359 ‒ How metabolic and immune system dysfunction drive the aging process, NAD, aging clocks, & more

1. 0:00 – 4:16

   0:01:20-Eric’s journey from virology to geroscience

   1. PAPeter Attia0:00

      I talk about these things called the four horsemen, the four things that are basically coming for us all. I really should have added a fifth horseman, and that is immune health.

   2. EVEric Verdin0:09

      Thank you for bringing this up. There are two organs that are rate-limiting in terms of your aging, and it's the central nervous system and the immune system.

   3. PAPeter Attia0:17

      What is our strategy for mitigating immune decline?

   4. EVEric Verdin0:20

      The proof is in the puddi- pudding, in the way that we know exercising and a combination of exercise is the best anti-aging intervention we have.

   5. PAPeter Attia0:30

      Turn over to where you wanted to around metabolism.

   6. EVEric Verdin0:32

      What is it about metabolism that really is so important? I'm convinced that it is fuel utilization. I think ketones are probably the, the cleanest fuel to burn in terms of, again, byproducts, oxidative stress.

   7. PAPeter Attia0:44

      You're going to put more GLP-1 in the system. You're going to overcome the resistance at the beta cell. You make more insulin. You now have better glucose control. Everybody wins.

   8. EVEric Verdin0:54

      I just wanted to really experiment for myself to try to see, okay, what is this drug really doing? And it's, it's been nothing short of remarkable, I think.

   9. PAPeter Attia1:02

      How could it be that supplementing NAD does not lead to a longer, better life or some health benefit? [upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia. [upbeat music] Uh, Eric, thank you so much for, uh, for coming to, to Austin. I know it wasn't just to talk to me. I know that, uh, half of it was, uh, was getting you to drive on the track at COTA tomorrow with me, so, uh, we're gonna have some fun there.

   10. EVEric Verdin1:32

       My pleasure.

   11. PAPeter Attia1:33

       But, um, as much as I think the two of us could sit here and talk about race cars for the next three hours, I don't think the audience would appreciate it or care for it as much as they will care for what we will talk about, which is, um, your work in geroscience. Um, so maybe give folks a little bit of a sense of what attracted you to this field and, uh, y- you know, how your, how your journey and background, uh, brought you where you are.

   12. EVEric Verdin1:59

       It's a bit of a serendipitous type of story in a way that, uh, I, I'm an MD by training from Belgium. Did my last year of medical school at Harvard, and this just, uh, uh, sort of opened my wor- my eyes to a whole world. Uh, I was the first person in my family to go to college, so this was, uh, you know, ending up at Harvard with some of the best teachers, some of the best students, was just mind-blowing. And I went to medical school wanting to do research. There was a-- I never had that sort of a doctor fiber, I call it, so really wanted to actually do research. And, um, and so after this, um, finished medical school and came back for directly a postdoc, uh, at, at the Joslin Clinic working on diabetes and metabolism. And, um, and so this is where the story gets ser- circuitous. Um, ended up becoming interested in the, the reason for, uh, the, the etiology of Type I diabetes, um, and worked on viruses and autoimmunity. Um, this eventually led me to, you know, mostly a career in virology, which confuses people. So I spent many years working on, on a variety of viruses, including HIV and, and herpes viruses and so on. And through that work, we ended up cloning a family of protein called the, um, um, some of the first epigenetic regulators, the HDACs. And the HDACs at the time, that w- that was 1996, we were responsible for the cloning of a whole family of these epigenetic regulators, um, ended up being important in aging. And starting in around 1995, 1996, my lab slowly shifted towards the study of aging. And to this point today, actually, I only have one last postdoc in the lab who's working on, on HIV. M- The whole lab is actually focused on, on epigenetics, immunology, and metabolism so that the interface between these, uh, these variables. So in some way it's, it's, it's the beauty of an academic career, which, um, I've just followed my interests and, uh, and sometimes followed the money a little bit in terms of funding.

   13. PAPeter Attia4:01

       Yeah.

   14. EVEric Verdin4:02

       Um, and, uh, and now, I mean, I have another, uh, you know, additional responsibility, which is to lead the Buck Institute for Research on Aging. Uh, so I, I split my time between the lab and, uh, the sort of more leadership type of activities.

2. 4:16 – 8:28

   How dysfunction in the immune system & central nervous system can drive aging

   1. PAPeter Attia4:16

      Y- You mentioned two things there, uh, metabolism and immunology. Um, talk a little bit more about how each of those individually contributes to aging. I think most people will intuitively understand it, but, but t- talk maybe a little deeper about it.

   2. EVEric Verdin4:31

      Well, first, immunology, uh, is central to aging in many respects. Um, one of the... And we c- I hope we can talk, get to talk about this later. There is data showing that there are two organs that are rate limiting in terms of your aging, and it's the central nervous system and the immune system. And the reason, uh, for this is actually, uh, one could have predicted this based on the fact that both organs are distributed organs. If you think of your immune system, it's located in pretty much throughout the whole organism, and so its activity can influence the, the well-being or the, the functioning of every single organ. The same goes for, uh, the central nervous system, and there's a recent study coming out actually from the lab of, uh, Tony Wyss-Coray showing that, uh, uh, those biomarkers that measure aging in those organs appears to be, uh, the most predictive of your lifespan. There's also, um, incredible data showing, um, that if you induce a specific lesion in the immune system, for example, uh, in m- in mice model, if you, if you knock out, uh, ERCC1, a DNA damage repair, only in, in the bone marrow so that the whole immune system is affected, you actually induce accelerated aging in the whole organism and senescence in every single organ. So there's the, the immune system, what it's-

   3. PAPeter Attia5:56

      In what, in what model?

   4. EVEric Verdin5:58

      Uh, it's been done in two different models. In mice, so th- that's been done with the ERCC1 mutation. It's also been done by knocking down the, the major transc- uh, Tfam, the major transcription factor for mitochondria. So if you induce mitochondrial dysfunction only in the immune system, you induce secondary senescence in the whole organism.

   5. PAPeter Attia6:15

      Do you think that would be true in mammals? Uh, sorry, in humans?

   6. EVEric Verdin6:19

      And it's, that, that's always-

   7. PAPeter Attia6:21

      Yeah

   8. EVEric Verdin6:21

      ... that's the million-dollar question. In, in some way, the, it's been shown in, in two different models in mice-

   9. PAPeter Attia6:27

      B6, which, which-

   10. EVEric Verdin6:28

       Um, yeah, B6, I don't remember the exact-

   11. PAPeter Attia6:30

       Okay

   12. EVEric Verdin6:30

       ... uh, strain of the mouse, but, uh, uh, there, there's no reason why it should be different, frankly. Um, and it speaks to the importance of the immune system. The, the second way for the immune system is through chronic inflammation, which is, you know, tied cause and effect in the whole aging process. Um, now, and, and we can talk about this later as well, I, I find it fascinating, you know, the, the whole idea of chronic inflammation, which is induced by the aging process, but which itself actually further accelerates aging. So there's really a lot of, uh, a lot of work that's being conducted in this area. Um, the other one that you were asking is metabolism, I think is-

   13. PAPeter Attia7:10

       Can I ask you a question before we go?

   14. EVEric Verdin7:12

       Yes. Yeah.

   15. PAPeter Attia7:12

       Um, that's a very interesting idea that two organ systems that are gonna be rate-limiting in age are the central nervous system and the immune system, both of which are distributed. Where would you put the endothelium in that list as well, right? The endothelium is also quite distributed across the organism, and do you think that there's an inevitability to, uh, basically endothelial damage as a process of aging, which of course results in the leading cause of death, the, the atherosclerotic diseases? Would you, would you, do you think of it the same way, or do you think of it as different?

   16. EVEric Verdin7:44

       It's not sort of defined as an organ by itself. It's a cell type, but I, I agree with you, has incredible importance. Uh, and especially as it, as it affects the, you know, the heart and the cardiovascular system-

   17. PAPeter Attia7:56

       And the brain

   18. EVEric Verdin7:56

       ... which is-

   19. PAPeter Attia7:56

       Yeah

   20. EVEric Verdin7:56

       ... and the brain. Um, but I, I think of it, of it as, uh, not so much as an organ, but as more as a sort of a principle that maintenance of barrier function-

   21. PAPeter Attia8:07

       Yeah

   22. EVEric Verdin8:07

       ... in, in not only in, in the endothelium, but also in the skin, in the blood-brain barrier, are emerging as key areas to focus on if you want to maximize your longevity.

   23. PAPeter Attia8:19

       Yeah. The, I wa- I want to come back to this in great detail, Eric, but let's, for the sake of summary and synthesis, turn over to where you wanted to around metabolism.

3. 8:28 – 17:32

   Role of metabolism & oxidative stress in aging

   1. EVEric Verdin8:28

      So metabolism is, uh, essential, uh, to life expectancy. If you look at, uh, a- and for a number of reasons, and, and, um, one of them I, I, I'm convinced even though that theory has been somewhat discredited, the whole oxidative stress theory of aging, I still think oxygen is one of the major, um, major problems associated with the aging process. You know, n- we have not been able to target the oxidative stress, uh, using antioxidant. That has failed. It doesn't mean that the whole oxidative stress theory of aging is not valuable. I think living in a, an oxidative environment is really, you know, is, is one of the mechanisms that leads to aging, not the only one. Aging is pleomorphic. Um, so-

   2. PAPeter Attia9:17

      But just to make sure folks understand what you're saying, Eric, um, you're saying that, um, that the, the generation of free radicals through oxygen, so I don't know how technical we want to get for people, but I, I, I, I think unfortunately we might need to get a little more technical and, and, uh, apologies to those who don't want to go this deep. But, but we have to talk about kind of what the role of the electrons are in oxygen and why, uh, free radicals form and, and what they do. So, so may- maybe we do go a little deeper here and explain what you're saying, 'cause it, it's a, it's a, it's a very important concept, and I think we should probe it.

   3. EVEric Verdin9:50

      Well, [laughs] it, I don't, I don't know how, how much, I mean, maybe you, you'd, you'd do a better job at, at, uh, at, uh, explaining this in, in a, in, in, for the lay- lay- layperson. I mean, oxidative stress is the fact that, um, pretty much the, the main, uh, um, metabolic reaction are dependent on oxygen, uh, which gives its electron, uh, it's, uh, in, in the so-called respiratory chain. There is leakage in, of these electrons that are traveling down this, in respiratory chain, leakage at s- at specific places. You know, if the process was 100% efficient, the whole energy would be transferred from, from, uh, metabolites such as, uh, fatty acid-

   4. PAPeter Attia10:30

      Glucose or, yeah

   5. EVEric Verdin10:30

      ... glucose and so on. But it turns out the m- the mechanism is less, i- is actually leaky. These electrons, uh, uh, reacting with oxygen can generate these, um, byproducts called radical oxygen species, which are highly reactive.

   6. PAPeter Attia10:45

      Right. So they're not chemically stable the way we think of a normal atom of oxygen.

   7. EVEric Verdin10:50

      No. And so they tend to react with proteins, with fatty acid, and they induce lesions. And we have a whole, uh, I mean, the, the, the importance of this system in terms of, um, of protection against it is highlighted by the number of, uh, molecular system that we have that are actually protecting against this. And-

   8. PAPeter Attia11:09

      And, and we know that as we age, that leakage increases.

   9. EVEric Verdin11:13

      Exactly.

   10. PAPeter Attia11:14

       So something about the integrity of the mitochondria and the respiratory electron transport chain degrades as we age, and therefore we see more and more of this leakage, yeah?

   11. EVEric Verdin11:25

       Yes. Absolutely. And so out of this came the whole idea, well, let's just suppress oxidative stress. And, you know, there are chemicals, even some as simple as vitamin E, vitamin C, that you could imagine that by chemical knowledge would be predictive to be, uh, able to quench-

   12. PAPeter Attia11:45

       That's right. Yep

   13. EVEric Verdin11:45

       ... these radical oxygen species. And so the, a number of, so-

   14. PAPeter Attia11:50

       So the idea, sorry to just keep interrupting you, but I, we'll play off to each other to do this.

   15. EVEric Verdin11:53

       No, no, this, this, this is great.

   16. PAPeter Attia11:53

       Yeah. So, so you eat, for example, an antioxidant, and as you said, it neutralizes that reactive oxygen species with its unstable electrons, kind of like you would throw a blanket on a fire that's simmering.

   17. EVEric Verdin12:06

       Exactly. And that was the hope. So, um, when the theory was proposed, um, a whole industry actually grew up out of this, the whole antioxidants and the antioxidant diet and the-

   18. PAPeter Attia12:19

       [laughs]

   19. EVEric Verdin12:20

       ... um, you know, the vitamins and, and so on. You can still, by the way, that, that whole industry is still existing today.

   20. PAPeter Attia12:25

       Sure does.

   21. EVEric Verdin12:26

       Now, um, What happened is that when clinical trials were conducted in this area, they failed. And, and so, you know, people who think relatively simply decided, well, the antioxidant failed, therefore the theory has no validity. And I would say not so fast, because it turns out that these radical oxygen species also have important roles. Um, they actually are inducing an inflammatory response which can be protective. And a good example is, uh, during ex-exercise. Uh, there is some evidence of activation of oxidative stress, uh, during e-exercise, and if you, you know, neuter this, for example, with anti-inflammatory, uh, you probably remember the data showing that anti-inflammatory drug tend to sort of suppress some of the beneficial effect of exercise.

   22. PAPeter Attia13:13

       Beneficial effects of exercise.

   23. EVEric Verdin13:13

       It's the same, same whole idea. And so this is one case in which these, um, radical oxygen species can have, um, a, a protective role and actually a, a, a signaling role. So when you suppress it completely with these sort of global non-specific antioxidant, essentially you, you not only killing the bad guys, but you're also suppressing an important signaling mechanism.

