BKBrian Kennedy18:26

       Well, sort of our, our entry into the mTOR pathway was in yeast. This is Matt Kaeberlein and I. And so we were screening the yeast deletion set d- wh- Uh, it's a set of strains which each gene is deleted And looking for ones-

   12. PAPeter Attia18:39

       How many genes, by the way, in yeast?

   13. BKBrian Kennedy18:40

       There are about 5,000. Uh-

   14. PAPeter Attia18:42

       Okay.

   15. BKBrian Kennedy18:43

       And then some of those are essential, so you can't screen those. If you knock them out, the yeast are dead.

   16. PAPeter Attia18:47

       Yep.

   17. BKBrian Kennedy18:47

       But about 70% of them, the yeast are still viable, and so we were trying to find ones where when you knock out a gene that the yeast live longer. Um, surprisingly, there were like 300 genes [chuckles] that, that met that description. And that one thing I learned from that is that extending lifespan, at least in a simple organism like yeast, and there's also data in worms, is much easier [chuckles]

   18. PAPeter Attia19:09

       Yep

   19. BKBrian Kennedy19:09

       ... than anybody would've ever expected, and we can talk about that in a minute.

   20. PAPeter Attia19:12

       But that's still a pretty cool tour de force in the '90s, right?

   21. BKBrian Kennedy19:15

       Yeah.

   22. PAPeter Attia19:15

       You guys were doing this in the early '90s.

   23. BKBrian Kennedy19:17

       We, we did the sirtuin stuff in the '90s. We did the full genome screen in the 2000s-

   24. PAPeter Attia19:21

       Okay

   25. BKBrian Kennedy19:21

       ... when I was in Seattle with Matt.

   26. PAPeter Attia19:23

       Yep.

   27. BKBrian Kennedy19:23

       And so, uh, but yeah, it w- it was a lot of work, and we, it, we did it brute force.

   28. PAPeter Attia19:28

       Yep.

   29. BKBrian Kennedy19:28

       We had people sitting at microscopes dissecting yeast all the time, and I think there were 80-some authors on that paper. You know, for a yeast paper, that might've been a record. [chuckles] So the, um... But anyway, we, one of the main, main things we hit was the mTOR pathway, and downstream of it is protein translation. We hit a lot of things in protein translation. And mTOR is a nutrient-responsive kinase, so it responds to the levels of carbohydrates and, and also amino acids that the cell encounters. And so that fit into the calorie restriction data, which I am sure you've talked about, that reducing calories can extend lifespan. So it seemed like it was gonna be very central from the beginning in, in modifying aging. Uh, and I think that's proven true. Turning down mTOR signaling across a wide range of species extends lifespan. And I think the data in humans is also pretty-- It's not f- it's not, uh, fu-fully validated, but I think that if you alter mTOR signaling in the right way, you can probably slow aging in humans too.

   30. PAPeter Attia20:27

       Now, why is it then that the first human brush with mTOR modulation shows up in the form of immune suppression?
6. 23:32 – 36:03

   Aging as a linear decline in resilience overlaid with non-linear health fluctuations

   1. BKBrian Kennedy23:32

      think that's one of the earliest events that's happening.

   2. PAPeter Attia23:34

      So let's go back to something you said a second ago, which is absent the equations biologists have to rely on their intuition.

   3. BKBrian Kennedy23:41

      Yeah.

   4. PAPeter Attia23:42

      And so if we believe in the primacy of that deterioration, that homeostatic deterioration that you just described-

   5. BKBrian Kennedy23:49

      Yeah

   6. PAPeter Attia23:49

      ... what is driving it? Is this entropy? What, what is it that is changing?

   7. BKBrian Kennedy23:55

      Well, you know, entropy's been used off and on ever since I started in the aging field. And-

   8. PAPeter Attia24:00

      You know, it's just a lazy term we use 'cause we don't have something better to say.

   9. BKBrian Kennedy24:03

      No, but I think it's, I think there's a nugget of truth in that. And, and I think ultimately... And, and I think that, you know, I work with Peter Fedichev at Jarrow, uh, and I think he's probably the deepest thinker in the aging field in terms of understanding this process of aging at a mathematical level.

   10. PAPeter Attia24:23

       Hmm.

   11. BKBrian Kennedy24:24

       Um, my only role in working with him is I had a ma-- I was a math major. Um, fortunately, I didn't try to pursue that [laughs] but I survived enough to get a math degree in college. Uh, and, uh, so I'm kind of his, uh- Not whisperer or translator. [chuckles] I take what he says and try to help him reframe it in a way that the, the rest of the world can understand. He, he really thinks about things deeply. Uh, and, uh, I think his view on it is that really what we're talking about is resilience. You know, you can imagine, you know, i- im- from an image, you could imagine that, you know, when you're young, you're living in this deep valley, you know, and you do all kinds of crazy things. You get too much fast food, you get sick, you know, and you diverge off the, the bottom of the valley, the lowest activation energy, and you're un- you're biologically, you look older, but you're in a deep valley. You keep getting pulled back to health. And so almost no matter what you do, at least in the short term, you're coming back into health. But if there are hills you can go over into what you would call failure states, which could be chronic diseases or could be some major functional decline, and that doesn't happen when you're young because it's a very steep hill. But these hills are coming down as you get older. And so when you diverge off the healthy state, it's harder to get you back, and occasionally you go over the side and then you're, you know, in a fr- in a kind of a frailty mode once you have a late, a later stage disease. So the question is how to mathematically model that. And it's, you know, it's more of a dynamic systems type of modeling. And, um, and when you look at the large data and you're-- I'm, I'm getting to the point where you're going to understand why, why I need the physicist [chuckles] but when you look at the large data, it, it almost looks like there's a linear accumulation of damage in, in-- So what we're doing now is we're trying to measure biologic age from large data sets like UK Biobank. Uh, and then we're breaking it down into principal components, and when you do that, a lot of the principal components don't track with aging. They track with sex or smoking or something else. Uh, the ones that track with aging, usually there are a couple of them. One of them is the primary driver, and it's kind of going up linearly, and that looks like damage, and that, that's probably the main driver of aging. I don't know, it doesn't have to be damage. It could be stochastic events. It could be subtle changes.

   12. PAPeter Attia26:50

       But when you say damage-

   13. BKBrian Kennedy26:51

       Yeah

   14. PAPeter Attia26:51

       ... do you mean DN-- Like what damage are you tracking?

   15. BKBrian Kennedy26:53

       Yeah, that's why I-

   16. PAPeter Attia26:54

       DNA damage?

   17. BKBrian Kennedy26:54

       That's why I was trying to back off a bit because-

   18. PAPeter Attia26:56

       Yeah

   19. BKBrian Kennedy26:56

       ... we don't-- It, it may be a cl- cluster of different types of damage. It may be stochasticity and not really defined as damage. Subtle changes here and there that each on their own have tiny little impacts, but when they start to add up, they, they put s- stress on this network and eventually it starts to break down. And so that looks linear, and the problem is that mortality looks exponential. [chuckles]

   20. PAPeter Attia27:20

       Yep.

   21. BKBrian Kennedy27:21

       And so if you model it into a mathematical equation that talks about these valleys going down, that's a linear change. But the, the chance the ball's going to go over the hill is an exponential change. And so what I like about it is you can fit human data into an equation that, that is compatible with Gompertz equations and exponential increase in mortality. So I think it's on the right track. I mean, there's probably a lot of changes. There's also another component usually in these biologic aging clocks that's age-related, and it's kind of oscillating, and it sort of oscillates around that first component going up. And I think that's why you see these methylation clocks are going up and down and changing and everything. And I think of that component as how well you're functioning at the damage state you're at. So you have all these events that are going bad, and that's defining sort of your age. Maybe it says you're fifty, but then you can be somewhere between forty and sixty depending on, you know, how, what your behavioral pattern is, what supplements or drugs you might be taking, and those things are, um, going up and down. So that's why when you get sick, you look older, and then you get better, you come back down. You're-- That first driver is not changing. It's the second one that's oscillating. And most of the interventions seem to affect the second one, which suggests that what we're doing right now is... All right, I'm going to say this and, and then I'm going to qualify it. It suggests that what we're doing right now is sort of working around the edges. You know, [chuckles] we're, we're, we're doing things that may have five or ten years impact on healthspan, which, by the way, is a revolution if that's successful. [chuckles] I'm not-- I think that's a major breakthrough in medicine if we can give everybody five or ten years of extra healthspan. But that these things may not impact maximum lifespan in humans, and they may not get us to one fifty or two hundred, and the kinds of ways to get there may be a totally different kinds of interventions. So we're thinking about that a lot with Peter right now. And, you know, I tr- I translated my research in-- Translate is a bad term. I switched my research into translation about ten years ago because I was like, "I don't want to be retired and eighty on a porch somewhere and not have any impact on humans." Uh, but now I'm starting to think back a little bit to basic science because I'm starting to think that the interventions that we need to develop if we really want to have the big changes are not being done yet, and we have to go back to some discovery science to do that.