   24. PAPeter Attia13:37

       There's another hypothesis that I would offer, which is, is it possible that, that there's a, there's still a net negative to the free radicals, so there might be some benefits, but more negatives, but it could be that the trials were using agents that were simply ineffective because the problem is we don't have a great biomarker for the state of free radicals. So it's sort of like saying, "I have a hypothesis that this biological process is bad. I can't measure it really, but I think it's bad. I have a drug that I think will tamp it down. Let's give the drug. The trial failed." Well, do you actually know if it tamped the thing down? Like, so you, you, we don't even know if we tested the hypothesis, correct? And so those would be kind of two distinct plausibilities.

   25. EVEric Verdin14:24

       I completely agree, and it's, it's quite often the case is that, I mean, the whole story of vitamin D is a good example-

   26. PAPeter Attia14:29

       Absolutely

   27. EVEric Verdin14:30

       ... where, where people are, will, will tell you, you know, vitamin D doesn't work because they conducted clinical trials, but they didn't, you know, fix, they didn't adjust the dose, they didn't measure the levels, so it, it's a bit the same, the same story. Uh, there are markers that you can, uh, actually do use i-in, in research environment like 5-hy-hydroxynonenal or protein carbonylation, which are i-indirect markers of lipid or protein, uh, oxidation.

   28. PAPeter Attia14:56

       And how efficacious and/or beneficial or, uh, I guess the word is maybe, uh, um, how complete are they in the scope of understanding, and have we demonstrated that mega doses of vitamin E or vitamin C will indeed suppress those markers in humans?

   29. EVEric Verdin15:12

       They're, they're not great.

   30. PAPeter Attia15:13

       Okay.
4. 17:32 – 23:42

   Other aspects of metabolism linked to aging: mitochondrial efficiency, fuel utilization, & glucose-modulating drugs

   1. PAPeter Attia17:32

      So tell me what else within metabolism you think is kind of a hallmark of aging. So, um, we obviously talked about the central part of metabolism, which is respiration and ATP generation and the leakage that occurs there. And, and basically, unfortunately, that just appears to be inevitable. Uh-

   2. EVEric Verdin17:54

      Yes.

   3. PAPeter Attia17:54

      But-

   4. EVEric Verdin17:55

      That, that's totally right. We will never stop the oxygen i-in our environment, so-

   5. PAPeter Attia17:59

      Yeah. Um, I do like to tell my patients that this is why I kind of harp on them to do a lot of zone 2 cardio training, right? So zone 2 very specifically by definition, right, is the canonical exercise you would do to maximize fat oxidation, which of course implies the most efficient use of the mitochondria. And the hypothesis, 'cause I don't think, you know, we don't have proof of this, but the hypothesis is training at that level for specific periods of time throughout the week is, is a way to improve the health and function of your mitochondria, which would hopefully imply that you're reducing that degradation of function. Do you think there's validity to that, at least, you know, first order logic?

   6. EVEric Verdin18:47

      Yeah. I mean, I, the proof is in the pudding, pudding in the way that we know exercising and a combination of exercise is the best anti-aging intervention we have to-

   7. PAPeter Attia18:58

      But do you think part of it is through that exact mechanism?

   8. EVEric Verdin19:00

      Yes. Yeah.

   9. PAPeter Attia19:00

      Yeah. I mean, that's-

   10. EVEric Verdin19:01

       Likely

   11. PAPeter Attia19:01

       ... that's been my hypothesis, but again, uh, the- we can't fully glean that in, in any human clinical trial.

   12. EVEric Verdin19:06

       No, hard to study. And I think, you know, your point allows me to sort of, to address your s- your, your question, what is it about metabolism that really is so important? I think, I, I'm convinced that it is fuel utilization. And you mentioned, you know, fatty oxidation versus glycolysis, and I'll add ketosis to this. I think if you think about, um, your metabolism is able to, to oxidize a number of different substrates: amino acids, fatty acids, glucose, and, and ketones.

   13. PAPeter Attia19:38

       And lactate.

   14. EVEric Verdin19:38

       And lactate.

   15. PAPeter Attia19:39

       Yep.

   16. EVEric Verdin19:40

       And every one of those actually burns with different efficiency. Both being a car aficionado, I, I think your audience probably knows also that, you know, there's different to burn diesel or to burn, uh, a, a hundred octane gas. And, you know, if you look at that hierarchy, I think ketones are probably the, the cleanest fuel to burn in terms of, again, byproducts, oxidative stress. Um, they, they seem to be really unique in this respect.

   17. PAPeter Attia20:06

       Yeah. How would you rank order from cleanest to dirtiest, inclusive of lactate?

   18. EVEric Verdin20:11

       Lactate, I would not be able to, to put it.

   19. PAPeter Attia20:13

       Okay.

   20. EVEric Verdin20:13

       I, I think it's probably clean. I would put it-

   21. PAPeter Attia20:15

       Yeah. I think, uh, my intuition is it is as well.

   22. EVEric Verdin20:17

       Yeah. But it would be the top would be, uh-

   23. PAPeter Attia20:19

       Beta-hydroxybutyrate

   24. EVEric Verdin20:19

       ... ket- ket- beta-hydroxybutyrate. Uh, acetoacetate is, is present at such low abundance, it's probably not relevant as, as a fuel, a fuel source. Uh, then fatty acid. Uh, next is, the worst is actually glucose. And when you think about metabolism and aging, for me, it goes to, um, a lot of the data that has emerged from, um, the ITP, for example, Intervention Testing Program. This, uh, this-

   25. PAPeter Attia20:45

       Rich Miller has been on several times.

   26. EVEric Verdin20:47

       Yes. I, I watched your, your recent podcast with, uh, Rich and, a- a- and others. Um, one of the remarkable thing when you look at the drugs that have a seven or, or whatever, 10 drugs that have emerged out of 80-

   27. PAPeter Attia20:58

       Yep

   28. EVEric Verdin20:58

       ... uh, they are really targeting glucose metabolism and, uh, you know, and, and very via completely different mechanism. Think about acarbose, which is blocking, you know, absorption of glucose. Think about the cana-

   29. PAPeter Attia21:12

       Canagliflozin

   30. EVEric Verdin21:12

       ... canagliflozin, which is, you know, targeting a protein that has nothing to do with links to, uh, protein, um, glucose reabsorption in the kidney. Think about metformin, which is, you know-
5. 23:42 – 29:45

   How inefficient glucose metabolism drives insulin, IGF-1 signaling, & accelerates aging

   1. PAPeter Attia23:43

      so what do you think it is about glucose metabolism that, that, that leads to this? Because for all intents and purposes, um, let's just go through the metabolic pathways, right? So glucose, six carbons, it gets broken down into pyruvate. You get your two pyruvates for one glucose, right? And then pyruvate can... It- let's just assume we're doing this under aerobic conditions, so we're not in a rush. We're going to take those pyruvates. Do they turn into acetyl-CoAs? I can't even remember.

   2. EVEric Verdin24:16

      Yeah.

   3. PAPeter Attia24:16

      To then enter the-

   4. EVEric Verdin24:17

      It's, it's actually one pyruvate, and that leads to, enters the mitochondria and, and becomes acetyl-CoA.

   5. PAPeter Attia24:23

      Acetyl. Okay, okay.

   6. EVEric Verdin24:24

      Yeah.

   7. PAPeter Attia24:24

      So what is it about that process that is not as efficient as when you are cleaving off carbons from a free fatty acid and those carbons are turning directly into, uh, I think just a straight acetyl-CoA and then entering, uh, the Krebs cycle? What, what is, what is the... I mean, it's a very subtle difference. Why does, why is one so much more inefficient?

   8. EVEric Verdin24:46

      You mean why is there more calories per fatty acid though?

   9. PAPeter Attia24:49

      No.

   10. EVEric Verdin24:50

       Or is that, is that-

   11. PAPeter Attia24:50

       No, no, no. That, that can be explained by the stoichiometry.

   12. EVEric Verdin24:52

       Yes. Yeah.

   13. PAPeter Attia24:52

       Why is one, quote-unquote, "dirtier"?

   14. EVEric Verdin24:54

       Oh, okay.

   15. PAPeter Attia24:55

       Yes, yes, yes.

   16. EVEric Verdin24:56

       I, I think, obviously, this is a really complicated question.

   17. PAPeter Attia25:00

       Yep.

   18. EVEric Verdin25:00

       So I, I don't know that I would be able to really tell you purely as fuels whether there is a difference. I think the biggest difference is in terms of the, the, the whole mechanism that they elicit. And when we think about glucose, I don't think necessarily of it, if you were to study it in, in a tissue culture dish, that one would be tox-- more toxic than the other. I don't think there's any evidence for this. But glucose, and particularly the form of glucose that we have not evolved to actually be exposed to, which is all the wheat products, you know, this fast form of glucose, um, elicits insulin secretion. And I think insulin and IGF-1, but particularly insulin, is the culprit in this whole process.

   19. PAPeter Attia25:46

       So you're not saying that one mole of glucose, one mole of free fatty acid, we know there's a difference in ATP generation, but you're not saying that there's a different... Assuming they're both going through the mitochondria, you're not saying there's a difference in free radical formation mole per mole? Or are you saying that it's this way?

   20. EVEric Verdin26:06

       Yeah.

   21. PAPeter Attia26:06

       There's another way to explain it, which is per mole of ATP, you need to run so much more glucose through that, of course, you're going to get more leakage.

   22. EVEric Verdin26:15

       Well, the, the, the key difference is that, um, the glucose is generating ATP not only via acetyl-CoA and pyruvate, but is also generating ATP in the intracellular-- intracytoplasmic components.

   23. PAPeter Attia26:29

       Right.

   24. EVEric Verdin26:30

       The fatty acids do not generate any.

   25. PAPeter Attia26:31

       That's right.

   26. EVEric Verdin26:32

       So I suspect that there might be-

   27. PAPeter Attia26:34

       Ah

   28. EVEric Verdin26:34

       ... a difference in terms of the amount of free radical that are, that are generated. Um, I-- There is evidence, but I, I would not be able to cite you the paper, that one cleans-- one burns clean, more cleanly than the other, and I suspect it's partly the cytoplasmic component o-of, of glucose. It's also less efficient, um-

   29. PAPeter Attia26:53

       Yeah

   30. EVEric Verdin26:53

       ... in terms of the amount, you know, o-of energy that's being generated per gram of fatty acid or per mole of fatty acid-
6. 29:45 – 40:48

   Metabolic effects of GLP-1 agonists

   1. EVEric Verdin29:45

      role in this as well.

   2. PAPeter Attia29:45

      Yeah, well, let's, let's talk about this because there is, at least for me, a great deal of confusion around this point. Now, we, um, we, we understand today the role that the gut plays in metabolism, and we understand that a lot of it is transduced through GLP-1. So endogenous production of GLP-1, uh, according to Ralph DeFronzo, the world's authority on this, is what's driving eighty percent of beta cell activity with respect to insulin. And therefore, when we have GLP-- when we have insulin resistance, we can't-- we're-- uh, the GLP-1 we're making is insufficient to generate the insulin that's required to cl- to, to manage the glucose. Makes sense if that's the case that giving exogenous GLP-1, you take a shot of tirzepatide or semaglutide, you're going to put more GLP-1 in the system. You're going to overcome the resistance at the beta cell. You make more insulin. You now have better glucose control. Everybody wins. Now, it's not clear that that has anything to do with the weight side of it, and that, that, that's a separate issue, and I want to actually talk about that because there are two very interesting theories as to why these things cause weight loss. But the point here is wouldn't you expect to see higher levels of insulin in someone taking a GLP-1 agonist to achieve that better glycemic control?

   3. EVEric Verdin31:13

      Yes. And, and that's not what you see. Um, so I... And I don't have an answer for this. Um, but I've, I've, I've seen the same thing. I've seen the same thing. Um, including personally, I've been experimenting with tirzepatide. Uh, my insulin is five now, which is, you know, lowest that you can possibly get it. Um, and I was expect- I was-- There was a part of me that was worried that I was going to go against my, my own whole theory about, you know-

   4. PAPeter Attia31:43

      Have you checked postprandially? Have you done an oral glucose tolerance test where you look at... 'Cause that might be something to do, um, to see what is happening to postprandial, um, insulin, along with postprandial glucose, which of course will be better.

   5. EVEric Verdin31:58

      No, I haven't. I haven't.

   6. PAPeter Attia31:58

      That, that would be an interesting test to do. Yeah.

   7. EVEric Verdin32:01

      And it-- I, I've worn a CGM. Uh, my A1C has gone from five point four, five point five to five point oh.

   8. PAPeter Attia32:09

      Yep.

   9. EVEric Verdin32:10

      And my insulin is down to five point oh as well, so.

   10. PAPeter Attia32:13

       And did you lose any weight?

   11. EVEric Verdin32:15

       I lost a little bit of weight, not a huge amount. Six or seven pounds, which was never the goal-

   12. PAPeter Attia32:20

       Yeah, yeah

   13. EVEric Verdin32:21

       ... you know, to start with. It was the, the whole idea was... And, and no loss of muscle mass, which actually is the big, uh, the big, um, bugaboo that, you know, people will have you, uh, fear. No loss of muscle mass if you are exercising, if you are. So for me, it's an experiment. It's not-- I, I haven't decided this is something I'm gonna continue.

   14. PAPeter Attia32:40

       Yeah.