   22. PAPeter Attia29:53

       So Brian, there's a lot you said there that's really interesting, and I'd like to unpack it both for myself and for the listener. The first thing you said I'm, I, I want to-- that I actually am not sure I understand is we have a linear process-

   23. BKBrian Kennedy30:09

       Mm-hmm

   24. PAPeter Attia30:09

       ... of, we're going to use the word damage loosely.

   25. BKBrian Kennedy30:12

       Yeah. Yeah.

   26. PAPeter Attia30:12

       Um, and that over time, that is increasing monotonically and linearly.

   27. BKBrian Kennedy30:20

       And, and not alterably. [chuckles]

   28. PAPeter Attia30:22

       No, exactly. Superimposed on that, so, so we have, you know, damage occurring this way. Superimposed on that, we have sort of cyclic-

   29. BKBrian Kennedy30:34

       Mm

   30. PAPeter Attia30:34

       ... episodic-
7. 36:03 – 42:18

   Speculating on the future of longevity: slowing biological aging through noise reduction & reprogramming

   1. PAPeter Attia36:03

      guess, and I'm hopeful that, that the listeners are, are with us, 'cause this idea of the, the linear and monotonic increasing-

   2. BKBrian Kennedy36:12

      Mm-hmm

   3. PAPeter Attia36:12

      ... in damage-

   4. BKBrian Kennedy36:13

      Mm-hmm

   5. PAPeter Attia36:15

      ... is, is the thing that has to be addressed if we're going to make a step function change-

   6. BKBrian Kennedy36:19

      Yeah

   7. PAPeter Attia36:19

      ... in human longevity.

   8. BKBrian Kennedy36:20

      I think so.

   9. PAPeter Attia36:21

      Right?

   10. BKBrian Kennedy36:21

       Yeah.

   11. PAPeter Attia36:21

       So we're, we're, uh, I like how you described it. We're really tinkering around the edges.

   12. BKBrian Kennedy36:25

       Yeah.

   13. PAPeter Attia36:26

       Right? Everything we do is tinkering around the edges. Um, but if we fundamentally wanna get to a point where maximal human lifespan is changed and healthspan is fundamentally altered, we have to bend the slope of that line.

   14. BKBrian Kennedy36:39

       Yeah.

   15. PAPeter Attia36:40

       So my first question for you is, what is the probability in your mind that rapamycin is doing that based on what you've seen in animal models?

   16. BKBrian Kennedy36:49

       Well, okay, so first of all, if you look at something like a worm, I think that the, the modeling's very different there.

   17. PAPeter Attia36:55

       Mm.

   18. BKBrian Kennedy36:56

       Worms are just kind of already in a failure state [chuckles] . They're, uh, they're, they're like designed to last for two weeks-

   19. PAPeter Attia37:02

       Yep

   20. BKBrian Kennedy37:02

       ... and they don't have that homeostasis that, that humans have. And so you can get huge impacts-

   21. PAPeter Attia37:07

       You can get fooled by interventions there.

   22. BKBrian Kennedy37:09

       Yeah.

   23. PAPeter Attia37:09

       Yep.

   24. BKBrian Kennedy37:10

       In worms or, or, or, or other organisms that, um, don't... The pathway may translate to humans, but the effect size in humans is gonna be much smaller. I suspect that's where rapamycin is, that it's, uh, it's gonna give you a healthier period if you take it the right way. Or, um, I don't think any intervention's gonna affect everybody, okay?

   25. PAPeter Attia37:29

       Yeah.

   26. BKBrian Kennedy37:29

       But a majority of people may benefit from that. But I think it's in the modest effect in size, not in the change the hill in size.

   27. PAPeter Attia37:37

       Not in change slope. Okay. I wanna come back and talk more about rapamycin and mTOR-

   28. BKBrian Kennedy37:41

       Yeah

   29. PAPeter Attia37:41

       ... 'cause you're, again, one of the few people, along with Matt, Dave-

   30. BKBrian Kennedy37:43

       Yeah
8. 42:18 – 47:14

   The role of the epigenome in aging, & the limits of methylation clocks

   1. BKBrian Kennedy42:18

      feasible strategy.

   2. PAPeter Attia42:18

      So as a thought experiment-

   3. BKBrian Kennedy42:20

      Yeah

   4. PAPeter Attia42:20

      ... if you took, um, if I could clone you right now or you had a twin.

   5. BKBrian Kennedy42:25

      Yeah.

   6. PAPeter Attia42:25

      Let's just say you've got a twin. Um-

   7. BKBrian Kennedy42:27

      One of me is enough in the world [both laughing] .

   8. PAPeter Attia42:30

      But you're in Singapore, so we're gonna have a North American version. We're gonna have the Singaporean version. So, so we have two of you, and in one of you, we're just gonna act as the control. We're gonna give you some vehicle. In the second one- Let's just assume I can use the fidelity of CRISPR to revert your entire epigenome-

   9. BKBrian Kennedy42:52

      Mm-hmm

   10. PAPeter Attia42:52

       ... in every cell of your body-

   11. BKBrian Kennedy42:54

       Mm-hmm

   12. PAPeter Attia42:54

       ... to what it looked like when you were 20.

   13. BKBrian Kennedy42:57

       Mm-hmm.

   14. PAPeter Attia42:57

       And any time it gets out of whack, I sm-

   15. BKBrian Kennedy42:59

       Yeah

   16. PAPeter Attia43:00

       ... I smack it right back to 20-year-old Brian.

   17. BKBrian Kennedy43:02

       Yeah.

   18. PAPeter Attia43:02

       Epigenome only.

   19. BKBrian Kennedy43:03

       Yeah.

   20. PAPeter Attia43:04

       Not genome.

   21. BKBrian Kennedy43:05

       Yeah.

   22. PAPeter Attia43:05

       Not proteome. Not meta- noth- I don't change anything but epigenome.

   23. BKBrian Kennedy43:10

       Well, those things are gonna change. Yeah.

   24. PAPeter Attia43:11

       Exactly. They're gonna affect everything else.

   25. BKBrian Kennedy43:12

       Yeah. Yeah.

   26. PAPeter Attia43:12

       But the, what is your, what is your guess as to the difference in lifespan and healthspan of those two versions of you?

   27. BKBrian Kennedy43:21

       That's a, that's an interesting question. Um, I think it w- I think there would be a difference for sure. I, I'm not sure it'd be a huge difference. Uh-

   28. PAPeter Attia43:29

       You don't think it'd be huge? That's interesting.

   29. BKBrian Kennedy43:30

       Well, I'm not, I'm, I'm not as sold on the primacy of the epi- epigenetics. I certainly you can modify-

   30. PAPeter Attia43:36

       So what would go wrong, right? So, so, so if you look at ... And by the way, I'm not, I'm, I don't know the answer, of course. I'm just kind of thinking through data that I've seen, right? So if you look at epigenetic code for two different hepatocytes, liver cells, one from a 20-year-old, one from a 50-year-old, uh, and then and I tell you which one's 20, which one's 50-
9. 47:14 – 52:16

   Balancing the quest for immortality with the urgent need to improve late-life healthspan

   1. PAPeter Attia47:14

      No. Do you believe that it, and this is just, again, we're in the philosophical. Well, I'll bring it back to reality at some point today. Um, do you think that immortality is impossible? Unless we define it through kind of like AI copying your brain. Let's put that... I mean physical immortality. Do you believe that that is, that is impossible?

   2. BKBrian Kennedy47:38

      Well, I, I like to tell people that I'm immortal because I think the mindset that it gives me is a very healthy mindset for me. [laughs] We can come to, you know, you, you talk a lot about the emotional aspects of aging in your book. I love that chapter. We can come to that later. But that's, I don't really believe it's true. I think the odds that you could achieve that level of change in aging is non-zero, but close. [laughs] So, so I, I'm skeptical that that can be done, I think it's fair to say. But I, I wouldn't rule out the possibility. Of course, nobody's ultimately gonna be immortal because you're gonna get hit by a bus sooner or later.

   3. PAPeter Attia48:13

      Yeah.

   4. BKBrian Kennedy48:13

      But what you're really talking about is being immortal in terms of dying from aging.

   5. PAPeter Attia48:17

      Yeah. Well, I guess what I'm really saying-

   6. BKBrian Kennedy48:19

      Yeah. Yeah

   7. PAPeter Attia48:19

      ... is can one ever get to the point where resilience is high enough-

   8. BKBrian Kennedy48:24

      Yeah

   9. PAPeter Attia48:24

      ... that you cannot die from disease?

   10. BKBrian Kennedy48:27

       I have seen nothing so far that suggests that's possible. Okay?

   11. PAPeter Attia48:32

       Yeah.

   12. BKBrian Kennedy48:32

       But, but that doesn't mean it isn't possible.

   13. PAPeter Attia48:33

       Yeah. Yeah. And then that gets even to physical frailty and sarcopenia-

   14. BKBrian Kennedy48:38

       Mm-hmm

   15. PAPeter Attia48:38

       ... and things like that-

   16. BKBrian Kennedy48:39

       Mm-hmm

   17. PAPeter Attia48:39

       ... where even when we see centenarians and supercentenarians, their frailty is still pretty remarkable

   18. BKBrian Kennedy48:47

       Meaning?