   15. EVEric Verdin32:40

       But I just wanted to really experiment for myself, just try to see, okay, what is this drug really doing? And it's, it's been nothing short of remarkable, I think, in some way. Um, uh, one of the most surprising has been for me the, this feeling of satiety. Um, you know, you hear about satiety. I, I was never in my whole life the type of person that felt full. I could always eat more. And, and all of a sudden, after about two weeks on this, I just looked at my plate. I said, "I'm full." And I heard myself saying this, and it just felt like, wow, this is really s- completely different. And for me, you know, the reason why I'm excited about these drugs is, um... And by the way, this is not an endorsement. This is something to de-

   16. PAPeter Attia33:21

       Yeah, yeah. This is self-experimentation and curiosity.

   17. EVEric Verdin33:23

       A self-experimentation, which is a, a long part of the tradition of our field, which I, I love. And, um, the, the whole idea is really to, um... For me, the, the, the thinking was one of the, the biggest advance in longevity medicine is this idea that a range is meaningless. And, and as a pr- practicing phys- physician, you know this. You know, I went to medical school, and we were told that, you know, your blood pressure has to be, you know, one thirty over ninety. That was a nor- still the normal range. So you could be one twenty-eight over, you know, eighty-eight, and you were still considered normal. The same thing, I went to see my personal physician and told him, "You know, my blood sugar is creeping up every year that I'm doing it, and now it's ninety-six fasting blood sugar, and I'm worried because soon I'm gonna be pre-diabetic."

   18. PAPeter Attia34:12

       And he said, "It's below a hundred. It's okay."

   19. EVEric Verdin34:14

       He told me, "You're normal. Don't worry."

   20. PAPeter Attia34:15

       [laughs]

   21. EVEric Verdin34:16

       And I told him, I said, "What is normal?" And I think this is, um, this really is where I think longevity medicine is going to make a, a, an important impact is really sort of revisit-

   22. PAPeter Attia34:26

       I, I can't tell you how many times I've had this argument with people about glucose. Um, and they're... And, and here's the funny thing. We have the literature. In other words, we have literature in non-diabetics-

   23. EVEric Verdin34:38

       Your A1C

   24. PAPeter Attia34:39

       ... that, that says the lower the A1C, the lower the all-cause mortality. It's a monotonic reduction that knows no lower limit.

   25. EVEric Verdin34:48

       I'm with you. But-

   26. PAPeter Attia34:49

       So, so we say that up to five point six is normal, and if you're at five point six, you're fine. And five point f- but, but five point five is better than five point six, and five point four is better than five point five, and five is better than five point four, and four point eight is better than five point one.

   27. EVEric Verdin35:03

       Yeah. I'm not there yet. [laughs]

   28. PAPeter Attia35:04

       Yeah, yeah. But my point is, uh, I also find it, um... I don't know what the word is. Maybe sad. I find it sad that we've, we've simplified this problem, uh, in a, in an effort to, to communicate but have lost the essence of where, where is lower better. Uh, 'cause it's not always true in biology, right? It's not... You know, when you look at TSH, for example, when you look at thyroid hormone, much more narrow band in which we would say there's optimal. Um, and lower is not... You know, if it's too low or too high, it's problematic. But it turns out that when it comes to average blood glucose in a, you know, non-type one diabetic or someone who's taking insulin, um, under natural physiologic circumstances, it's, it's just better to be lower. Um, and as you age, it just keeps creeping up.

   29. EVEric Verdin35:52

       Same thing for blood pressure.

   30. PAPeter Attia35:53

       Yes.
7. 40:48 – 45:11

   Immune health as a “fifth horseman”

   1. PAPeter Attia40:48

      So, okay, we spent a little more time on metabolism than we did immune, uh, health and the immune system overall. I'd actually like to go back and talk about it a little bit more. Um, I think, a-again, the listeners of this podcast are very familiar with the metabolic stuff. We haven't had as many discussions on the immune system. Um, talked about it at length, uh, with respect to cancer. Uh, had Steve Rosenberg on a few years ago. That was a fantastic discussion explaining the role of the immune system in cancer, which I think we're gonna have to talk about here because, I mean, I, I certainly feel convinced that a big part of why cancer incidence goes up, uh, exponentially with age is the declining immune system, not just the accumulation of mutations, although I, I, I imagine they both play a role. Um, but I will tell you something else, Eric, which is, uh, you know, I wrote a book a couple of years ago about this space, and in the book, I talk about these things called the Four Horsemen. And I describe them as the, the four things that are basically coming for us all if you out-- if you manage to outlive youth, right? So if you're, you know, th-this is not to diminish the role of trauma and other things that are, that are, that are, that are deadly. But, but for many people living in OECD nations, it's gonna come down to ASCVD, cancer, dementing and neurodegenerative diseases, and metabolic diseases. And people often say, "Peter, is there anything you wish you'd written in the book that you would-- if you go back in time, you would do?" And I say, "Yeah, there, the, there are probably many things if I thought about it," but the first thing that jumps out is I really should have added a fifth horseman, and that is immune health and the types of infections that ravage people in old age that a young person wouldn't even laugh at-

   2. EVEric Verdin42:32

      Thank you

   3. PAPeter Attia42:32

      ... or would laugh at, right? So-

   4. EVEric Verdin42:33

      Thank you for bringing this up-

   5. PAPeter Attia42:35

      Yeah

   6. EVEric Verdin42:35

      ... because we, you know, the immunology field somewhat, um, uh, immunology and aging have been, uh, not really mixing very well.

   7. PAPeter Attia42:42

      Yep.

   8. EVEric Verdin42:42

      One, one problem is that immunology is an extremely complex and advanced field, probably one of the, a-along with neuroscience, one of the most complex. Um, so when you go to an aging meeting, there is no one talking about immunology. You go to immunology meeting, there are very few people talking about aging. Um, and we try to navigate-- Even the nomenclature is, is being used differently. You know, people-

   9. PAPeter Attia43:06

      Oh, interesting

   10. EVEric Verdin43:07

       ... in, uh, in, uh, In immunology, talk about immunosenescence, meaning aging of the immune system. They don't mean senescence the way we talk about it in the aging field.

   11. PAPeter Attia43:16

       Yeah, that's so interesting.

   12. EVEric Verdin43:17

       So that yields all kinds of crazy com- uh, communication problems.

   13. PAPeter Attia43:21

       Yeah, because y- if you're in the aging field, then you hear immunosenescence, you think of SASPs and things-

   14. EVEric Verdin43:25

       Yes

   15. PAPeter Attia43:26

       ... that are being secreted by T cells.

   16. EVEric Verdin43:27

       No. It just means aging of the immune system. Um-

   17. PAPeter Attia43:30

       Uh-huh.

   18. EVEric Verdin43:30

       Now, the reason why I think this is, um, a, a tragic failing for, for both field is what happened during COVID. It was became obvious that, you know, being infected was not, uh, you know, your risk of infection was not linked to your age. The virus infected everyone across, but the outcome could be completely different with eighty-four excess, eighty-four fold excess mortality if you were above seventy-five. Eighty-four fold.

   19. PAPeter Attia43:58

       Hm.

   20. EVEric Verdin43:58

       Now, you know, when this happened, um, and, and we can go in, in terms of trying to understand why did, why did this happen, what are the, the reasons for this, um, I, I went and started to look at the literature. Um, influenza, it's exactly the same thing. RSV, same thing. So all of these viruses that are, you know, that you can contract in later years will kill you, you know, at with really significant rates. You know, influenza, I think thirty thousand people die every year from influenza. Um, you know, the mortality in terms of, um, uh, COVID was really highly segregated into the older part of the population, or in that part of the population that showed accelerated aging, uh, obesity and so on. So I think there's a, there's a lot there.

   21. PAPeter Attia44:44

       Do you think that, that most of the, um, mortality, any, any time we saw a gap in mortality, whether it was young versus old, whether it was obese versus non-obese, diabetic versus non-diabetic, 'cause we're, a- any, any time you looked at that, you saw a difference in mortality. Do you believe that it was always a difference in immune function? I mean, with young versus old, it's very obvious, but do you think that was also true in the other comorbidities?

   22. EVEric Verdin45:09

       Yes. Yeah, I would say

8. 45:11 – 50:26

   How the innate & adaptive immune systems work together to build immune memory

   1. EVEric Verdin45:11

      so.

   2. PAPeter Attia45:11

      Yeah.

   3. EVEric Verdin45:11

      And it, it comes from two, two reasons. One is, you know, there are two broad immune system, the, what we call the innate and the adaptive immune system.

   4. PAPeter Attia45:21

      Yes.

   5. EVEric Verdin45:21

      I don't know if you want me to-

   6. PAPeter Attia45:22

      I would. I actually was gonna say, I think it is worth going full bore on this. I think it is time for people to roll up their sleeves and understand arguably the most interesting system in the human body. I am biased. I, I spent two years at the NCI doing immunology, but I think this is such an interesting field.

   7. EVEric Verdin45:40

      Yeah, so our immune system is, is built to recognize foreign elements. That really is why it evolved. It has two lines of defense against microbes, bacteria, viruses, fungi, all of those. We are constantly bombarded by those. It, it is actually amazing because, I mean, the, the evidence of this is if your immune system doesn't function, um, the bubble-

   8. PAPeter Attia46:04

      It's incompatible with life

   9. EVEric Verdin46:05

      ... it's incompatible with life.

   10. PAPeter Attia46:06

       Yep.

   11. EVEric Verdin46:06

       So we are, uh, you know, we're colonized with bacteria in and out-

   12. PAPeter Attia46:09

       Hm

   13. EVEric Verdin46:09

       ... on our skins, everywhere. So we constantly respond to them in an appropriate manner. And so-

   14. PAPeter Attia46:15

       And we survive everything, including disruptions to the barriers.

   15. EVEric Verdin46:19

       Absolutely. Absolutely. And so we have two lines of defense in the immune system. First, the so-called innate immune system, which is your macrophages, your dendritic cells, but also pretty much every cell has a whole series of mechanism that are, uh, not pathogen specific. That is, they will recognize an intruder, be it a virus, be it a fungi, be, uh, bacteria, and it will activate a first line of defense. Those line of defenses are non-specific, and therefore they're less effective. Um, and they give time to the so-called adaptive immune system, which is the second part, which is made up of T cells and B cells, and both of those cells have highly selective defense mechanism. The, the B cells make antibodies, which will go, uh, recognize a bacteria or, or, or a fungus or, or, or a virus and, and, and the T cells, which are able to actually kill the infected cell itself. So it will recognize when a cell is colonized by a foreign, uh, uh, pathogen and will, um, will kill it. Um, so the, you know, the time course of these is that, you know, once you get, you encounter a pathogen, you will be activate your innate immune response. Typically, you know, it can be fever, it can be all kinds of symptoms, but activation of this defense, and this gives the, the whole organism a couple of weeks to actually build the defense for the specific, uh, that they will specifically recognize this organism. Um, now the beauty-

   16. PAPeter Attia47:57

       Let's talk a little bit, let's talk a little bit about memory-

   17. EVEric Verdin47:59

       Yes

   18. PAPeter Attia47:59

       ... within that system.

   19. EVEric Verdin48:01

       The, the beauty of the adaptive, uh, so the DNA immune system does not really have a mem- a true memory. It will always react in the same way no matter how many times you've, you, you encountered the, the-

   20. PAPeter Attia48:11

       So the same, you get the, if you, if you get the same vir- so if your, if your kids are ping-ponging the same respiratory virus at you from school-

   21. EVEric Verdin48:18

       Yes

   22. PAPeter Attia48:18

       ... your innate immune system has the same playbook.

   23. EVEric Verdin48:23

       Yes.

   24. PAPeter Attia48:23

       Fever. Uh, you're gonna get red. You're gonna, like, what- whatever-

   25. EVEric Verdin48:26

       Inflammation.

   26. PAPeter Attia48:26

       Yeah, inf- you're gonna get sore.

   27. EVEric Verdin48:28

       Yes.

   28. PAPeter Attia48:28

       All of those things are gonna happen regardless.

   29. EVEric Verdin48:30

       Exactly, yeah. Um, and that's in contrast to the adaptive immune system because once the initial response has been generated, either via an infection or a vaccination, this is what a vaccination is, it presents you with a given fraction, fraction or the whole virus or a part of it, your body will mount a response, and this will yield, um, this will lead to the amplification of a subset of cells that are selective. So think about your, either your T cells or your B cells. None of them are the same. We have a process by which we generate so-called diversity, which is, um, uh billions of different, uh, forms of antibodies or, or T cell receptors that are recognizing, in principle, every chemical structure or every protein from, from a, from a microorganism. Now, what happens during the initial encounter, either be it a vaccination or an infection, is those B cells or those T cells that have, um, a receptor that is able to recognize the pathogen will become amplified, and they will churn out large amount of the antibody or, or, or the T cell clones. Once the job has been done, they will contract, but they will not contract back down to the same level. They will become what we call memory T cells or memory B cells, so that if you encounter the same antigen in the future, the reactivation process is shortened, the maturation happens faster. So eventually, that's the whole idea of the vaccination, is to sort of get yourself ready with a s- a subset of memory, uh, T cell clones or B cell clones that once the, uh, the true, uh, virus will come, you will be able to mount a response within a few days or, or, or up to a week. And so that's how vaccination

9. 50:26 – 55:48

   Why vaccines lose effectiveness with age

   1. EVEric Verdin50:26

      works. Now, what's interesting during aging is, and people are not aware of this, um, if you're above 70, um, most vaccinations do not work. And so people then will ask, they actually-- your immune system has aged, and your vaccination rate really decreases very strongly. Uh, uh, from what I remember, this might be different in different populations, but vaccination rate success is close to 30% if you're above 70.

   2. PAPeter Attia50:55

      Now, what w- during COVID, what was the risk reduction for a person over 75 who was vaccinated versus not vaccinated?