   19. PAPeter Attia48:48

       Uh, m- meaning, like, they still look pretty feeble and frail. Like-

   20. BKBrian Kennedy48:51

       Th- th-

   21. PAPeter Attia48:52

       I mean, age adjusted, they're great.

   22. BKBrian Kennedy48:54

       Yeah. Yeah.

   23. PAPeter Attia48:54

       But at the end of the day-

   24. BKBrian Kennedy48:56

       Yeah

   25. PAPeter Attia48:56

       ... like, when they're 110-

   26. BKBrian Kennedy48:58

       Yeah

   27. PAPeter Attia48:58

       ... they still look like someone who's in the final years of their life-

   28. BKBrian Kennedy49:02

       Yeah

   29. PAPeter Attia49:02

       ... just as someone would if they were 84, 85.

   30. BKBrian Kennedy49:05

       Yeah. I mean, I had two grandmothers that lived to almost 100. One died at 99, and the other 101. And th- the one at 101, I would say that at 90... She was driving at 95. I think she quit driving. She bowled a 238 game at 93. She was, looked like a s-
10. 52:16 – 57:27

    Comparing the big 4 chronic diseases: which are the most inevitable & modifiable?

    1. BKBrian Kennedy52:16

       Yeah

    2. PAPeter Attia52:16

       ... cardiovascular disease, cancer, uh, dementing diseases, and metabolic diseases-

    3. BKBrian Kennedy52:22

       Yeah

    4. PAPeter Attia52:22

       ... right? Those would be the big four. I've often maintained that the, that the least inevitable of them is ironically the one that is the most deadly today, which is cardiovascular disease.

    5. BKBrian Kennedy52:32

       Yeah, I, I agree with that.

    6. PAPeter Attia52:33

       The atherosclerotic diseases, so cerebro and, and, and cardiovascular, um, ironically the most preventable.

    7. BKBrian Kennedy52:39

       Yeah, I think so, too.

    8. PAPeter Attia52:40

       Both because we have the best understanding of what causes them, and we couple that with the most tools to prevent them, whether it be, uh, tools to combat hypertension, dyslipidemia, et cetera.

    9. BKBrian Kennedy52:49

       And they're responsible to, uh, responsive to l- to lifestyle-

    10. PAPeter Attia52:52

        Yeah

    11. BKBrian Kennedy52:52

        ... modification. I mean [laughs]

    12. PAPeter Attia52:54

        Which of those major diseases, of the other three, dementing, cancer, metabolic, do you believe is the most inevitable to our species?

    13. BKBrian Kennedy53:05

        I wouldn't put, uh, metabolic-

    14. PAPeter Attia53:06

        I agree

    15. BKBrian Kennedy53:07

        ... in that category-

    16. PAPeter Attia53:07

        Yep

    17. BKBrian Kennedy53:07

        ... for sure, 'cause I see that more like cardiovascular.

    18. PAPeter Attia53:10

        I, I agree. Yeah.

    19. BKBrian Kennedy53:11

        Um.

    20. PAPeter Attia53:12

        So of the other two, cancer and dementing or neurodegenerative diseases, which one is just seemingly inevitable?

    21. BKBrian Kennedy53:19

        We don't know enough about dementia to answer, but I will say that cancer is a little bit different than these other diseases, I think, and it's not a, it, it, and it may be less modifiable by, uh, longevity interventions. Um, dementia, we, we just don't know. My guess is it's highly modifiable, too, but, uh, there's not enough data to be sure of that like there is for metabolic and cardiovascular disease. But cancer is, is, is an accumulation of mutations, so it's a, a more defined event that's happening. It's also a impact on the immune system that's different a little bit than normal aging, so it may be less, um, approachable from a longevity viewpoint.

    22. PAPeter Attia53:58

        Y- yeah, it's funny. That's exactly my view, uh, that cancer is the most inevitable of these diseases.

    23. BKBrian Kennedy54:06

        Yeah.

    24. PAPeter Attia54:06

        Do you think that the inevitability or the age-related component stems more from the accumulation of mutations or the weakening of the immune system?

    25. BKBrian Kennedy54:18

        It's probably both. I mean, you, you don't get to cancer without the right mutations happening. Um, but I think we're learning more and more that the immune system is playing a major role in it, and that we can see that very clearly from the interventions that improve immune function, and they're having a big role in certain types of tumors. And, but I think that's gonna be true for Alzheimer's and, uh, dementia as well. We've completely underestimated the role of inflammation in the immune system in th- those diseases as well, and they may be the primary drivers. You know, I, I, I kind of have got s- I'm very frustrated by some of these fields. One of them is Alzheimer's. You know, the, um, c- I kind of feel like, you know, the, the one of these Alzheimer's researchers, they're gonna die at some point of 90, and on their, on their tombstone, it's gonna be like, you know, major accomplishment was to completely remove plaques from the brain. Died of Alzheimer's at 94. You know, it's, it's, [laughs] it's, uh, the, the-- there's been so much focus on one or two mechanisms of disease that we spent 30 years not studying the others, which may be more important.

    26. PAPeter Attia55:21

        Why do you think that-- I mean, I write about it in the book.

    27. BKBrian Kennedy55:23

        Yeah.

    28. PAPeter Attia55:23

        But I, I'm really curious as to why you think that's happened. And, and 'cause that's not a-- unfortunately, that's not an isolated incident in science.

    29. BKBrian Kennedy55:31

        No.

    30. PAPeter Attia55:31

        So why do you think it's happening in a field where the results are otherwise so dismal?
11. 57:27 – 1:09:14

    Exploring potential benefits of rapamycin: how Brian is testing this & other interventions in humans

    1. PAPeter Attia57:27

       Do you believe that the primary effect of rapamycin is tamping down maladaptive, um, inflammation through obviously the intermittent, uh, blunting of mTOR?

    2. BKBrian Kennedy57:40

       I think that's one of the major things certainly. Um, you know, that there's good evidence for enhancement of autophagy. There's good evidence for changes in protein translation, and those things are not mutually exclusive to inflammatory changes anyway. Um, but I think those are the three things that we have pretty good evidence for. Uh, and, uh, so I-- but I, I really think that all of these interventions that we're looking at are restoring dynamic range. They're not-- It may take super physiologic changes to, to change that linear line, right? But I don't think that's what we're looking at right now. We're restoring things that happened when you were young.

    3. PAPeter Attia58:16

       So given that we're not likely to have, uh, human clinical trials of rapamycin that study aging for the simple fact that we don't even know what an aging biomarker is, um, we're gonna largely be extrapolating from animal data if we have to make decisions about humans using rapamycin for geroprotection.

    4. BKBrian Kennedy58:39

       All right. I'll, I'll push back a little bit, and then w-- I know where we're going with this.

    5. PAPeter Attia58:42

       Yep.

    6. BKBrian Kennedy58:42

       But we're doing a study like this in, in Singapore on humans.

    7. PAPeter Attia58:46

       Okay.

    8. BKBrian Kennedy58:46

       It's a six-month intervention with rapamycin. Um, and we're looking at as many different parameters of a-- We're not doing disease. In fact, we're not taking people with disease.

    9. PAPeter Attia58:54

       Yeah, you can't in six months. Yep.

    10. BKBrian Kennedy58:56

        We're taking people that are forty to sixty. They may have a precondition for a disease, but they don't have-

    11. PAPeter Attia59:01

        They're healthy

    12. BKBrian Kennedy59:02

        ... anything that would be defined as a disease.

    13. PAPeter Attia59:04

        Okay.

    14. BKBrian Kennedy59:04

        Um, so it could be, you know, high glucose but not diab-- you know. And, and so the, um, and then we're looking at changes in a r- wide range of different biomarkers, clocks which-

    15. PAPeter Attia59:15

        So tell me a little bit more about the study. So how many subjects?

    16. BKBrian Kennedy59:18

        Um, we're doing these-- I don't remember the exact numbers. It's somewhere around one fifty to two hundred, so it's not huge.

    17. PAPeter Attia59:25

        And how you're dosing it?

    18. BKBrian Kennedy59:26

        Um, intermittently. Uh-

    19. PAPeter Attia59:28

        Once a week?

    20. BKBrian Kennedy59:29

        Yeah.

    21. PAPeter Attia59:29

        How much?

    22. BKBrian Kennedy59:29

        Yeah. Uh, I think it's five milligrams is what's in the protocol. Uh, it's being run by Andrea Meyer, which is one of my collaborators in Singapore.

    23. PAPeter Attia59:36

        Got it. So five milligrams of rapamycin once a week-

    24. BKBrian Kennedy59:40

        Yeah

    25. PAPeter Attia59:40

        ... for six months.

    26. BKBrian Kennedy59:42

        Yeah.

    27. PAPeter Attia59:42

        And then let's go through all the different measurements.

    28. BKBrian Kennedy59:45

        Yeah. So a range of clocks, inflammatory cytokine panels, um, functional measures, pulse wave velocity, um, DEXA, um, strength measurements, um, cognitive measurements, uh, and, uh, I'm still missing a couple of them. But the i-

    29. PAPeter Attia1:00:02

        Now, do you expect to see changes in strength or cognition or things like that? I mean, do you, do you, do you worry that those are kind of the wrong outcomes to look for in a six-month study of people that are young?