   3. EVEric Verdin51:04

      Oh, it was almost complete reversal of, of the effect, uh, in, in terms of the protection.

   4. PAPeter Attia51:10

      Meaning it was highly-

   5. EVEric Verdin51:11

      Oh

   6. PAPeter Attia51:12

      ... highly protective.

   7. EVEric Verdin51:13

      Oh, you mean-- Yeah, it was, it was protective.

   8. PAPeter Attia51:14

      So how-

   9. EVEric Verdin51:15

      Yeah, that's true

   10. PAPeter Attia51:15

       ... how do we reconcile those two facts?

   11. EVEric Verdin51:16

       That's true. Um, [sighs] and I don't know. I, to be honest, I don't know how this has been studied. Um, I don't know. Uh, I, I, I would be happy to, to, to read about this.

   12. PAPeter Attia51:33

       Okay.

   13. EVEric Verdin51:33

       How-

   14. PAPeter Attia51:34

       Because the COVID vaccine f- uh, seems to have had a remarkable risk reduction in very old people. Didn't, didn't seem to have an impressive risk reduction in younger people, uh, because the absolute-

   15. EVEric Verdin51:48

       Yes

   16. PAPeter Attia51:48

       ... risk was so low, it didn't seem to matter that much, but boy, did it matter in older people.

   17. EVEric Verdin51:52

       But did it matter by at the population level or at the individual level? This is what I'm not sure about.

   18. PAPeter Attia51:59

       I, I, I certainly don't wanna go on record saying something that I don't-

   19. EVEric Verdin52:02

       Yeah, it's the same, same for me. We, we-

   20. PAPeter Attia52:04

       That I, that I-

   21. EVEric Verdin52:04

       We can scratch this

   22. PAPeter Attia52:04

       But my, my recollection-- Yeah, I mean, we, we, you know, I, I think we can find the answer and put it in the show notes.

   23. EVEric Verdin52:10

       Yes.

   24. PAPeter Attia52:10

       My recollection, uh, which could be wrong, is that the older a person got, the greater the benefit they got from COVID vaccines, um, with respect to mortality. Um, so I guess the question is, let's maybe talk about other vaccines. Is that not the case with influenza? Is that not the case with pneumococcus or any of the other vaccines that are used primarily in older adults?

   25. EVEric Verdin52:40

       In, in general, um, at least, and I'm not a, a vaccine specialist, but, uh, the, the thinking is that, um, there's a dramatic decrease in the efficiency of vaccination against influenza, against RSV, against all of those as you age. Um, the thinking then is how, how does it work at the population level? And this is where the whole concept of herd immunity, uh, works, is that if you limit the spread of the infection in a family, for example, you're le- much less likely to infect-

   26. PAPeter Attia53:11

       Yeah

   27. EVEric Verdin53:11

       ... grandpa, who, who is, you know, who will-

   28. PAPeter Attia53:13

       I see. I see.

   29. EVEric Verdin53:14

       So that, that's been my understanding-

   30. PAPeter Attia53:16

       Yeah, yeah
10. 55:48 – 1:06:09

    Exploring growth hormone, thymic regeneration, & the role of exercise in slowing immune aging

    1. PAPeter Attia55:48

       a little bit. Are you referring to that Fahy paper from about seven or eight years ago that looked at growth hormone with metformin and DHEA or something like that?

    2. EVEric Verdin55:56

       Y- that's one, but that Fahy paper was actually, um, inspired by work o- of a colleague of mine when I was at the Gladstone Institute-

    3. PAPeter Attia56:05

       Okay

    4. EVEric Verdin56:05

       ... um, who, um, uh, did this, uh, actually Mike McEwen and colleagues did this in patients with HIV, uh-

    5. PAPeter Attia56:14

       Okay

    6. EVEric Verdin56:14

       ... who, who were chronically infected with HIV, where they lose a lot of their CD4 T cells.

    7. PAPeter Attia56:19

       Yep.

    8. EVEric Verdin56:19

       And there was an interest in trying to see if you could actually ... A- and so there's a big lesion initially in infection, and there was, um, uh, an attempt to actually try to see if you could regenerate these populations to bring them back to a normal. Because even though we had great, uh, drugs against HIV, they could not bring those patients back to normal. There was a remaining sort of, uh, original insult. So they did a trial, um, uh, with, uh, human growth hormone that were able to show some degree of, uh, thymogenesis and, and increase in naive T cells in, in these patients. And I believe the Fahy trial, um, actually tried to reproduce this. I think there's a second Fahy trial that is ongoing or s- but I haven't seen the results of this.

    9. PAPeter Attia57:07

       Yeah, I mean, the first one was... I, I don't remember the results, but, uh, the cocktail was a little suspect.

    10. EVEric Verdin57:15

        I see.

    11. PAPeter Attia57:15

        The GH made sense, if that's your hypothesis. I believe, I've never spoken with Greg, but I believe reading the trial, the metformin, which was really given at a homeopathic useless dose, I think it was only given at 500, so apologies if it wasn't, but I think it was only given at 500, was meant to offset the glucose metabolism, uh, disturbances of GH. Do you remember why the DHEA was given?

    12. EVEric Verdin57:41

        No.

    13. PAPeter Attia57:42

        There was some reason for it that, uh, made sense on paper but didn't make sense sort of physiologically. Now, the more important question is if, if, if-- My, my take on that trial was it was a single active agent, which was growth hormone. Like, I don't think DHEA does anything. I don't think 500 of metformin does anything. So the question is, and it was a very small trial, and I think it was open label. So-

    14. EVEric Verdin58:05

        And I have, I have significant problem with the readout of that, that trial also.

    15. PAPeter Attia58:08

        So that's what I wanted to ask you about. Remind me of the readout.

    16. EVEric Verdin58:11

        The readout was, uh, one of the clocks.

    17. PAPeter Attia58:15

        Ah, that's right. This was-

    18. EVEric Verdin58:17

        And-

    19. PAPeter Attia58:17

        Steve Horvath was the other author on that paper.

    20. EVEric Verdin58:19

        Exactly. And, and, um, and actually this is, [laughs] this whole story sort of pushed us into a whole project that we've published on, on, uh, on what we call entrant clock. Um, because there was indeed, in the experiment, um, they obs- in the patients, they indeed observed some increase in nai- in the fraction of naive T cells, which tells you and me that something worked. The fraction of naive T cells increased, um, with respect to the memory T cells. The naive T cells are the ones that are generated in the thymus.

    21. PAPeter Attia58:54

        Yeah.

    22. EVEric Verdin58:54

        They are, they're naive because they have never met their cognate antigen, and they sit there waiting for something to happen. So the whole idea of, uh, treating with human growth hormone was to induce thymogenesis and to restore the pool of these naive T cells. So I think to some degree it worked at low level. Uh, then they used the clock, uh, on the whole blood. And my worry, uh, when I saw the paper, which is a worry that actually existed, pre- predated this, uh, and was also a worry when people were using telomere, telomere length, is the idea when you sample the blood, as an immunologist, I know this is a highly dynamic, uh, organ. Uh, think about the blood as an organ. We enumerate at this point today with the best technology more than 500 different populations of cells in the blood. Suppose that these cells vary in response to any intervention and that these cells individually have a different epigenetic age, you would have the impression that you are rejuvenating, you know, which is, was the claim of that Fahy paper, that they had rejuvenated people. But in effect what you would do is simply change-

    23. PAPeter Attia1:00:05

        Yeah. It's like you're on a sine wave that goes like this.

    24. EVEric Verdin1:00:08

        Yes.

    25. PAPeter Attia1:00:08

        And you take two sample points. You, they could be here, they could be here, they could be here. You don't... And by the way, as you probably know, Matt Kaeberlein has famously purchased, I think, four or five of the commercially available aging clocks. Uh, he bought them in duplicate and did all of them, sampled them all simultaneously, right? So two of this, two of this, two of this, two of this simultaneously. Take 10 samples. And not only do all the clocks disagree with each other, but even within the same clock there was disagreement, significant disagreement.

    26. EVEric Verdin1:00:41

        Yeah.

    27. PAPeter Attia1:00:41

        Um, so yeah. I mean, I want to actually come back and talk about clocks in, in some detail, but given that that study was done years ago with an older clock, I, I think the clock part of it is not even remotely interesting. I think the more interesting question is was there i- i- was there genuine thymic regeneration? If so, how do we reconcile a very pressing and vexing question within geroscience, which is the role of growth hormone, right? So I've never taken growth hormone. I've never-- I shouldn't say I've never prescribed it. I've prescribed it in very rare circumstances for injury, uh, healing. Um, but I've never prescribed it for quote, unquote, "longevity benefits," but a lot of people are out there doing so. And as such, I've had lots of patients who come to my practice who have been taking or are on growth hormone. And I will say this, to a person, every single one of them has said, "I feel so much better when I take growth hormone than when I do not." I mean, across the board, 100%. And I can't actually point to evidence that tells them it's bad to take. I can just sort of say it doesn't make sense to take if our goal is to reduce the risk of cancer and if our goal is to slow the aging process. Um, so what is your take on that? I- I- I-- Just, just your intuition, uh, or is there any data you're aware of that would, would lead one to think that, well, maybe we could pulse a little bit of growth hormone here and there if we get some thymic regeneration. We don't have to be on it all the time. I mean, how, how would you think about that?

    28. EVEric Verdin1:02:17

        I do worry about it, for I'm not a specialist on growth hormone itself. Um, it induces diabetes. It induces glucose intolerance. So from that angle, I do worry about what it would do chronically, especially in someone young. For me, I really s-- It's a bit like, uh, increasing your protein intake. Um, if you are... You know, there's, like, clear evidence that increasing your protein intake, especially as you age, becomes beneficial, and the people who have higher protein intake, um, uh, actually do better in terms of muscle mass and so on. So in someone, uh, who is sixty-five to seventy, who is starting to feel, you know, uh, the effect of, or, or manifests some form of sarcopenia, there might be a benefit for that person to actually increase muscular mass and, and all the benefits with this, especially if it's not done continuously.

    29. PAPeter Attia1:03:14

        But, but, I mean, I would argue there's no doubt that there's benefits, but you're gonna get far more efficacy from testosterone or anabolic steroids when it comes to m-mitigating sarcopenia. Growth hormone actually is not remarkable at inducing muscle mass. It's nowhere near as effective, um, as testosterone. It's more effective at, um, eliciting fat loss. But I wonder if there's something that goes beyond that, 'cause I, I think when, when people tell me they feel better on it, I think they're talking about, like, less aches and pains, like just joints just feel better. I don't think anybody's saying they feel better because their thymus is more plump. But I wonder if... Like, that to me would be a reason to potentially consider a schedule, you know, a, an intermittent schedule of something if it's... Again, going back to my macro thesis here, which is I've been harping on these four horsemen, four horsemen. Well, if we introduce a fifth horseman, w-what is the strategy? 'Cause I can give you chapter and verse the strategy for how you will mitigate heart disease, cancer, all of these other conditions. What is our strategy for mitigating immune decline?

    30. EVEric Verdin1:04:24

        I would say the same as, as a strategy that would mitigate decline in every other organ. You know, and there's clear evidence that peop- exerci- the effect of exercise on, on, on, uh, on immunology is the same as in every single-
11. 1:06:09 – 1:13:08

    Challenges of identifying reliable biomarkers for immune function, & the potential of rapamycin analogs to enhance vaccine response

    1. EVEric Verdin1:06:09

       We just completed a study, uh, where we are looking for novel biomarkers that are predictive of whether you will respond to a vaccination or not. And this is something done in collaboration with Mark Davis at Stanford, uh, using the One Thousand Immunome Project, which is, is one of the largest studies studying aging in the immune system, uh, only, only in humans. And, and so we've been able to, uh, studying people to identify some metabolites that are associated with poor response to vaccine. And so those are not only markers, but they could also become, uh, tools that we include in a- as adjuvant or as a, as a pre- pretreatment therapy. Uh, I'm sure you're familiar with the, the work of, uh, Joan Mannick.

    2. PAPeter Attia1:06:50

       Of course. Yeah, I was gonna ask you about Mannick and Gluckstein in a moment.

    3. EVEric Verdin1:06:53

       Yeah.

    4. PAPeter Attia1:06:54

       But before we do, I wanna go back to this point here, which is, um, you know, biomarkers are so important. And when I think about cardiovascular disease, uh, and even though it's the leading cause of death, why I tell my patients it's the one you need to be least afraid of if you're willing to be proactive in management. And it comes down to the fact that we just have such a clear understanding of how the disease works, and we have exceptional biomarkers Right? So we, we can measure the things that are causing the disease. We can measure inflammation. We can measure ApoB. We can measure VLDL cholesterol, LP little a. We also-- We can measure blood pressure. We can measure metabolic health, and we know how to address those things, and we know that when we address those things, we can measure whether what we're doing is working. Okay. So problem solved, basically. Um, when it comes to the immune system, let's-- we're gonna talk about Manich and Klickstein in a moment, but as we saw from their paper ten years ago, um, they gave a, a rapamycin analog to people, uh, people who were in their sixties, vaccinated them, and demonstrated that, oh, boy, you got a much better immune response. Okay. They were able to demonstrate that using laboratory techniques. I, I'm sure they used flow cytometry or something like that to measure it. Um, how close are we to being able to do that sort of thing commercially? By, by commercially, I mean, uh, over the counter, like, uh, you know.

    5. EVEric Verdin1:08:31

       Well, not close. I think in, in, in that study, they actually measured antibody titers.

    6. PAPeter Attia1:08:36

       So even more complicated-

    7. EVEric Verdin1:08:38

       Yes

    8. PAPeter Attia1:08:38

       ... than flow cytometry.

    9. EVEric Verdin1:08:39

       Yes.

    10. PAPeter Attia1:08:39

        Okay.

    11. EVEric Verdin1:08:39

        And so, um, i-in that case, they definitely showed a, a, an enhancing effect with a, a known, uh, you know, uh, geroprotector. Uh, uh, this was a rap-

    12. PAPeter Attia1:08:52

        A suspected geroprotector-

    13. EVEric Verdin1:08:53

        Yeah

    14. PAPeter Attia1:08:53

        ... at least in humans, we hope. Yeah.

    15. EVEric Verdin1:08:54

        Exactly, a rapalog, and they showed, uh, not only, um, uh, increased titers, but also protection, increased protection. Eventually, the, the clinical trial failed for a whole series of other reasons, which were in part due to the way that, that, that, that the, the FDA imposed the trial to be generated. I think it just complicated the, the whole picture.

    16. PAPeter Attia1:09:17

        Yeah. By the way, for folks listening to us who are confused by that, um, Matt Kaeberlein and I had a specific discussion, 'cause it wasn't the 2014 trial. It was a later trial where they-- It wasn't the RAD001 trial. It was the, it was the other trial that failed. Uh, and I actually don't remember the reason, but, but Matt ex-

    17. EVEric Verdin1:09:39

        I got a-

    18. PAPeter Attia1:09:39

        Matt explained it. It was very clear that it was a tragedy of bureaucracy.

    19. EVEric Verdin1:09:45

        It is.

    20. PAPeter Attia1:09:46

        And, um, and it shouldn't be viewed as a black eye on that molecule.

    21. EVEric Verdin1:09:50

        Yeah. And, um, I think, you know, Matt is more of a specialist in the whole-

    22. PAPeter Attia1:09:54

        Yeah

    23. EVEric Verdin1:09:54

        ... rapamycin, so I will defer to what he said. But, uh, the-

    24. PAPeter Attia1:09:57

        We'll, we'll link in the show notes to where that-- to, to where Matt and I had that discussion.

    25. EVEric Verdin1:10:00

        Yeah. My inter- my-- What I've heard from anyone that I've talked to, including Joan, is that this was, uh, in some way bungled, which, which is sad, because sometimes things like this can put a field back for, you know, a number of years-

    26. PAPeter Attia1:10:13

        Yep

    27. EVEric Verdin1:10:13

        ... and, and discourage investors. We have a, um, a startup that originated at the Buck called Eovien, which has raised fifty million dollars, again, coming up with rapalogs, novel rapalogs that are gonna be, I think, revisiting that whole, that whole picture. Uh, so quite excited. The field is, is far from being dead.

    28. PAPeter Attia1:10:32

        Will we ever be able to measure this in people the way we measure hemoglobin A1C or things like that, or is it gonna be one of those things where it's a bit of a leap of faith, and you're gonna have to look at the clinical trial where the outcome was there, and then you're just gonna have to say, "Well, even though there was probably massive he- heterogeneity amongst the participants in the trial, we're gonna dose this thing individually"? I mean, it's a little bit like, you know, you brought up vitamin D earlier. I mean, one of the problems with the vitamin D trials is that they're all garbage, right? Because they all just give people a given dose. They don't measure the response. They don't measure compliance. A vitamin D trial should be done based on target level, not target dose. And so we, we run the risk here of the same thing in a much more complicated system.

    29. EVEric Verdin1:11:19

        Agree. Uh, that being said, measuring pathogen-specific titers is done routinely in the clinic. Uh, by the-- You know, I, I don't know if you did this, but I just had my, uh, measles titer, uh, measured because I'm, I'm-- I was born in 1957, which is right the age at which-- Uh, before 1957, everyone was, um, uh, exposed-

    30. PAPeter Attia1:11:44

        Yeah
12. 1:13:08 – 1:18:50

    How rapamycin’s effects on the immune system vary dramatically by dosage & frequency

    1. PAPeter Attia1:13:08

       Um, let, let-- You wanna just say a little bit more about that trial? So that was, at least for me, a-- That was, that was a very pivotal moment in my journey in this, uh, uh, in this space and in understanding th-this world. So that was December of 2014 that that paper came out.

    2. EVEric Verdin1:13:24

       Yes.

    3. PAPeter Attia1:13:24

       And, uh, if I recall Roughly 300 plus participants divided into four groups. So placebo group, a group that got one milligram every day, a group that got five milligrams once a week, and a group that got 20 milligrams once a week. Uh, so two, two people were pulsed, uh, one much higher than the other, and then one given daily and then a placebo. I believe they were all over 65. I think the study was done in Australia. And as you said, they were, um, put on their whatever treatment was for four weeks, immunized, I think it was another four weeks, and then a six-week washout, and then the titers were checked. And the best response, I think, was in the five milligram pulse and the 20 milligram pulse. The one milligram daily still had a better response than the placebo, but not as strong as the two pulse doses. But the five and the 20 weekly were nearly identical, but the 20 had much more side effects. So I think that-- And, and again, I, I don't remember perfectly, so correct me if I'm wrong.

    4. EVEric Verdin1:14:26

       You remember pretty well. Uh [laughs]

    5. PAPeter Attia1:14:28

       The takeaway was basically five milligram pulse was the sweet spot. You get all the benefit without the side effects.

    6. EVEric Verdin1:14:34

       Reason why-- No, I, I think, uh, that's, that's how I remember that trial as well, although I'm, I'm always impressed by how you remember the, the all of the details of these clinical trials. Uh, what was remarkable about that data was the fact that, um, this is from a drug that is not-

    7. PAPeter Attia1:14:52

       Is supposed to be an immune suppressant

    8. EVEric Verdin1:14:53

       ... an immunosuppressant. And, you know, it's been a long road for the longevity field to try to get our colleagues who are actually using, uh, rapamycin as an immunosuppressant to have, to have them believe that, um, this actually has an effect on immunity, and not only not immunosuppress-suppressive, but actually a promoting immunity. So it is-

    9. PAPeter Attia1:15:13

       How do you reconcile that?

    10. EVEric Verdin1:15:15

        Uh [sighs]

    11. PAPeter Attia1:15:16

        Uh, meaning-

    12. EVEric Verdin1:15:17

        Well, the-

    13. PAPeter Attia1:15:17

        Not, not, not, not their disbelief, which is warranted, but how do you reconcile that one molecule can be-- If, if give it-- So if you think about the doses we used to give rapamycin, it's not actually used that much, by the way, um, today in, um, in, in, in the, in the, uh, transplant clinic. Uh, so, so FK506, uh, sirolimus has largely-- Uh, pardon me. Um, uh-

    14. EVEric Verdin1:15:41

        Ever, ever-

    15. PAPeter Attia1:15:42

        Ev- No, no, no, I'm blanking on what FK506's real name is. But anyway, whatever. It's, it's largely displaced, uh, sirolimus, which is rapa. But that said, when we used to give it out, we were giving two to four milligrams a day.

    16. EVEric Verdin1:15:55

        Yeah.

    17. PAPeter Attia1:15:55

        Now, let's just assume that it was indeed contributing to prevention of organ rejection. Do you think it was doing so because that's a high enough dose of constitutively giving a drug that it suppresses the immune system? Or do you think it was only suppressing the immune system because it was given being, it was being given in combination with two other drugs, and it was only as part of that sea of other drugs that it has the immunosuppressive effects?

    18. EVEric Verdin1:16:22

        No, I, I think there's clear evidence it, it is immunosuppressive by itself. And I can tell you that for the period when I was on rapamycin, um, I would take either four or six milligrams a week-

    19. PAPeter Attia1:16:35

        Mm-hmm

    20. EVEric Verdin1:16:35

        ... every morning, so once a week. So and I-- The biggest-

    21. PAPeter Attia1:16:39

        Yep

    22. EVEric Verdin1:16:39

        ... difference between the two, you know, the immunosuppressive and the, uh, sort of, uh, geroprotective effect is really the amount.

    23. PAPeter Attia1:16:45

        Frequency.

    24. EVEric Verdin1:16:45

        The frequency and the amount. Um, the reason why people adopted this sort of once weekly dose is to fir-first, not have any immunosuppression, and second, to mitigate the, uh, secondary effect, which are thought to be caused by, uh, inhibition of mTORC2, which is the second complex.

    25. PAPeter Attia1:17:03

        Right, this is the glucose issues.

    26. EVEric Verdin1:17:03

        Yeah, the glucose, uh, effect. And that seems to be working largely. Um, what was, uh, in my case, remarkable is that every time I took my dose, not two, my-- I did, only did two for a couple of weeks, but either four or six. The next morning, I would have a pimple on my nose. So I was immunosuppressed, clearly, uh, every single time.

    27. PAPeter Attia1:17:24

        For a day.

    28. EVEric Verdin1:17:25

        Yeah, for a day, for a day or two. And, you know, I sort of made peace with it in the fact that if I had a really heavy workout, I would have exactly the same thing. Exercise is immunosuppressive. If you, if you, if you go all out, you know, you can get a cold. You can, you know, you're temporarily fragilized after a, a really heavy exercise. So I think, um, the, the difference really between these, these, these two, these two world of immunosuppression, which clearly has been documented by clinical trials, it is immunosuppressive by itself, uh, versus the beneficial effect on the immune system to me is a question of dosage and frequency.

    29. PAPeter Attia1:18:03

        And yet, I cannot reconcile the unambiguous success of the interventions testing program where those mice were eating rapamycin in every single bite of food they took. In fact, they were consuming it more continuously than even the most immune-compromised patient. And without exception, every single ITP study of rapamycin, whether they started in old mice or young mice, rapa alone, rapa with another drug, it just doesn't matter. It always worked. How do we reconcile that?

    30. EVEric Verdin1:18:41

        I, I-- We do have-- Well, I don't have the answer, but I can, I can sort of, uh, talk about it. In a way, I just--

13. 1:18:50 – 1:27:50

    Limitations of mouse models & the need for cautious interpretation of rapamycin’s benefits in humans

    1. EVEric Verdin1:18:51

       There's something that worries me about our reliance on the mouse as a model system, um, uh, for aging, for studying aging, and how relevant it is to us as a species.

    2. PAPeter Attia1:19:03

       Even mice that are of the qual-- I mean, 'cause we would all admit that the ITP mice are the best. They're the Ferrari of mice.

    3. EVEric Verdin1:19:10

       Exactly. The ITP is the best because, uh, is the best way to address this question, uh, because they're using, uh, uh, mice that are, you know, crossed.

    4. PAPeter Attia1:19:19

       Yep.

    5. EVEric Verdin1:19:19

       So it's not, you know, what-

    6. PAPeter Attia1:19:20

       Not inbred. Yep.

    7. EVEric Verdin1:19:21

       Not inbred. When you're using Black 6, you're essentially doing the experiment on N of one. And the whole world, I mean, like, eighty percent of the work that's being done in mice is done on, on Black 6. This is we're all studying the same person. Um, so obviously, when you go and try to transfer this to a human population with all of its variation. So the ITP did the right thing. That being said, and this is not an attack on ITP. I think ITP is a great program and should be funded, and we should continue to study this. I just worry about the overreliance on ITP alone, and I think We should have another system that studies, um, uh, primate interventions with drugs. There are a number of primates, non-human primates, that are actually much closer to us. The reason I worry about mouse is, is something that actually Steve Austad, um, that you've had on, on this podcast as well.

    8. PAPeter Attia1:20:13

       Yes, a month twice.

    9. EVEric Verdin1:20:14

       Uh, Steve is a good friend, and he came up with something called the longevity quotient, which I think is, uh, something that people do not pay attention enough. So the longevity quotient is this idea that, um, if you look across the animal kingdom, the larger you are, the longer you live. Okay? So you can take thousand species and you can weigh, you know, you're, on, on the X-axis you have their, their size, on the Y-axis their, um, their life expectancy.

    10. PAPeter Attia1:20:44

        It largely rises to the right.

    11. EVEric Verdin1:20:46

        A- and you can see a, a monotonous curve. Now, there are exceptions to this. Um, one of them is, um, naked mole rats.

    12. PAPeter Attia1:20:56

        Dogs.

    13. EVEric Verdin1:20:56

        N- yeah, naked mole rats-

    14. PAPeter Attia1:20:58

        Yep

    15. EVEric Verdin1:20:58

        ... for example. Uh, naked mole rats, you know, are living way above, so they're-

    16. PAPeter Attia1:21:03

        They, they live above, they punch above their weight. Dogs tend to punch below their weight.

    17. EVEric Verdin1:21:07

        Exactly. Although in dogs it v- again-

    18. PAPeter Attia1:21:09

        Varies by, within the size thing it seems to hold

    19. EVEric Verdin1:21:10

        ... this is, this is between species.

    20. PAPeter Attia1:21:12

        Yep.

    21. EVEric Verdin1:21:12

        Then when you look intra-species, it gets even more complicated, which is the larger dog live shorter, uh, than the smaller dogs.

    22. PAPeter Attia1:21:19

        Yep.

    23. EVEric Verdin1:21:19

        The, the Great Dane versus the Chihuahua, and that is down, actually that's driven mostly by growth hormone, which is again another, another reason why we should look at, you know, taking growth hormone as an anti-aging drug with some degree of circums-pection because, uh, in dogs, the more growth hormone you have, the larger you are and the shorter you live. We know also in humans, the, the larger you are, the taller you are, the shorter you live. So n- are these effect of growth hormone? Yes. Are they only important while during the growth phase? That, that's a possibility, but it's something that really gives me pause to go back to our discussion about growth hormone. Now, where was I? I sort of lost my train of thought.