    30. BKBrian Kennedy1:00:15

        Yeah. Well, I think that, you know, this comes back to what do you measure?
12. 1:09:14 – 1:13:41

    Testing alpha-ketoglutarate (AKG) for healthspan benefits in aging [1:01:45];

    1. BKBrian Kennedy1:09:14

       great.

    2. PAPeter Attia1:09:14

       So let's talk a little bit about alpha-ketoglutarate and why-

    3. BKBrian Kennedy1:09:17

       Yeah

    4. PAPeter Attia1:09:18

       ... w- walk us through the rationale for how that came to be something that you would put through this-

    5. BKBrian Kennedy1:09:23

       Yeah

    6. PAPeter Attia1:09:23

       ... type of rigorous program.

    7. BKBrian Kennedy1:09:25

       Yeah. So a company, full disclosure, that I'm involved with, uh, p- uh, PDL Health, uh, they have a product Rejuvin now. They came to us many years ago at the Buck and working with Gordon Lithgo and I, and they were like, "Let's screen natural products, uh, that would have an impact on aging," because, you know, their, the mindset of, um, the CEO of the, what became the CEO of this company was that I, I, I can't get drugs approved for aging at any time in the near future. Let's work with natural products. And also-

    8. PAPeter Attia1:09:54

       So things that the FDA just calls grass-

    9. BKBrian Kennedy1:09:56

       Yeah

    10. PAPeter Attia1:09:56

        ... out of the gate. Okay.

    11. BKBrian Kennedy1:09:57

        And let's, let's look for combinations of things that work together, um, because we can get IP around combinations. We can't get IP around single natural products. Um, so we screened a lot of things in worms, and AKG came out as one of the best things in worms, and then we started testing interventions in mice, and that's led now to we're testing, like we do four or five different intervention studies in mice every six months now. Um, not just with natural products and not just for this company, but we built that into our own kind of ITP in mice too, although we do it differently. But anyway, AK- AKG came out as one of the biggest effects, and then in the mouse studies, we found that for male mice, there was a combined effect with, uh, vitamin A. And, uh, vitamins are an interesting discussion [laughs] too. Uh, and there was also a combined effect with both sexes with vitamin D, and so that led to this product Rejuvin, which is AKG, time-release AKG. Very important because otherwise it's like in a, it goes away in five minutes if you don't have a time-release version.

    12. PAPeter Attia1:11:01

        Tell, tell folks what alpha-ketoglutarate is.

    13. BKBrian Kennedy1:11:03

        Yeah.

    14. PAPeter Attia1:11:03

        It shows-- It's a part of the... Is it part of the Krebs cycle?

    15. BKBrian Kennedy1:11:06

        It's, yeah, it is. It's a, the TCA cycle-

    16. PAPeter Attia1:11:08

        Yep

    17. BKBrian Kennedy1:11:09

        ... the Krebs cycle, central metabolite involved in hundreds of reactions. It's a lot like NAD.

    18. PAPeter Attia1:11:13

        Yep.

    19. BKBrian Kennedy1:11:14

        Uh, they're, they're doing different things, but they're both central metabolites. They're both going down with aging in organisms.

    20. PAPeter Attia1:11:19

        Yep.

    21. BKBrian Kennedy1:11:20

        And the idea is supplementing them back up would be beneficial. Um, and so when we did that with AKG in mice, we see about a five to ten percent increase in lifespan, but a dramatic increase in frailty. So when we-

    22. PAPeter Attia1:11:33

        Meaning a decr-

    23. BKBrian Kennedy1:11:34

        Or a decrease in frailty.

    24. PAPeter Attia1:11:34

        Yeah, yeah. I know what you mean. Yeah.

    25. BKBrian Kennedy1:11:35

        Yeah. So the mice, I would argue that you're extending healthspan.

    26. PAPeter Attia1:11:38

        You're squaring the longevity curve-

    27. BKBrian Kennedy1:11:39

        Yeah. Yeah

    28. PAPeter Attia1:11:39

        ... as we talk about it. Yep.

    29. BKBrian Kennedy1:11:40

        Yeah. So, um, you know, if we could, if that translated to humans, it would be a big impact, and so that's what led to the human product.

    30. PAPeter Attia1:11:47

        By the way, I think that if you did not extend lifespan by a day-
13. 1:13:41 – 1:17:35

    Exploring urolithin A’s potential to enhance mitochondrial health, reduce frailty, & slow aging

    1. BKBrian Kennedy1:13:41

       of thing so.

    2. PAPeter Attia1:13:41

       Did you guys do a study on urolithin A as well?

    3. BKBrian Kennedy1:13:44

       We haven't published it yet, but I am happy to talk a little bit about it. We don't have human data, but the mouse data is really good on urolithin A. I, I'm a believer. It, it worked-- In our hands, the first-- Well, this is why we haven't published yet, because when we did it, it dramatically reduced frailty in male mice, but not females, and so we're repeating that because I, I-- there may be sex-specific differences, but we were the first ones to see that, so we want to go back and see what's going on.

    4. PAPeter Attia1:14:09

       Now, I feel like I've, I feel like I've written a newsletter on this where I came down on the side of this isn't doing anything. Um, is-- Am I mistaking this for a different molecule? Is this the one that, in theory, enhances mitochondrial function? Is that the-

    5. BKBrian Kennedy1:14:26

       Yeah

    6. PAPeter Attia1:14:26

       ... the thought, the, the, the assumed-

    7. BKBrian Kennedy1:14:28

       The idea is it enhances mitophagy, so turnover-

    8. PAPeter Attia1:14:30

       Yeah

    9. BKBrian Kennedy1:14:30

       ... of damaged mitochondria. I'm not sure I completely agree with that. We do see that in cell culture, but we also see mitochondrial biogenesis. And so-

    10. PAPeter Attia1:14:38

        Hmm

    11. BKBrian Kennedy1:14:38

        ... these two things are connected, right? If you induce mitochondrial biogenesis, you'll also induce mitophagy, and so it's kinda-- I'm not sure whe-wh-who's-- which, where is the chicken and where is the egg in this, but it does seem to, uh, in-induce mitochondrial turnover. But we also find other pathways. We've done-- We-- When we look at a molecule, if we don't know enough about it, we, uh, like rapamycin, we know it binds to mTOR. Urolithin, we don't know what it does. And AKG also, we know a lot of things it can do. We don't know which ones are relevant for aging. Uh, for urolithin, we went back and did this screening assay to, a proteomics thermal shift assay that, to look for binding partners for the compound, and we have some.

    12. PAPeter Attia1:15:17

        So how-- Tell me about the history that led to using it.

    13. BKBrian Kennedy1:15:20

        Well, for us, I mean, uh, Johan Auwerx published this, uh, data that it was slowing aging in mice, and that's, uh, led to a lot of research, so we weren't the first ones to study urolithin. Uh, and a lot of what we do is testing interventions that come from other labs because if I'm going to do a human study, I want to at least see it repeat in my hands in an animal first.

    14. PAPeter Attia1:15:42

        Absolutely. Yeah.

    15. BKBrian Kennedy1:15:42

        If it doesn't repeat in my hands, that doesn't mean it doesn't work. It may mean the conditions are different, but I think it does-- if it does repeat, it makes an argument for robustness. Um, and so that's why we started urolithin. We've, we also see positive effects of spermidine and glycine and other things. Um, but, um, yeah. So, uh, we, we didn't make the initial discovery on urolithin, but, you know-

    16. PAPeter Attia1:16:08

        So we don't know the mechanism of action.

    17. BKBrian Kennedy1:16:09

        Well, they would argue it's increased mitochondrial turnover, but we have-

    18. PAPeter Attia1:16:12

        But we don't have a target.

    19. BKBrian Kennedy1:16:13

        We have targets we haven't published yet. [chuckles]

    20. PAPeter Attia1:16:15

        Oh, you do?

    21. BKBrian Kennedy1:16:15

        Yeah, yeah.

    22. PAPeter Attia1:16:16

        Okay. Are you-- Did you guys discover the target?

    23. BKBrian Kennedy1:16:18

        Yeah. We, we've got a couple new targets that we haven't published yet, so, that could explain some of the effects.

    24. PAPeter Attia1:16:24

        And have you studied this in humans yet?

    25. BKBrian Kennedy1:16:26

        No, not yet. That's planned, but hasn't been done yet.

    26. PAPeter Attia1:16:30

        This might be actually one of the ones where I would say, unlike in the RAPA trial, you actually want to come up with primary outcomes that are quite different here.

    27. BKBrian Kennedy1:16:39

        Yeah.