    24. PAPeter Attia1:22:00

        You were still trying to make the argument for why ITP mice-

    25. EVEric Verdin1:22:04

        Yes

    26. PAPeter Attia1:22:04

        ... given rapamycin with every bite of food-

    27. EVEric Verdin1:22:06

        Yes

    28. PAPeter Attia1:22:06

        ... somehow live longer.

    29. EVEric Verdin1:22:07

        So, um, again, going back to respiratory quot- the, the longevity quotient, um, mice are also an exception. They punch below their, their weight, so they live shorter than they should based on, so o- on their, you know, on their size, and humans is the biggest exception. We live about six, five to six times longer than we should, uh-

    30. PAPeter Attia1:22:31

        Based on our size
14. 1:27:50 – 1:37:10

    NAD, sirtuins, & aging: scientific promise amid commercial hype

    1. EVEric Verdin1:27:50

       something else on top of that.

    2. PAPeter Attia1:27:52

       So earlier, you brought up the sirtuin story and NAD. I, I'd love to spend a little bit of time there. Um, I was at a talk recently, and as always, I get asked questions about stuff like that, and I got asked the, the question about NAD. And I said, "Look, this is one of those things where if I tell you the following facts," and I said, "I'm going to tell you three facts." NAD is completely ubiquitous throughout the body, and, um, it is absolutely essential for the most important chemical reactions that happen in the body. You cannot undergo redox reactions, metabolic reactions without NAD. Um, that is, that is point one. Point two is a class of proteins called sirtuins rely heavily on NAD as the substrate in the process of repairing DNA. That is fact two. Fact three is, as you age, NAD levels decline precipitously. Okay, those are three facts, and I don't believe-- Is there any dispute to any of those facts?

    3. EVEric Verdin1:29:03

       No.

    4. PAPeter Attia1:29:03

       Okay.

    5. EVEric Verdin1:29:03

       No controversy.

    6. PAPeter Attia1:29:04

       Okay. Armed with those three facts, how could it be that supplementing NAD does not lead to a longer, better life or some health benefit? Um, [clears throat] that's a logical conclusion, right? Now-

    7. EVEric Verdin1:29:23

       Well, not completely because, uh, you are assuming, you know, it, it depends also what is the reason why NAD levels decrease.

    8. PAPeter Attia1:29:32

       Yes.

    9. EVEric Verdin1:29:32

       A-and it depends also what supplements or how you remedy this, this decrease.

    10. PAPeter Attia1:29:37

        Yes, yes, yes. No, no, there's, there-

    11. EVEric Verdin1:29:37

        And this is something I'd love to talk about CD38 and, and some of the work that we've done.

    12. PAPeter Attia1:29:41

        Yeah, yeah, yeah. So, so, so, so it could be that NAD levels go down because their consumption goes up.

    13. EVEric Verdin1:29:46

        Exactly.

    14. PAPeter Attia1:29:46

        Right? So there's, there's, as we age, there's more DNA damage, there's more consumption, the sirtuins need more of it, and it goes up. And then, of course, the question would become, is the current level of NAD that we have rate limiting to that reaction? If not, then all the extra NAD in the world should have no benefit because you're just adding more substrate to a reaction where it's not needed. Uh, conversely, if NAD levels are going down because there's a production issue, and if you provided more of it, you could actually do more good. Well, then it could be the exact opposite story. So let me pause there for a moment and have you fill in the edges of everything I just said so that we can go deeper into this discussion. So maybe explain a little bit what NAD is, explain, you know, what it means in redox, and obviously, let's talk about sirtuins and the role that NAD plays there.

    15. EVEric Verdin1:30:34

        Lots to unpack there.

    16. PAPeter Attia1:30:35

        I know. I know.

    17. EVEric Verdin1:30:35

        It could be a two-hour, uh, [laughs] a two-hour podcast. Um, but one, it's one area that we've worked on for the last twenty-five years. So we, we were responsible for cloning the human sirtuins, actually, after Lenny Guarente published, you know, his paper on, on SIRT2 in yeast. We, uh, with a graduate student-

    18. PAPeter Attia1:30:53

        Matt was the first to publish this, wasn't he?

    19. EVEric Verdin1:30:55

        Uh, Matt, uh-

    20. PAPeter Attia1:30:56

        Camerlan.

    21. EVEric Verdin1:30:57

        Yeah.

    22. PAPeter Attia1:30:57

        Yeah.

    23. EVEric Verdin1:30:57

        Actually, Matt and, uh, Brian, I mean, that-

    24. PAPeter Attia1:30:59

        Yep

    25. EVEric Verdin1:30:59

        ... the whole, and, and, and David, I mean, that whole gang was the or- original gang, along with Lenny Guarente, were, uh, uh, uh, paved the way for a lot of the, what we know. I eventually, you know, like, one thing that I would, um, just start by saying is that it pains me in some way in a field that is so rich and has generated so much data that there's a whole cloud sort of lying on top of sirtuins and NAD that, you know, there's nothing, there's nothing there. I, I just tell people it is an incredibly, uh, studied, uh, system. Uh, we are still s- juggling the complexity, and I would argue that any, any field where, um, the, the same degree of, of investigation will be conducted will have the same controversy. This is the nature of science. The beauty of science is that it's incredibly messy on the way, on the way up, but eventually, things are, are getting clarified. And I think in, in the terms of the sirtuins, we're still right in the middle of it. So there's some complete garbage, I completely agree with you.

    26. PAPeter Attia1:32:01

        And, and by the way, I'm not completely dismissive. What I will say has made, has made this field complicated is that the leading proponents of it have all opted for a commercial pathway.

    27. EVEric Verdin1:32:12

        Agree.

    28. PAPeter Attia1:32:12

        And therefore, they have opted not to study this in a rigorous way, but to study it in a commercial way. And Unfortunately, I mean, I understand why you would do that. Like, that's, that's the nature of it, and this is not a molecule that you can put, um, uh, y- y- you're not gonna generate intellectual property in the same way that you would, um, around a novel drug. And so it poses a limitation to how these things can be studied. But unfortunately, that coupled with the, uh, resveratrol fiasco, uh, and I, I really, unless you think otherwise, Eric, we don't need to talk about resveratrol. But I, I am-- I remain completely convinced that resveratrol had zero benefit whatsoever.

    29. EVEric Verdin1:32:54

        Yeah.

    30. PAPeter Attia1:32:54

        I think it is an absolutely, uh, useless molecule. Um, so I think that resveratrol debacle, um, the overhype complete debacle of that, coupled with the fact that all of the participants in the NAD landscape are doing it through their own commercial enterprise with their own proprietary blend, has, has resulted in this inability to drive forward in this field.
15. 1:37:10 – 1:45:41

    How CD38 drives age-related NAD decline, influences immune function, & may impact longevity

    1. PAPeter Attia1:37:11

       we're now ready to then move on to if we believe with some conviction that restoring NAD levels in an aging individual is beneficial, we now have to deal with the same problem you deal with any small molecule, or large molecule for that matter. How do you get it in the body?

    2. EVEric Verdin1:37:33

       Yeah.

    3. PAPeter Attia1:37:34

       So how-- what are the ways in which you could get NAD into the body, directly or indirectly?

    4. EVEric Verdin1:37:40

       So that brings me to maybe another element of the biochemistry. W- obviously-- So one thing that has emerged is this idea that, um, w- the question as to why do NAD level decrease, and there's been lots of theories. Uh, activation of the PARPs, that se- seems to be, uh, happening in C. elegans. But it, in mammals, uh, this is the work of, uh, Eduardo Cini, who w- was the first one to show that CD38, uh, appears to be the major driver of the decrease of NAD during aging. And the way that he's demonstrated this, and we've actually repeated some of his results and, and, and published on this as well. If you study an, a mouse that's knocked out for CD38, you find that NAD levels actually do not decrease during aging. And that's pretty much across all organs. And I think that what this does is really brings, uh, the whole question is in terms of what should we be targeting. Now think about-

    5. PAPeter Attia1:38:40

       Did we talk about what CD38 is doing specifically?

    6. EVEric Verdin1:38:43

       Yeah, so CD38 is a, um, as a membrane-anchored protein, some of it is facing, um, outward on the outside of the cell. Some of it, it's facing inward. Um, for example, in T cells, it's mostly facing inward, um, no, outward. In macrophage, it's mostly facing inward, and it is an NAD hydrolase. Now, what is it doing in the immune system? Why do we have it? Not entirely clear. One idea is that, uh, because it, it is present in T cells-

    7. PAPeter Attia1:39:14

       Is it on non-immune cells?

    8. EVEric Verdin1:39:16

       Uh, endothelial cells-

    9. PAPeter Attia1:39:17

       Okay

    10. EVEric Verdin1:39:18

        ... as well. Um, one idea, at least for the immune system, is that it might come up and, and eat up all the NAD that's local in the extracellular fluid, although there's not much of it, and limit the abilities as part of the innate immune response and part- limit the ability of bac- of bacteria and other organism to actually access these micronutrient for their own growth. That's one thinking, but I think it's a lot more complicated than this, and we're, we're really in the middle of it. I have a, a good part of my lab actually studying the role of CD38 in the immune system and in endothelial cells and in the brain as well.

    11. PAPeter Attia1:39:54

        Now, you mentioned a moment ago that the CD38 knockouts do not see a decline in NAD with aging.

    12. EVEric Verdin1:40:00

        Zero, and they live longer.

    13. PAPeter Attia1:40:01

        I was just about to say, what is the phenotype of a CD38 knockout? What deficiency do they have?

    14. EVEric Verdin1:40:06

        Uh, nothing that we can tell, and they live longer.

    15. PAPeter Attia1:40:09

        How much longer?

    16. EVEric Verdin1:40:10

        Uh, 15%.

    17. PAPeter Attia1:40:13

        That's comparable to rapamycin.

    18. EVEric Verdin1:40:14

        Yeah, yeah. Yeah, they-- it, it's pretty significant. This has been published by Eduardo Cine.

    19. PAPeter Attia1:40:19

        Why do you think that is? Do you-- in other words, do you think that that is true, true, and unrelated to the increased pool of NAD?

    20. EVEric Verdin1:40:26

        Now, CD38... So that's, that's a key question-

    21. PAPeter Attia1:40:31

        Yeah

    22. EVEric Verdin1:40:31

        ... and that's one that's not been answered. Um, and I would say if I had to go on a limb, I would say it's not linked to the NAD decrease, um, because it turns out that-

    23. PAPeter Attia1:40:42

        Sorry, just to make sure everybody understands what you're saying. You're saying your belief is that the CD38 [clears throat] mouse does n- the knockout does not live longer because he has more NAD. That's just another b- issue we're seeing, and that there's something else about that mouse.

    24. EVEric Verdin1:40:57

        Yes.

    25. PAPeter Attia1:40:58

        Okay.

    26. EVEric Verdin1:40:58

        Or it might be partially-

    27. PAPeter Attia1:41:00

        Mm-hmm

    28. EVEric Verdin1:41:00

        ... partially the NAD and partially the other mechanism I'm about to discuss. One thing that's remarkable is that, uh, as we age, us and mice, we see an increase in CD38 level, um, across the organism, especially in the immune system. We've published a paper showing that the SASP from senescent cells is a very powerful inducer of CD38 expression in macrophages. So that's one mechanism by which, uh, we're linking, you know, senescence and the SASP to increase CD38, leading to a depletion of NAD and other effect.

    29. PAPeter Attia1:41:34

        And yet we have no idea what it's doing other than hydrolyzing NAD.

    30. EVEric Verdin1:41:37

        It has a cognate receptor on other cells. It's part of the-- You know, it's-- They don't seem to be immune deficient. Uh, they don't-- It's really one of these players that, uh, p- p- people-- There are hundreds of papers.
16. 1:45:41 – 1:52:24

    How NMN & NR supplementation interact with CD38 & NAD metabolism

    1. EVEric Verdin1:45:41

       the metabolites. Nicotinamide. Now, one important thing is nicotinamide, um, metabolism is either salvaged, um, back to NAD or methylation by an enzyme. Uh, and this is important for supplementation because it turns out CD38 not only cleaves NAD, but it also cleaves NMN, which is one of the-

    2. PAPeter Attia1:46:02

       One of the two oral precursors

    3. EVEric Verdin1:46:03

       ... one of the two precursors, NMN and NR. So when you actually are-- have increased CD38 activity and you take NMN, you churn through this pathway and you actually, you increase your nicotinamide and you increase its methylation.

    4. PAPeter Attia1:46:16

       So NMN is also cleaved by CD38?

    5. EVEric Verdin1:46:18

       Yes.

    6. PAPeter Attia1:46:18

       Into what?

    7. EVEric Verdin1:46:19

       Into, uh, well-

    8. PAPeter Attia1:46:21

       Nicotinamide plus something that's not ADP ribose.

    9. EVEric Verdin1:46:23

       Yes, exactly. Yes, yes.

    10. PAPeter Attia1:46:25

        Okay.

    11. EVEric Verdin1:46:25

        And so when you do this, you're increasing your level of nicotinamide to the point that, uh, it's shunting to methyl nicotinamide starts depleting your, your one carbon cycle. So what you see in a number of people actually on NMN is their homocysteine level going up, including me. Um, I, I stopped taking it when I saw this. I thought this is not... I was taking about a gram of NMN for a while, uh, and then I saw my homocysteine level going up, I think as a reflection of this, this pathway, and basically stopped it.

    12. PAPeter Attia1:46:58

        Now, why is it, Eric, that the increased pool of nicotinamide preferentially goes down a methylation pathway as opposed to the salvage pathway to give you more NAD?

    13. EVEric Verdin1:47:08

        Yeah. I, I don't think it goes pref- preferentially. It just depends how much you're-

    14. PAPeter Attia1:47:12

        It's just the more you put in, even if it splits stoichiometrically or stochastically even-

    15. EVEric Verdin1:47:19

        Yeah

    16. PAPeter Attia1:47:19

        ... it's, it's, you're just gonna sal- you're gonna take away one carbon.

    17. EVEric Verdin1:47:22

        Yeah. And I do not know what the, the relative proportion is, but clearly the more you drive the system, uh, with NMN, uh, the more you're gonna yield, uh, these. And we can measure not only-

    18. PAPeter Attia1:47:33

        How much did your homocysteine go up, by the way?

    19. EVEric Verdin1:47:35

        Up to 15.

    20. PAPeter Attia1:47:37

        From?

    21. EVEric Verdin1:47:38

        From typical seven.

    22. PAPeter Attia1:47:40

        Wow. That's a-

    23. EVEric Verdin1:47:40

        Yeah

    24. PAPeter Attia1:47:41

        ... big jump.

    25. EVEric Verdin1:47:41

        Yeah. Yeah, yeah.

    26. PAPeter Attia1:47:42

        And then how long did it take to resolve once you stopped the NMN?

    27. EVEric Verdin1:47:45

        Well, I only-- I measure typically every three months.

    28. PAPeter Attia1:47:48

        Okay.

    29. EVEric Verdin1:47:48

        So a- after, after three to six months, it had gone back to normal, to seven to eight.

    30. PAPeter Attia1:47:53

        What about NR, nicotinamide riboside? How is that treated by CD38?
17. 1:52:24 – 1:59:50

    Intravenous NAD: limited evidence & serious risks

    1. PAPeter Attia1:52:25

       okay. What about intravenous NAD?

    2. EVEric Verdin1:52:27

       [laughs] So that, that is sort of one of my pet peeves. Um, and again, you know, I try in everything to be, to remain open-minded to things that I don't know and don't understand. My prediction is that, first, NAD is not a, an extracellular molecule. NAD does not exist, or almost does not exist at all in your plasma. It is an intracellular, and as I mentioned, you know, high concentration in mitochondria, somewhat lo- much lower in the cytoplasm and the nucleus. So the whole idea of injecting intravenous NAD is, first, it's too big to be absorbed by cells. So what is the body doing with it? There is a famous paper by, uh, Joshua-

    3. PAPeter Attia1:53:13

       Josh Rabinowitz

    4. EVEric Verdin1:53:14

       ... Rabinowitz that showed that if you inject it actually intravenously, you actually get it mostly ca- catabolized by the liver into nicotinamide. Now, nicotinamide i-is one of the fraction of, uh, niacin. You can buy this at the pharmacy for very cheap. You can go into a, a, an IV clinic and get a seven hundred dollar injection of NAD. Um, very few studies, one or two. I, I've read both of them. They're interesting. Um, so my opinion is that NAD intravenously is not something that should be done. Um, the same thing for intra-- you know, subcutaneously. I've seen another company that sells it, um, subcutaneously. Really no evidence for doing this. Now that being said, I've heard, a-and this is why I try to remain open-minded, because they're obviously-- we don't know everything. Um, I have heard sort of, uh, anecdotal evidence of dramatic effect in some patients with Parkinson's. People really describing sort of a, not a miraculous, but a near miraculous effect right after the infusion, having increase in motor performance that you can really assess in someone who's-

    5. PAPeter Attia1:54:29

       Yeah

    6. EVEric Verdin1:54:29

       ... has severe Parkinson's. So, um, again, not studied systematically. There's a lo-

    7. PAPeter Attia1:54:37

       Is there-- Mechanistically, is there a reason you could explain that?

    8. EVEric Verdin1:54:40

       Yes. There's a-

    9. PAPeter Attia1:54:40

       Through dopamine or something else?

    10. EVEric Verdin1:54:42

        There's a whole lit-literature on, uh, on the effect of, uh, NAD precursors and so on, on, uh, on Parkinson's, mostly animal models. And I think there are lots of clinical trials going on in Parkinson's as well. So but more using the standard NR and NMN. Uh, the, the thing that I've described is more s- a couple of friends who've told me, "I've seen this." Um, um, not enough to, you know, to, to make a product, but enough maybe to question. Maybe this is-- there is something more to it than, than, than what we truly know. But, you know, the proliferation of these intravenous clinic, frankly, is-

    11. PAPeter Attia1:55:19

        How complicated is it to produce a bag of intravenous NAD?

    12. EVEric Verdin1:55:24

        I don't think it's very expe-- uh, very complicated. I mean, I, I, I've never made it. I, I know, um, making NMN, uh, uh, at purity is, is really, it's not, you know... Took some effort to scale it up, and for some of the companies that have been doing this. Right now, there's like one major supplier out of China that pretty much everybody uses. Um, but in terms of NAD, I don't think this is, this is an industrial process and, and I, I, I can tell you it's not seven hundred dollars.

    13. PAPeter Attia1:55:52

        Yeah, I'm sure it's not. So do you think d-- I-if, if a person was going to supplement with one orally, do you think there's a case for NR being superior to NMN?

    14. EVEric Verdin1:56:03

        I would say no. Uh, I would say take them both. Uh, if you're gonna do something and you want to a bit of an insurance-

    15. PAPeter Attia1:56:11

        Hmm

    16. EVEric Verdin1:56:11

        ... you know, let's say, and, and I, I did this for a while. I, I'm not doing it right now. Uh, you know, take two hundred and fifty milligrams of each and, and, and you'll have a half a gram. Uh, you are in a sa-- relatively safe dose. Follow your homocysteine. Um, if you are, you know, sixty or above, you, you could make the case. This could be part of a, of a stack. Although, this is the same thing that we see with so many of these supplements right now. You know, how, which one do you take? Which ones are beneficial? There's one, a little bit of a dark cloud, a link to, um, uh, NAD supplementation, is the demonstration that the susp- Is actually, uh, dependent, uh, on, um, on NAD levels. And so when you are actually, uh, increasing NAD levels, you might be increasing these pro-inflammatory markers.

    17. PAPeter Attia1:57:04

        So because, let me make sure I understand why. Because the SASPs, which for folks listening, these are the soluble products made by the senescent cells that effectively are doing all the bad things that we don't want to see senescent cells doing. So now they are dependent on CD38 to some extent. So as CD38 goes up, they go up, and are you saying as you give more NR and more NMN-

    18. EVEric Verdin1:57:30

        You might churn it up.

    19. PAPeter Attia1:57:31

        You might be churning up the SASPs?

    20. EVEric Verdin1:57:33

        Yeah. The other thing also is there's been some-

    21. PAPeter Attia1:57:35

        By the way, all of this sp- let me, let me finish.

    22. EVEric Verdin1:57:37

        Yes.

    23. PAPeter Attia1:57:38

        You, you finish your point and then I want to make a broader point.

    24. EVEric Verdin1:57:40

        No, it, there's, there's also some, uh, worry about the fact that, uh, supplementing with some of these s- uh, these, uh, precursors might also accelerate tumor growth. So this would not have an effect in, in, in you and I who don't have a cancer, but if it's, uh, someone out there who has a, an early form of a cancer, this could lead to an acceleration. This is something that's been shown in animal models that it giving some, you know, some pause to some people in terms of recommending this to be, uh, taken over by everyone.

    25. PAPeter Attia1:58:11

        Now, the, the folks who make this have strenuously denied that there is any, um, any validity to those animal models that have suggested that or the, um-- And some of this has been done in, in, in, um, in vitro as well, correct? Um, so how... I, I'm not fam- I'm not very familiar with that literature. I saw, I remember seeing one study. It was very small. Uh, y- you know, my take on it was I guess if you had cancer, this might be a bad idea to take. Uh, but, but, but I didn't find it that convincing. So, so is it-

    26. EVEric Verdin1:58:47

        I, I agree with you.

    27. PAPeter Attia1:58:48

        Yeah.

    28. EVEric Verdin1:58:48

        And it's, it's, it is a general consideration for our whole field of longevity research is, uh, you know, better is the enemy of good, uh, is something that, uh, was, uh, sort of drilled into me as I went through medical school. You know, uh, we have a term in French, which is, uh, sort of like therapeutic, uh, overdoing it. You know, just, uh, doing too much. There's such a thing as overdoing it for your patients. And in this case, the whole longevity field, you know, is embracing a whole series of these, um, intervention. I mean, there's not a, a week that doesn't go by that I don't see a new supplement being touted online and so on, and I read about all of them. The question is, um, which ones should you be taking? Uh, which ones are actually risky? Which ones are not? And, and to me, this is part of the whole balance or the equilibrium that I'm trying to reach. You know, if there's something that really has a beneficial effect, you wanna be on it as soon as possible. If not, um, you know, why

18. 1:59:50 – 2:06:26

    Interleukin-11 (IL-11) as a new target in immune aging, the dual role of chronic inflammation in aging, & the need for better biomarkers to guide interventions

    1. EVEric Verdin1:59:50

       take the chance?

    2. PAPeter Attia1:59:51

       Yeah. I think that's, I mean, uh, you've said it. I-- That's the point I was gonna make at the outset, but, but you, you've said it so much better. Um, let's pivot a little bit to t- a couple other things I wanna chat about quickly. Let's talk about interleukin-11. So big trial last fall that looked at blocking interleukin-11, which is a molecule that's made by immune cells, plays an important role in inflammation. Um, and this was done in mice, and those mice lived longer. What do you make of the study?

    3. EVEric Verdin2:00:20

       Read the paper. Like you, I don't have sort of inside knowledge about inter-- Of, of course, when the paper came out, it was like, "Interleukin-11?" I mean, we-- As an immunologist, you talk about one, interleukin one, two-

    4. PAPeter Attia2:00:32

       Two, yeah

    5. EVEric Verdin2:00:32

       ... four-

    6. PAPeter Attia2:00:32

       Four, seven

    7. EVEric Verdin2:00:33

       ... six, seven, you know, but 11, never heard about it. So I went to, and there's actually, you know, it goes up to like 30. So I, I went and read the paper. It's, it's an inflammatory marker. So again, it could be a-

    8. PAPeter Attia2:00:46

       On par with one and six?

    9. EVEric Verdin2:00:48

       No. I would say n- probably not. Um, so it came out a little bit in the left, out, out, out of the left field. Um, but it sort of makes sense in the context of what we know about the inflammatory response linked to aging. So and maybe this is where I can, I can add one point is when we think about the chronic inflammation of aging, sort of inflammaging, um, it is both cause and effect. We talked about how the immune response, um, helps you to protect yourself against, um, uh, the innate immune response against pathogen as a first line of defense. The innate immune response also has another important role, is that it recognizes damage, any kind of damage. If you cut yourself, if you have a, a wound of, of, you know, uh, inside of your organ-

    10. PAPeter Attia2:01:39

        Coronary artery.

    11. EVEric Verdin2:01:40

        Huh?

    12. PAPeter Attia2:01:41

        A coronary artery.

    13. EVEric Verdin2:01:41

        A coronary artery, the, this will act any kind of damage, unfolded proteins. There's all kinds of things. So the innate immune response will be triggered and will activate itself. So as we age and as damage slowly accumulates, because aging is an, is a slow, irreversible accumulation of damage, um, eventually, your immune system responds to this by becoming chronically activated. And so the problem is that you might think, well, this is great because you're actually repairing all of this damage. The problem is the activation of the immune response by itself becomes problematic because these cells, macrophages, for example, are powerful, uh, tissue remodeler. And so the immune system in this case is sort of Dr. Jekyll and Mr. Hyde. It's helping, but it's, it's facing an insurmountable amount of damage, and eventually, its activation leads to NAD depletion. That's one of the things that it does, but many other things, stem cell dysfunction and mitochondrial dysfunction. So the whole idea here is that, um, uh, IL-11 might simply be, I mean, is one of the c- key markers of this chronically, um, activated immune system. So this is not something I imagine you're going to give to a 20-year-old, but in someone who's getting really in the part where chronic immune age, immune activation is present, um, could really play an, an important role in the future. And what the paper showed was, again, in mice, but from what I understand, is already an existing molecule. Uh-

    14. PAPeter Attia2:03:15

        Yes

    15. EVEric Verdin2:03:15

        ... and they are actually recently was con- conducted by a company that has another, a novel inhibitors of, of IL-11. You could imagine this to become part of the whole armamentarium that we have against aging.

    16. PAPeter Attia2:03:29

        And then how do you see playing that off something on the other end of the spectrum? Because, because we're really trying to deal with two sides of this system. We want to tamp down the part that's overactive, and we want to ramp up the part that's underactive. So we've got basically the only example we have over here is rapamycin. This one does this, and then we now have IL-11 inhibition or n- I mean, they use knockout mice, but block this, that did good things. So is this one of those things where you need to do both toge- oh, and by the way, maybe you have growth hormone over here as well, right?

    17. EVEric Verdin2:04:00

        Yeah. IL-1 there also.

    18. PAPeter Attia2:04:01

        Yes.

    19. EVEric Verdin2:04:01

        Anti-IL-1-

    20. PAPeter Attia2:04:02

        That's right. So-

    21. EVEric Verdin2:04:02

        ... as well, which has been shown to-

    22. PAPeter Attia2:04:04

        Block IL, yeah, block IL-1, block IL-11, give growth hormone, give rapamycin. I mean, but here's the problem. You get into this reductionist state, which is like the whole NAD world of NR and NMN. Hey, it sounds great, but what if there's unintended consequences we can't see? Like, even as much as I love thinking about this and want to do all of these things, I start to think, "Man, what is the probability we're going to get this right?"