    28. PAPeter Attia1:16:39

        This is where-

    29. BKBrian Kennedy1:16:40

        Yeah

    30. PAPeter Attia1:16:40

        ... uh, for example, I'd want to see fat oxidation.
14. 1:17:35 – 1:26:50

    Potential of sublingual NAD for longevity

    1. BKBrian Kennedy1:17:35

       So it's kind of you win twice with some of these. And I, I'll tell you what happened recently. I've been very skeptical of NAD. Uh, uh, not that going down and restoring it won't be good, but I'm skeptical it's going through sirtuins. I think it could be doing a lot of other things. Uh, but I'm also skeptical that NR, NMN are really changing NAD levels that much, and our mice don't really respond in our studies with NR, NMN. I've never noticed anything taking NR. Again, that's just one person, but that's me.

    2. PAPeter Attia1:18:04

       And, and, and when I last looked at this, and I know I'm going to get a lot of hate mail, 'cause I always get hate mail when I talk about this.

    3. BKBrian Kennedy1:18:11

       [chuckles]

    4. PAPeter Attia1:18:12

       The only study I've seen in humans that shows a real benefit of NR was in patients with ALS that had-

    5. BKBrian Kennedy1:18:22

       Mm-hmm

    6. PAPeter Attia1:18:22

       ... the, the patients in the NR group had a, a longer time before requiring ventilation than the patients on the placebo.

    7. BKBrian Kennedy1:18:29

       Yeah.

    8. PAPeter Attia1:18:30

       Uh, is there another study I'm missing?

    9. BKBrian Kennedy1:18:32

       Well, there have been healthspan studies arguing improved healthspan, but I-

    10. PAPeter Attia1:18:35

        But, but by what metric?

    11. BKBrian Kennedy1:18:37

        Yeah, I don't re-- I, I can tell you we've done them as well, and, and we do see very subtle changes with NR and, uh, and that, th- that are aspects of the frailty measurements we do.

    12. PAPeter Attia1:18:48

        In, in mice or in humans?

    13. BKBrian Kennedy1:18:49

        In mice, but it's not enough to really convince us it's statistically significant. So-

    14. PAPeter Attia1:18:53

        Yeah

    15. BKBrian Kennedy1:18:53

        ... I, I'm, I wouldn't be shocked if there's a tiny effect is what I'm saying. But it's, um-

    16. PAPeter Attia1:18:57

        Okay. And why do you think that is? Do you think it's that NR-

    17. BKBrian Kennedy1:19:01

        Yeah

    18. PAPeter Attia1:19:01

        ... and NMN are not efficient vehicles to generate enough NAD?

    19. BKBrian Kennedy1:19:05

        Yeah, I think that's one thing for sure. But Well, let me tell you the rest of the story, 'cause I- I've pretty much given up on the pathway, and a company that, um, came to me and wanted to test one of their products, and it-- this company is called iX Biopharma. Anyway, they have a new product that's sublingual NAD. So they, they don't, they, they specialize in technology for sublingual delivery, and they make other things too, uh, by egg or sublingual.

    20. PAPeter Attia1:19:30

        So we'll just explain to folks why that matters.

    21. BKBrian Kennedy1:19:32

        Yeah.

    22. PAPeter Attia1:19:32

        You can't take NAD orally-

    23. BKBrian Kennedy1:19:33

        Yeah

    24. PAPeter Attia1:19:33

        ... 'cause it just gets destroyed.

    25. BKBrian Kennedy1:19:35

        Exactly. Yeah.

    26. PAPeter Attia1:19:35

        So typically, people take-

    27. BKBrian Kennedy1:19:37

        Yeah

    28. PAPeter Attia1:19:37

        ... NAD intravenously.

    29. BKBrian Kennedy1:19:38

        Yeah.

    30. PAPeter Attia1:19:39

        But if you take something under the tongue, you get this magical property where it dissolves, and it enters the circulation without passing through the digestion-
15. 1:26:50 – 1:34:33

    Other interventions that may promote longevity: spermidine, 17𝛼-estradiol, HRT, & more

    1. PAPeter Attia1:26:50

       Yeah. Um, you mentioned spermidine a moment ago.

    2. BKBrian Kennedy1:26:52

       Yeah.

    3. PAPeter Attia1:26:52

       Let's talk about that. It's getting quite a bit of buzz.

    4. BKBrian Kennedy1:26:55

       Yeah.

    5. PAPeter Attia1:26:55

       Um, tell us, tell us everything about spermidine.

    6. BKBrian Kennedy1:26:58

       Well, so, uh, we studied that a while ago when I was at the Buck, and, uh, we wanted to look at-- We were confused because at that time, the data was spermidine could extend lifespan, but it didn't impact metabolism. And I'm like, "Almost everything in a mouse [laughs] that extends lifespan has some impact on metabolism." So we did a high-fat study with spermidine, and, and we, and we showed that in old animals, spermidine could suppress the metabolic, uh, dysfunction that came from a high-fat diet in mice. But we had some control mice too, and actually not many, but the con-- 'cause of the desi- the study wasn't designed to do lifespan, but we left them alive and looked at survival, and the spermidine extended the lifespan of the mice too.

    7. PAPeter Attia1:27:40

       Has spermidine been studied in the ITP?

    8. BKBrian Kennedy1:27:43

       I don't think it has.

    9. PAPeter Attia1:27:44

       I don't think it has, does it?

    10. BKBrian Kennedy1:27:44

        Don't think it has. Don't quote me, but I don't think it has.

    11. PAPeter Attia1:27:49

        Okay. Yeah.

    12. BKBrian Kennedy1:27:50

        Um, and so we, we were able to repeat the lifespan effect in mice even though that wasn't the goal of our study and, and show that it, it restores metabolism in a, in a, a calorie challenged context. Um, and so that's what made me believe that, that, you know, we-- it's a robust molecule, that we can see that effect as well. So I, I, I would say I'm optimistic about spermidine as well, that we haven't done a lot with it.

    13. PAPeter Attia1:28:13

        Where does spermidine occur in nature?

    14. BKBrian Kennedy1:28:15

        [sighs] In your-- Um, I actually don't remember [laughs] the answer to that.

    15. PAPeter Attia1:28:24

        But it's naturally occurring.

    16. BKBrian Kennedy1:28:25

        It, uh, it does naturally occur, yes. Yes. Yes.

    17. PAPeter Attia1:28:27

        So there's no, um-

    18. BKBrian Kennedy1:28:29

        I think it's in certain, certain foods or have it, but I'm, I'm worried I'm conflating that with the urolithins, so I don't know.

    19. PAPeter Attia1:28:35

        Okay. Have you guys looked at alpha-estradiol 17?

    20. BKBrian Kennedy1:28:39

        No, we haven't looked at that. Um, I, I, I wish we looked at it.

    21. PAPeter Attia1:28:42

        That would be an interesting one to look at.

    22. BKBrian Kennedy1:28:43

        Yeah. I, I agree. And I, I'm also run director of an Asian center for reproductive longevity and equality in, in, in US and Singapore, where we're looking at ovarian aging.

    23. PAPeter Attia1:28:54

        Mm-hmm.

    24. BKBrian Kennedy1:28:55

        And there's two things I've l-- It's, it's made me-- This is like, you know, it's like PhD biologist, you know, all of a sudden I'm getting asked a million questions about HRT, so I decided I better learn something. [laughs] Um, but there's two things that I've learned from this. One is that geroprotectors tend to extend fertility in mice.

    25. PAPeter Attia1:29:14

        Yep.

    26. BKBrian Kennedy1:29:14

        And it's not just one thing. It's spermidine, it's AKG. It's been shown for metformin and rapamycin in, in, in one of the-

    27. PAPeter Attia1:29:20

        There's a RAPA trial going on, I think, in Columbia or Cornell

    28. BKBrian Kennedy1:29:23

        ... yeah, in my-- Yeah. So, yeah.

    29. PAPeter Attia1:29:24

        Yeah.

    30. BKBrian Kennedy1:29:24

        And, uh, so that's one really potentially, uh, useful avenue of translation for these geroprotectors. I'm really excited about that. The other thing I think, and maybe-- The-- You're-- You have more expertise than I do, so you're-- please disagree, is that the question should not be, should a woman do HRT? The question should be, is there any reason a woman should not do HRT?
16. 1:34:33 – 1:45:01

    Biological aging clocks, clinical biomarkers, & a new path to proactive longevity care

    1. PAPeter Attia1:34:34

       So do you think that there could be value in this as a tool, right? And, and, and let me hold the bar as high as I think it would need to be to justify their use. So right now, we have this thing called chronologic age. Um, I can look at your birth certificate, I can know how old you are, and based on that, I can make an estimate of how much longer you will live.

    2. BKBrian Kennedy1:34:56

       Mm-hmm.

    3. PAPeter Attia1:34:57

       So if I look at a person who's 40 years old and I know nothing else about them, and then I see another person who is 65 years old, and I know nothing else about them, I can say with a high degree of confidence that the 65-year-old person will live, you know, I'm making this up because I'm not an actuary, but somewhere between 20 and 30 more years.

    4. BKBrian Kennedy1:35:21

       Yeah.

    5. PAPeter Attia1:35:21

       And the 40-year-old person, I can say with a pretty high degree of confidence will live s- you know, whatever, somewhere between, uh, call it, you know, 30 to 50 more years or something like that.

    6. BKBrian Kennedy1:35:32

       Mm-hmm.