    23. EVEric Verdin2:04:31

        Agree, and the immune system is, uh, an incredibly tenuous system, which is in really delicate balance. So the balance is too much immunity, y- you might say, "Well, this is good." Protection against cancer, protection against, uh, microbes, you know, protection-

    24. PAPeter Attia2:04:49

        Right, but then you get autoimmunity, because there was-

    25. EVEric Verdin2:04:51

        But then you get autoimmunity. Not enough immunity, well, you, you run the risk of being, you know, killed by a pneumonia or some kind of infection. And there's a-

    26. PAPeter Attia2:04:59

        But at least you don't have too much inflammation.

    27. EVEric Verdin2:05:01

        Yes.

    28. PAPeter Attia2:05:01

        Yeah. Yeah.

    29. EVEric Verdin2:05:02

        So there's a very fine balance, and, um-

    30. PAPeter Attia2:05:03

        Well, this, this gets to this is why I wish we had a dashboard. I, we, what are the biomarkers we can use for these things? Because we don't have this problem with blood pressure. We don't have this problem with thyroid hormone. We don't have this problem with so many things that we treat because we can measure what we care about.
19. 2:06:26 – 2:20:48

    Biological aging clocks

    1. PAPeter Attia2:06:26

       okay, where do you want to begin? There are so many of these things out there.

    2. EVEric Verdin2:06:30

       Yes.

    3. PAPeter Attia2:06:30

       Some of them are commercially available. Some of them are just tools of research at the moment. Some of them aim to tell you an actual age, an actual number that represents your biologic age as opposed to your chronologic age. Some of them don't aim to tell you that at all. They just want to tell you a rate of aging. Uh, some of them look only at the epigenetic signature. In other words, they look directly at the methylation, uh, sequence. Others look at a host of markers, including some very simple serum biomarkers like glucose levels and vitamin D levels and things like that. So how do you make sense of all of those tools?

    4. EVEric Verdin2:07:12

       Right now we don't. [laughs] Um, I think, so first, first statement is they are not ready for prime time in terms of patient management. They are research tools. Uh, uh, and I think I-

    5. PAPeter Attia2:07:29

       Which is interesting because they're far outside of research labs at this point.

    6. EVEric Verdin2:07:32

       Yes. They are available commercially. Um, I've done the same thing. I don't remember who told, you told me someone, actually, was it Matt?

    7. PAPeter Attia2:07:40

       Matt Kaeberlein.

    8. EVEric Verdin2:07:41

       Matt, uh, measured his clocks. I do the same thing, actually. I measure them every three months, and, uh, I use-

    9. PAPeter Attia2:07:47

       It's just a scatter plot.

    10. EVEric Verdin2:07:48

        It's a scatter plot in a way. You know, I'm between twenty-five and sixty-eight, uh, which is, of course, I like the clock that, you know, show me to be young. But, uh, so that being said, um, so we know that, you know, we're learning. So we know that, for example, you, you alluded to the fact that they, they can vary the same clock. There's circ- circadian variation, for example. Five years, so your age can vary by five years using some of the clocks, depending on when you measure, uh, when you, you sample.

    11. PAPeter Attia2:08:18

        What time of day.

    12. EVEric Verdin2:08:19

        Yeah, what time of day. Which is, you know, that's biology. That just tells you, you know, the epigenome is something that's highly dynamic. And so that's something, as we learn, obviously, you know, the companies will, will encourage you to measure it and, you know, to draw the blood always at the same time. Um, now the whole field right now is pretty much focused, pr- almost completely focused on, um, DNA methylation. I, you know, and Steve Horvath has done beautiful work. I mean, it's really pioneering work identifying and all this, and, uh, Morgan Levine and, and others have, have gone on. You know, uh, uh, Dan Belsky, I think with denatine pace, uh, which is a- another epigenetic clock that measures the pace of aging. By the way, I think this is probably my favorite because it, it really, uh, seems to be, um- uh, responding to interventions. You know, if you go-- if you change your diet or if you do something, you will see your, your pace of aging, uh, changing. So I think that one to me seems, uh, more promising. Um, but it's a whole small... You know, we don't know really how to use these tools clinically. That's the problem. They're, they're, they're nice gadgets to, to buy, you know, and the, the companies are selling you supplements, and then they're selling you the, uh, the tests with it. I don't know what to make of it. Um, personally, I think this is not ready for prime time. It's something that should be done, uh, in the future. Uh, it might become in the future.

    13. PAPeter Attia2:09:48

        Would you agree with my stern words on this? Because I've, I've made a lot of enemies by saying that if, as a consumer, you encounter a company that is selling you a test, especially a test that is not validated in any clini-clinically meaningful way, and then in the same breath selling you a supplement to fix the result of that test, you need to run.

    14. EVEric Verdin2:10:18

        I agree.

    15. PAPeter Attia2:10:18

        I mean, I, I just, I, I don't have the patience for that kind of behavior.

    16. EVEric Verdin2:10:23

        Someone told me actually, um, recently that, uh, one of these tests actually that you can measure, almost everyone who, who gets their result is low. And of course-

    17. PAPeter Attia2:10:36

        Low being good or bad in this test?

    18. EVEric Verdin2:10:38

        Or whatever. No, it's bad.

    19. PAPeter Attia2:10:39

        Bad, yeah.

    20. EVEric Verdin2:10:40

        It is insufficient.

    21. PAPeter Attia2:10:41

        Yeah.

    22. EVEric Verdin2:10:41

        And the, the next step is the recommendation. You have to buy this supplement to solve the problem. So yes, I, I think, you know, um, again, it's the same thing with the sirtuins and the NAD. Let's not throw out the baby with the bathwater. There is a whole series of these players. Uh, I'm not disputing their honesty or, or their good intention. Uh, from what I've seen, I think it's too early.

    23. PAPeter Attia2:11:05

        And what do you think is the biggest problem? Is the biggest problem the biologic noise in the system, which means even if you had the absolute perfect tool to measure and you knew exactly what to measure, the movement of that thing is so great that the probability that you're capturing a meaningful value is irrelevant. In other words, imagine that there's a variable that moves like this, but on the small level, it's moving like this. And I'll give you an example. Imagine you were measuring heart rate, but you could only sample it milliseconds at a time, and what you were actually measuring was heart rate variability instead of heart rate. It would be useless. It's too noisy.

    24. EVEric Verdin2:11:48

        Agree. Agree. I agree.

    25. PAPeter Attia2:11:50

        So, so do you think that's the problem?

    26. EVEric Verdin2:11:51

        No, I don't think that's a problem. And I, I'll, I'll, I'll speak personal experience. I, you know, I, I work with TruDiagnostic. They-- when you get, you know, they use the Epic array, and you get not one clock, you get dozens. So I get all of them. And they tend to be reproducible, you know, every three months, unless I make some interventions. But in general, there is some consi-cons-cons-consistency, and I, I'm not the only one who has seen this. So my advice, if you really are determined to use them, use all of them. They all are sort of, uh, different mirrors of, of your reality. You know, these-- the problem of the methylation clocks is that there's a very tenuous link between the change of methylation at any given site and the biology. So when, you know, typically the clock will measure about five hundred, uh, will rely-- each clock would rely on about five hundred different methylation sites, but they're not attached to a specific gene, so you don't really know what it means.

    27. PAPeter Attia2:12:52

        But how are they even doing that? They're not measuring with point arrays. How, how are they-

    28. EVEric Verdin2:12:57

        No, they do this with arrays. Epi-

    29. PAPeter Attia2:12:58

        They're doing this with an array?

    30. EVEric Verdin2:12:59

        Yeah. They have about twenty m- twenty million methylation sites that they assess, but each clock uses a subset, four or five hundred. Now, the biggest problem with the clocks from my perspective-
20. 2:20:48 – 2:31:46

    Potential of proteomics-based aging clocks for detecting organ-specific decline

    1. EVEric Verdin2:20:48

       um, what really excites me right now is the whole idea that the field is, is moving on to the next stage, which is non-epigenetic clocks. Uh, because I'm still frustrated as a biologist trying to understand what are, what are, what are these clocks-

    2. PAPeter Attia2:21:02

       It should be everything. Well, I mean, why would we do, why-

    3. EVEric Verdin2:21:05

       Yes

    4. PAPeter Attia2:21:05

       ... I mean, it doesn't make any sense to me w- that we wouldn't look at the metabolome, the proteome, and the epigenome. I mean, we should look at every, I mean, there's the, uh, there's no excuse today with the compute power not to do that, right?

    5. EVEric Verdin2:21:15

       We have clocks based on fundus. We have clocks based on skin. We have clocks based on facial recognition. So the clocks are going to be, uh, measured, you know, using dozens of different, uh, uh, biological variables. Uh, any biome, uh, uh, com- small company, uh, in the Bay Area is using it. The tongue, a tongue picture, the old doctor looking at your tongue, so you can actually use machine learning to recognize patterns of, uh, you know, discoloration. And, and, and, and, um, another, you know, exciting really story was, I, I don't know if you're familiar with, uh, Tony Wyss-Coray's paper, uh, using proteomics. He has shown, for example, proteome in plasma changes throughout life.

    6. PAPeter Attia2:21:58

       Yep.

    7. EVEric Verdin2:21:59

       Pretty dramatic manner, uh, which is really completely mind-boggling for me to, to see that you can be so different as you age, uh, in terms of your whole blood proteome.

    8. PAPeter Attia2:22:09

       Why? I mean, wouldn't you ex- if, if the epigenome is changing, then gene expression is changing. If gene expression is changing-

    9. EVEric Verdin2:22:16

       No, no, you would

    10. PAPeter Attia2:22:17

        ... pro- yeah, yeah, yeah, it's... Okay.

    11. EVEric Verdin2:22:18

        But we haven't, we haven't, you know... So they've used this to... That it would change to such a degree.

    12. PAPeter Attia2:22:24

        Yeah.

    13. EVEric Verdin2:22:24

        I mean, uh, Tony has a beautiful slide which shows, you know, all of the proteome in the blood and how the colors change across age.

    14. PAPeter Attia2:22:32

        And, and do you think that most of those changes are pr- post-translational?

    15. EVEric Verdin2:22:36

        No, most of them are probably expression level.

    16. PAPeter Attia2:22:39

        It's expression.

    17. EVEric Verdin2:22:39

        Yeah, it's expression.

    18. PAPeter Attia2:22:40

        Okay.

    19. EVEric Verdin2:22:41

        Um, so people are building transcriptomics clock. And so, um, Tony now has a study that is, I believe, in press or coming out soon, um, where they've gone back using this proteomics clock, and they've done this, um, uh, on a UK Biobank, more than 40,000 different people. And this is the study I, we started this discussion on, uh, identifying which organs are, uh... So what they, what Tony did was actually remarkable. He looked at each of these proteins that are in the blood and selected some that were predictive to be coming from unique organs. So imagine the, what you know about how you measure a tropomyosin for, for heart attack.

    20. PAPeter Attia2:23:26

        Yep.

    21. EVEric Verdin2:23:27

        So they did this. They went and looked in every single organ and say, "Okay, what proteins are specific of this organ, and which ones actually can be measured into the plasma?" And using this, they were able to generate what they called an organ-specific clock. So what they, sim- simply from a blood draw, they're able to, um, to really determine, um, do you have a frailty point i- in your... When I look at you, do you, is there, like, suffering happening in-

    22. PAPeter Attia2:23:54

        And this is Tony's work through the proteome?

    23. EVEric Verdin2:23:56

        Yeah.

    24. PAPeter Attia2:23:56

        Yeah.

    25. EVEric Verdin2:23:56

        To- Tony Wyss-Coray. It's a, it's a new startup called Vero, uh, which is, um, I've... I, I mean, full disclosure, I've joined the board of this company, but I, I, I, I only joined the board because I was really excited about what they're trying to do. And I think it really brings a whole new dimension to these, uh, predictive biomarker, which is more aligned to what you and I have seen as physicians. You know, just kind of simple-minded. If, if the protein is released into the blood, it shouldn't be there, uh, it might be indicating, uh, uh, some suffering. And I, I've discussed with some colleagues who have used these clocks and have identified some abnormal aging in, in a unique organ, only to go back and find that there was indeed one problem, without going into, you know, what the issues were. But you can put-

    26. PAPeter Attia2:24:45

        Yeah, I mean, the challenge, the thing that, the reason I tend to be a slow, um, adopter of these things is even if that's the case, the question is how much noise is in the system. So I go and do that test on a patient, and it comes back and says, "Oh my God, there's something wrong with your liver. Your kidney's a bit too old. You're this, you're that, you're this, you're that." So I have two fundamental questions. The first is, could I have figured that out another way? So if it's telling me your liver is angry or something's wrong with your liver, how do your transaminases look, right? If it's telling me something's wrong with your kidney, could I have picked that up on a urinary analysis looking at, you know, 20, you know, creatinine clearance or, you know, cystatin C or something else? In other words, is it giving me information that I can get elsewhere in a more reproducible, more validated fashion? The second thing is, let's say it tells me seven things are not perfect, and I ultimate- and by the way, everything looks perfect. So I have my standard assays. Everything looks awesome. This test says, "Oh my God, these s- six or seven things are problematic." And I go poking around, poking around, poking around, and I find out one of them is indeed not working, but the other six were perfectly fine. So now we have this huge false positive situation.

    27. EVEric Verdin2:26:01

        That's, that's the whole MRI-

    28. PAPeter Attia2:26:02

        It's, it's the same problem... Yeah, exactly. It's the same problem we have with cancer screening, which is, you know, buyer needs to be aware of the Pandora's box you open, and at least with MRI, you're dealing with imaging. But this sounds, like, exciting, and yet it's a bit of a black box-

    29. EVEric Verdin2:26:16

        Agreed. But-

    30. PAPeter Attia2:26:17

        ... where it's going to spit out, "Oh my God, there's something wrong with your left testicle."

Episode duration: 2:31:46