    7. PAPeter Attia1:35:34

       Um, now to me, that's a pretty good test.

    8. BKBrian Kennedy1:35:38

       Mm-hmm.

    9. PAPeter Attia1:35:38

       Right? I know, I know, I know a me- I know a knowable, measurable thing about them. Um, it's measurable by knowing their birth date, right? Um, and it predicts future life.

    10. BKBrian Kennedy1:35:50

        Mm-hmm.

    11. PAPeter Attia1:35:51

        So do you think biologic clocks will ever serve a purpose like that, where I could, um, take two 50-year-olds and one of them has a biologic age of 40 and one of them has a biologic age of 60 according to the clock, and that those numbers will actually be better at predicting future life than their chronologic age of 50? Or do you put yourself in the camp that says, "No, Peter, that's a ridiculous standard that no biologic clock could ever come to, but it might tell me about their health. It might be yet another biomarker that says, 'Hey, the guy at 40 is just healthier than the guy at 60.' And somehow, by the way, it's picking that signal out of a data field that I can't pick out anywhere else-

    12. BKBrian Kennedy1:36:38

        Yeah

    13. PAPeter Attia1:36:38

        ... 'cause they otherwise look identical."

    14. BKBrian Kennedy1:36:40

        We measured this recently, uh, 'cause we, uh, uh, collaborators of mine at NUS and, uh, uh, Jan Gruber and Feng Sheng, uh, and I had this small role in this project. Um, they decided-- Feng Sheng's a, a geriatrician. He sees people all the time, uh, frustrated. You know, what can-- Geriatricians have limited things they can do. They're seeing people that already have multimorbidity and, uh-

    15. PAPeter Attia1:37:05

        Mm.

    16. BKBrian Kennedy1:37:07

        You know, he, you know, the clocks are not that useful, and so he's wanted to like, "How do we create a reliable clock that a doctor can understand?" And so we-

    17. PAPeter Attia1:37:15

        For what purpose?

    18. BKBrian Kennedy1:37:17

        For, um, biologic age. I'll, I'll tell you what I think the purpose is for it in a minute.

    19. PAPeter Attia1:37:21

        Okay.

    20. BKBrian Kennedy1:37:22

        Um, uh- And this build is-- so they're first generation and second generation clocks. The first generation clocks try to predict your chronologic age, and the second ones predict some outcome. So the question is, we want to predict mortality. We don't want to predict your chronologic age.

    21. PAPeter Attia1:37:36

        Yep.

    22. BKBrian Kennedy1:37:36

        So intrinsically, if it works, it's going to do better [chuckles] than the, than chronologic age for the second generation clocks. Um, so we took NHANES-

    23. PAPeter Attia1:37:45

        Yeah

    24. BKBrian Kennedy1:37:45

        ... you know, data collected around 1999, 2000, mortality data for two hundred months. Uh, and we just-- and, and these parameters are nice and because you can actually do a consumer test of HbA1c, you know. [chuckles]

    25. PAPeter Attia1:37:59

        Yep.

    26. BKBrian Kennedy1:37:59

        There are many labs that do that. It's reproducible to a large extent, much better than DNA methylation. And doctors use all these parameters. So at-- the things that are in NHANES, like LDL, you know, all the things in your book, [chuckles] inflammatory markers, you know, um, medical tests, uh, you know, some so- some cognitive self-reported stuff. So we just took everything as a feature and used AI, uh, linear model to try to predict mortality. Um, and, uh, they're on-- we're on the second generation of this clock now. Uh, and it predicts mortality better than any other parameter in NHANES. It's way better than ASCVD. Uh, there's cardiovascular disease measurement. Um, and so recently, the methylation data came out on NHANES, and so we could go back and compare the mortality prediction for methylation clocks. Some of the first generation clocks are worse than chronologic age. Your passport is better than they [chuckles] are at predicting mortality, which to me means that they're not useful because, y- you know, even if they're not designed to predict mortality, if they don't capture some element of that, what are they measuring, you know? The second generation clocks like GrimAge and PhenoAge, they do better job than chronologic age for sure.

    27. PAPeter Attia1:39:17

        At predicting mortality?

    28. BKBrian Kennedy1:39:18

        Predicting mortality, yeah.

    29. PAPeter Attia1:39:19

        And just to be clear, we've captured that out of the NHANES database?

    30. BKBrian Kennedy1:39:23

        That's from NHANES. That's the only thing we've looked at right now.
17. 1:45:01 – 1:51:19

    Evaluating rapamycin, metformin, & GLP-1s for longevity in healthy individuals

    1. BKBrian Kennedy1:45:01

       the standard things. And so-

    2. PAPeter Attia1:45:02

       So do you think metformin will have, um, geroprotective properties in people who are metabolically healthy?

    3. BKBrian Kennedy1:45:11

       Skeptical. But I, I think what it is saying is that if you catch preconditions early enough, you keep, you, you p-protect against the other failure states a little bit too. So it, it's, uh-

    4. PAPeter Attia1:45:22

       So you're more optimistic that rapamycin would be geroprotective in humans than metformin?

    5. BKBrian Kennedy1:45:26

       Yeah, uh, that would be my prediction, yeah.

    6. PAPeter Attia1:45:28

       Do you think there is a drug out there that you think is more, um, likely to be geroprotective in humans than rapamycin at this time?

    7. BKBrian Kennedy1:45:37

       Well, the, the GLP, um, drugs, uh, and SGLT2 I think are interesting. I don't think-

    8. PAPeter Attia1:45:44

       I agree, yeah

    9. BKBrian Kennedy1:45:44

       ... we have the data right now, but it's definitely... Again, I don't know in people that are... You know, if you're obese, I n-

    10. PAPeter Attia1:45:52

        Yeah. Let-

    11. BKBrian Kennedy1:45:52

        No [laughs]

    12. PAPeter Attia1:45:52

        Okay. So let me, let me restate the question.

    13. BKBrian Kennedy1:45:54

        Yeah.

    14. PAPeter Attia1:45:54

        If, if we, if we just took a population-

    15. BKBrian Kennedy1:45:57

        Yeah

    16. PAPeter Attia1:45:57

        ... of middle-aged-

    17. BKBrian Kennedy1:45:58

        Yeah

    18. PAPeter Attia1:45:58

        ... healthy individuals-

    19. BKBrian Kennedy1:46:00

        Yeah, yeah

    20. PAPeter Attia1:46:00

        ... and we des- we could design an experiment where-

    21. BKBrian Kennedy1:46:04

        Yeah

    22. PAPeter Attia1:46:04

        ... you had the placebo arm-

    23. BKBrian Kennedy1:46:05

        Yeah

    24. PAPeter Attia1:46:05

        ... the metformin arm, the rapamycin arm-

    25. BKBrian Kennedy1:46:08

        Yeah

    26. PAPeter Attia1:46:08

        ... the SGLT2 inhibitor arm, and the GLP-1 agonist arm, what is your prediction in length of life or additional years of life given in that, uh, six-arm study or whatever it is?

    27. BKBrian Kennedy1:46:20

        I, I think the, the, the last three would be comparable. Metformin, I'm skeptical of.

    28. PAPeter Attia1:46:25

        So RAPA, SGLT2-

    29. BKBrian Kennedy1:46:27

        Yeah

    30. PAPeter Attia1:46:27

        ... GLP-1.
18. 1:51:19 – 1:53:37

    Why muscle, strength, & fitness are the strongest predictors of healthspan

    1. BKBrian Kennedy1:51:19

       I, I think lean muscle mass is, like, super important. [laughs] Yeah, it's probably better to have high lean muscle mass and be a little bit more fat than it is to be low on both is my best guess.

    2. PAPeter Attia1:51:30

       Now, what do you make of the data that I talk about all the time, which look at the hazard ratios for mortality based on high VO2 max and high muscle mass and high strength, and how those three things stand out so far above anything else? Uh, meaning, like, when you look at hazard ratios associated-

    3. BKBrian Kennedy1:51:54

       Yeah

    4. PAPeter Attia1:51:54

       ... with smoking-

    5. BKBrian Kennedy1:51:55

       Yeah

    6. PAPeter Attia1:51:55

       ... type 2 diabetes-

    7. BKBrian Kennedy1:51:56

       Yeah

    8. PAPeter Attia1:51:56

       ... even cancer-

    9. BKBrian Kennedy1:51:57

       Yeah

    10. PAPeter Attia1:51:57

        ... um, they are not as lethal as being incredibly weak, incredibly low in muscle mass, and incredibly low in fitness.

    11. BKBrian Kennedy1:52:07

        Yeah.

    12. PAPeter Attia1:52:08

        And do you-- how much causality do you think is there versus how much of that is just those are just such good markers of health?

    13. BKBrian Kennedy1:52:15

        I think there's causality there. I think it's super important, but it may only be important for squaring the curve. I, I don't think there's much evidence that maximum lifespan is extended by these things. And we don't have the human data, of course. The animal data-

    14. PAPeter Attia1:52:27

        We can't do the experiment.

    15. BKBrian Kennedy1:52:28

        The animal data's pretty much with exercise says you square the curve. Again, that's, I agree with you. It's a revolution if we can do that. Uh, I'm not, I'm not being negative about it, but I-

    16. PAPeter Attia1:52:38

        Yeah, but-

    17. BKBrian Kennedy1:52:38

        ... don't know about maximum lifespan, whether there'd be an effect or not. But I believe it so much that I put a lot of effort in increasing my lean mass, you know. And, and so I-- that's why I started resistance training, 'cause I wasn't getting as much from running. I get, I get more mindfulness from running. [laughs]

    18. PAPeter Attia1:52:54

        Yeah.

    19. BKBrian Kennedy1:52:55

        You know? I g- I get, uh, but I did a lot more resistance training too, so.

    20. PAPeter Attia1:53:00

        Yeah. I, I, I typically will tell patients that exer-- you should really think of exercise-- Yeah, I, I do actually think it's, it's reducing your risk of chronic disease.

    21. BKBrian Kennedy1:53:11

        Mm-hmm.

    22. PAPeter Attia1:53:11

        Um, but then you still get into the whack-a-mole game.

    23. BKBrian Kennedy1:53:13

        Mm-hmm.

    24. PAPeter Attia1:53:13

        If it lowers your risk of Alzheimer's disease, it might not have much of an impact on cancer risk.

    25. BKBrian Kennedy1:53:17

        Yeah.

    26. PAPeter Attia1:53:17

        It's unclear. But, um, if it didn't, if it lowered your life expectancy by six months, it would still be worth it based-

    27. BKBrian Kennedy1:53:25

        Probably, yeah

    28. PAPeter Attia1:53:26

        ... on the healthspan benefits that you get-

    29. BKBrian Kennedy1:53:27

        Yeah, probably

    30. PAPeter Attia1:53:27

        ... and the quality of life that you would enjoy-
19. 1:53:37 – 1:56:06

    Why combining too many longevity interventions may backfire

    1. BKBrian Kennedy1:53:37

       interventions. [laughs] You know, first of all, I will say two things before I say what I'm gonna say. One is that I believe we need to empower people to make decisions on their own health. And so I support hackers. If they wanna, you know, educate themselves and try different things and they know what the benefits and risks might be and what we know and we don't know, more power to them. I feel like part of the reasons we get such low compliance in medications is that we don't empower people. We don't give them choices. They don't know why they're doing things. We just tell them what to do, and people don't respond well to that. So having said that, I can't pick three interventions that work well together [laughs] in a, in a mouse. You know? And we do these studies all the time. The thing-- they're more likely to cancel each other out than to have additive effects. And so if you're mixing 20 colors of or taking 20 pills, it's like mixing 20 colors of paint together. You're gonna get some ugly gray outcome. Or at best, you're gonna get an unknown outcome that we can't predict.

    2. PAPeter Attia1:54:37

       Hmm.

    3. BKBrian Kennedy1:54:37

       So I'm, I're really cautious and wanna tell people that, you know, there are a lot of people out there promoting doing a million different things at the same time. I try one or two things at the same time. [laughs] And I, I try to see how my body responds. I measure things. Measure-- even simple measures are useful. Uh, and I think that, um, if you're doing 10 things, you're, you don't have any idea what's working and what's not working and whether things might be impairing each other, and I really think that's a scary path to go down.

    4. PAPeter Attia1:55:08

       Now what about, for example, how are you deciding to use the alpha-ketoglutarate and the NAD if-- I mean, 'cause you've s- you've seen at least some evidence that each of those individually works.

    5. BKBrian Kennedy1:55:20

       Yeah. I, I've been using the, the, the Rejuven with the AKG for a long time because I, I was involved in the research. You know, I'm on the, I'm actually on the board of the company. [laughs] I, I, I-- it's something I've done and I've just taken for years. And I add one thing to it and take it away. So I've tried astaxanthin. I've tried fucoidan. I've tried rapamycin. I've tried a bunch of other things too, so. And I try to measure before and after. I've got-- I'm, I'm getting better at that. When I first started doing it, I wasn't measuring that much. But, uh, and so that-that's the approach I take. Um, but I, I never take like six things at one time.

    6. PAPeter Attia1:55:57

       Yeah.

    7. BKBrian Kennedy1:55:57

       And, and it's, it's kind of intuitive. If something's interesting to me, you see an effect on the mice, I wanna try it. So like, I wanna do urolithin and astaxanthin next

20. 1:56:06 – 2:02:07

    How AI integration could accelerate breakthroughs in aging research

    1. BKBrian Kennedy1:56:06

       and-

    2. PAPeter Attia1:56:06

       If you had significantly more resources, right? So let's say you had, um, a budget that is... What, what is your current budget this year for both animal and human research?

    3. BKBrian Kennedy1:56:18

       Uh, it's complicated because we have multiple streams. I would say we probably spend about four million a year in total.

    4. PAPeter Attia1:56:23

       Okay. So if that number were multiplied-

    5. BKBrian Kennedy1:56:25

       Yeah

    6. PAPeter Attia1:56:25

       ... by ten-

    7. BKBrian Kennedy1:56:26

       Yeah

    8. PAPeter Attia1:56:27

       ... um, or twenty.

    9. BKBrian Kennedy1:56:28

       Yeah.

    10. PAPeter Attia1:56:28

        Like if you had a hund- twenty-five. If you had a hundred million dollar annual budget to do world-changing translational geroscience, what would you be doing different?

    11. BKBrian Kennedy1:56:40

        I, I think the scale would be one. We just can't-- When you do a combination in mice, you've got four groups, you know? [chuckles] And I think we-- if we had more money, we could design sort of multifactorial clinical studies and preclinical studies where we're testing many compounds at the same time. We're sort of doing nested groups, you know, and, and we could get a indication for things that actually could be additive together, uh, not just things that are working on their own. Right now, we struggle to get to that next step for finances, and we could apply those to human studies and combine it with lifestyle interventions too. The other thing we really believe is that when you have a compound like urolithin, you're never gonna really know what to combine it with unless you know what the compound's doing. So we do a lot of discovery stuff now trying to figure out w- not what pathway. If you take a drug like rapamycin, it affects every hallmark. That doesn't tell you the primary thing the drug is doing. In this case, we know it binds TOR. Urolithin, we don't know. So we need to know what that molecule's binding to in the cell. And if we understand the mechanism at that level, we can combine it better with other interventions and start to understand how to put the puzzle together of what we need to combine to get the biggest effect.

    12. PAPeter Attia1:57:55

        Do you have enough human resources to deploy that kind of capital if it were available?

    13. BKBrian Kennedy1:58:01

        It would take a center to do it, but yeah, we could build it. And, and Singapore is very motivated, by the way. I have to give the government credit. They've understood the aging problem before almost anybody. It's taken them a long time to really figure out what to do about it. And, uh, you know, so they went through kind of early stages of putting roofs on sidewalks, so people walk an extra hundred steps in the hot sun. You know, that sort of stuff [chuckles] helps. But, you know, uh, but now I think they're really motivated to commit to, to targeting healthspan, which I... You know, if they do, th- it's the right place to be because it's a small island. It's a compliant population. They believe in their government.

    14. PAPeter Attia1:58:38

        What's the population?

    15. BKBrian Kennedy1:58:39

        It's five million, and then one extra-- one million workers and five million people that live there permanently. Uh, I think that it's a good place to, to really take studies, not just in the clinic, but move them into the community and actually get validation in large populations. And that's why I like being in Singapore. I think the opportunity's there to make it a, a, an example for how to do healthspan. It's already very long lived, by the way. So, you know, it's, uh, it's among the top three in the world, depending on what statistics you want. But the healthspan, the people still have morbidity there. They still have ten, twelve years of sickness and decline. If you-- There's a lot of frailty there. You can see that just walking around. So there's room for improvement, for sure.

    16. PAPeter Attia1:59:21

        How will AI help in this field? Do you, do you think it will allow for more intelligent experiments? Will it allow for better signal detection in messy data? Like, I mean, where-- how do we unleash AI on this problem?

    17. BKBrian Kennedy1:59:35

        We're, we're using it now already for clocks and signal detection. We're using it to pick drugs now. Um, we're-- we just published a paper with Gero Fullen in Germany, where we're trying to, um, improve how to ask large language models quest-- uh, medical questions related to longevity. Uh, you know, I, I, I talk to a lot of doctors, and they say that you shouldn't be asking Perplexity these questions, and I'm like, "I'm a realist." [chuckles] You know, people are asking. So let's figure out how to get them the questions asked-

    18. PAPeter Attia2:00:03

        Yeah

    19. BKBrian Kennedy2:00:03

        ... in the right way to get the right answer.

    20. PAPeter Attia2:00:04

        But I'm thinking more in terms of the research.

    21. BKBrian Kennedy2:00:06

        No, yeah, I'm just giving you examples there.

    22. PAPeter Attia2:00:08

        Yeah, yeah, yeah.

    23. BKBrian Kennedy2:00:08

        I think that, um, I think what's gonna happen next is AI's gonna start telling us what questions to ask.

    24. PAPeter Attia2:00:14

        Yeah.

    25. BKBrian Kennedy2:00:14

        Right now, it's telling us how to analyze our data.

    26. PAPeter Attia2:00:16

        Yep.

    27. BKBrian Kennedy2:00:17

        It's still not very good at telling us what the next question is, and I think that, that's the, that's the sort of the threshold.

    28. PAPeter Attia2:00:23

        How do we get it there? How do we-

    29. BKBrian Kennedy2:00:25

        Uh, well, yeah.

    30. PAPeter Attia2:00:25

        I mean, this is a very difficult que- I-
21. 2:02:07 – 2:10:50

    Need to balance innovation with safety in longevity clinics

    1. PAPeter Attia2:02:07

       So what are you most excited about trying to uncover truth or high probability of truth in the next five years?

    2. BKBrian Kennedy2:02:18

       I think experimentally, at least preclinically, we wanna find interventions that really combine together to have synergistic impacts. I don't think there's much out there. There's rapamycin and metformin and a couple other things from the ITP, but they're small effects. Can we break through a barrier and get 50, 60% effects in mice by combining things together? I, I think that's what preclinically we're excited about. And the other thing I'm excited about is going back to this entropy question. Are there new classes of interventions that change that primary, um, linear accumulation of, of quote unquote damage? Um, I'm also really excited now that I'm working with longevity clinics in various countries and, uh, um, so we're applying the clock we built. We're also helping them try to decide which interventions to do and ho- hopefully collect data so it can be analyzed because I think there's so much going on. I, I tell this joke all the time, I'm getting scared to tell it more, but, um, you know, it used to be that yeast and worms and flies were the model organisms for aging research, and now billionaires are the model organisms 'cause they're doing all kinds of stuff I can't even test, and I'm really curious to see what's happening. Uh, some of it I, I guess might work, some of it I guess might not work, but we're, we're-- we can't find out any other way, and I, I don't wanna see these clinics working in, in, in isolation and nobody's ever at least learning what, what's coming out of the data, even if it's not perfect. So I'm excited to work with these clinics and, and go see what they're doing right now. That's maybe not the answer to your question, but there's a lot of cutting edge stuff going on, and I will pretty much work with people if they're doing something I consider safe and if they're honest about the data on efficacy. Those are the two things I ask, transparency and safety. And, uh, and then I'm happy to, to like try to interact.

    3. PAPeter Attia2:04:12

       What are you seeing that you're worried about? What trends do you see that people are doing from a, from a biohacking longevity standpoint that, that have you concerned? Uh, either-

    4. BKBrian Kennedy2:04:21

       Yeah

    5. PAPeter Attia2:04:21

       ... and I'll put this in two buckets. The, the higher bucket would be safety.

    6. BKBrian Kennedy2:04:25

       Yeah.

    7. PAPeter Attia2:04:25

       The second bucket would be predatory behavior around basically people getting their, you know, having, having their money wasted, even if the agents that are being sold are not necessarily harmful.

    8. BKBrian Kennedy2:04:36

       Yeah. I, I think the first one, I, I, I'm excited about gene therapy. Don't, don't get me wrong. I think it's interesting, and it may really change the field going forward. I even kinda like follistatin, uh, but I'm-

    9. PAPeter Attia2:04:47

       Follistatin is a protein.

    10. BKBrian Kennedy2:04:49

        Yeah. Yeah. But I think that those treatments are not very well proven yet, and I would not do it. I, I ask the question, would I do it myself?

    11. PAPeter Attia2:04:56

        You, you wouldn't spend $100,000 for follistatin gene therapy?

    12. BKBrian Kennedy2:05:00

        I probably don't have to spend the money, and I still haven't done it [laughs] so. Uh, I, I've done MSCs though, yeah, IV, to try that, and I think, you know, stem cells, it, it's a, it's a different question there. I think if you're repairing soft tissue damage or something like that and injecting them directly, it probably works. Um, for aging, I have no idea, but I think it's probably safe if you have a, somebody that's a good practitioner that knows what they're doing. But I think there's a lot of-- this is the problem with stem cells. You go places, and you really don't know who you're working with and, you know, if they're really treating the cells correctly, if you're putting the right things in your system, and so there, there's a safety concern there based on the practitioner, I think. Um, and so those are things that concern me. I, I, I'm-- I haven't gotten totally on board with growth hormone yet. I mean, I think probably used correctly might be okay. The data's in- interesting.

    13. PAPeter Attia2:05:56

        Are you aware of human data that, uh, and I'm in your camp, by the way, which is-- I actually had a bunch of friends over for dinner last night, and this came up and, yeah, I was sort of, uh, I said, "Look, I, I, I can't point to a study that tells you this is, this is a bad idea."

    14. BKBrian Kennedy2:06:10

        Yeah.

    15. PAPeter Attia2:06:11

        And I've never spoken to a person who takes a modest, judicious dose-

    16. BKBrian Kennedy2:06:16

        Yeah

    17. PAPeter Attia2:06:16

        ... of growth hormone who doesn't tell me they feel better.

    18. BKBrian Kennedy2:06:18

        Yeah. I agree.

    19. PAPeter Attia2:06:19

        So it's hard to believe-

    20. BKBrian Kennedy2:06:20

        [laughs]

    21. PAPeter Attia2:06:20

        ... it's not making people feel better.

    22. BKBrian Kennedy2:06:22

        Yeah.

    23. PAPeter Attia2:06:23

        Um, I also have never seen data to suggest it initiates cancer.

    24. BKBrian Kennedy2:06:28

        Yeah.

    25. PAPeter Attia2:06:29

        But it seems very biologically plausible that if you have cancer, small amounts of cancer-

    26. BKBrian Kennedy2:06:36

        Yeah

    27. PAPeter Attia2:06:36

        ... your probability that this becomes clinically significant is higher in that camp.

    28. BKBrian Kennedy2:06:40

        Seems like it. I agree.

    29. PAPeter Attia2:06:41

        Yeah. Um, again, I say that with no data.

    30. BKBrian Kennedy2:06:43

        Yeah, me too. [laughs]
22. 2:10:50 – 2:12:31

    Peter’s reflections on emerging interventions & the promise of combining proven aging compounds

    1. PAPeter Attia2:10:50

       Well, there are a lot of things we talked about today, Brian, that I can't wait to follow up on myself, so I'm really looking forward to the NHANES, uh, second gen clock paper.

    2. BKBrian Kennedy2:10:59

       Yeah.

    3. PAPeter Attia2:10:59

       That'll be interesting.

    4. BKBrian Kennedy2:11:00

       Yeah.

    5. PAPeter Attia2:11:00

       Again, my personal curiosity there will be, is that clock providing value over all the other data we have?

    6. BKBrian Kennedy2:11:06

       Yeah. Yeah.

    7. PAPeter Attia2:11:06

       My intuition is it won't.

    8. BKBrian Kennedy2:11:08

       Yeah.

    9. PAPeter Attia2:11:08

       But the fact that we now at least have a clock that can outperform biologic age-

    10. BKBrian Kennedy2:11:12

        Yeah

    11. PAPeter Attia2:11:13

        ... uh, or pardon me, chronologic age-

    12. BKBrian Kennedy2:11:15

        Yeah

    13. PAPeter Attia2:11:15

        ... is a step in the right direction. Uh, I'm gonna be very interesting to see some of the data that you've talked about a- as far as alpha-ketoglutarate. Um, you've also piqued my curiosity with the sublingual, um, LAD, uh, NAD, I'm sorry. And so that's, that's really interesting. Have you been able to measure NAD levels in your RBCs and track them?

    14. BKBrian Kennedy2:11:35

        I haven't done it myself. There have been some studies done that-

    15. PAPeter Attia2:11:38

        On that exact supplement?

    16. BKBrian Kennedy2:11:39

        Uh, yes. I, I'm-- I don't think, think anything is published. It's done by the company, but, uh.

    17. PAPeter Attia2:11:46

        Okay. And I do like this idea of taking ITP winners and combining them and seeing-

    18. BKBrian Kennedy2:11:54

        Yeah

    19. PAPeter Attia2:11:54

        ... if we can get... I mean, if you could get accretive value, I mean, that would be remarkable.

    20. BKBrian Kennedy2:12:00

        Yeah.

    21. PAPeter Attia2:12:00

        But even if you could just get additive benefit-

    22. BKBrian Kennedy2:12:02

        Yeah

    23. PAPeter Attia2:12:02

        ... it would be pretty amazing.

    24. BKBrian Kennedy2:12:03

        Yeah. Yeah, I think so, too, right now. I think that's still a hangup for the field.

    25. PAPeter Attia2:12:07

        Well, this was super interesting, Brian. I, um, I, I really appreciate you making the time to come out here.

    26. BKBrian Kennedy2:12:13

        Oh.

    27. PAPeter Attia2:12:13

        I know that being on a plane for that long is not always fun, but, uh-

    28. BKBrian Kennedy2:12:17

        That's where I live anyway, so it's fine. [laughs]

    29. PAPeter Attia2:12:20

        [laughs] Thank you.

    30. BKBrian Kennedy2:12:20

        Thanks a lot. [outro music]

Episode duration: 2:12:31