The Peter Attia Drive - #359 ‒ How metabolic and immune system dysfunction drive the aging process, the role of NAD, promising interventions, aging clocks, and more

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:21.520 into something accessible for everyone. Our goal is to provide the best content in health and

00:00:26.720 wellness, and we've established a great team of analysts to make this happen. It is extremely

00:00:31.660 important to me to provide all of this content without relying on paid ads. To do this, our work

00:00:36.960 is made entirely possible by our members, and in return, we offer exclusive member-only content

00:00:42.700 and benefits above and beyond what is available for free. If you want to take your knowledge of

00:00:47.940 this space to the next level, it's our goal to ensure members get back much more than the price

00:00:53.200 of a subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.000 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Eric

00:01:06.160 Verdon. Eric is a physician scientist who spent two decades uncovering how epigenetics, metabolism,

00:01:12.140 and the immune system drive aging, and now serves as the president and CEO of the Buck Institute for

00:01:18.280 Research on Aging. In this episode, we discuss Eric's path from studying viruses and HDACs to

00:01:24.940 leading the Buck Institute and focusing on aging research, how aging changes the immune and nervous

00:01:31.300 system, thymus shrinkage, for example, loss of T-cell diversity, chronic inflammation, and weaker

00:01:37.280 vaccine response, and why these changes can ultimately shorten lifespan, metabolic drivers of aging, oxidative

00:01:43.660 stress, fuel choice, insulin, and IGF-1 signaling, and practical tips on zone 2 cardio, ketogenic nutrition,

00:01:52.040 and GLP-1 drugs, why NAD levels fall with age, the role of sirtuins and CD38, what NMN, NR, IV NAD can and

00:02:03.400 can't do, and the importance of stopping NAD loss, drugs that have the potential to slow aging, including

00:02:10.380 optimal rapamycin dosing, growth hormone-based thymus regrowth, blocking IL-11 or IL-1, and how these

00:02:18.360 things might compare with, say, exercise, current ways to measure biologic age, and the limits of

00:02:24.840 today's epigenetic clocks, new proteomic and organ-specific tests, and how combining multiple

00:02:30.640 metrics with wearables may guide personalized longevity care. So, without further delay, I hope you enjoy

00:02:36.820 my conversation with Dr. Eric Ferdin. Eric, thank you so much for coming to Austin. I know it wasn't

00:02:47.540 just to talk to me. I know that half of it was getting you to drive on the track at Coda tomorrow

00:02:52.140 with me, so we're going to have some fun there. My pleasure. But as much as I think the two of us

00:02:57.200 could sit here and talk about race cars for the next three hours, I don't think the audience would

00:03:02.620 appreciate it or care for it as much as they will care for what we will talk about, which is

00:03:07.580 your work in gyroscience. So, maybe give folks a little bit of a sense of what attracted you to

00:03:13.080 this field and how your journey and background brought you where you are. It's a bit of a

00:03:18.500 serendipitous type of story in a way that I'm an MD by training from Belgium, did my last year of medical

00:03:24.520 school at Harvard, and this just sort of opened my eyes to a whole world. I was the first person in my

00:03:30.540 family to go to college. Ending up at Harvard with some of the best teachers, some of the best

00:03:34.620 students was just mind-blowing. And I went to medical school wanting to do research. Never had

00:03:40.160 that sort of a doctor fiber, I call it, so really wanted to research. And so, after this, finished

00:03:45.820 medical school and came back for directly a postdoc at the Charleston Clinic working on diabetes and

00:03:51.480 metabolism. So, this is where the story gets circuitous. Ended up becoming interested in the reason for

00:03:57.780 the etiology of type 1 diabetes and worked on viruses and autoimmunity. This eventually led

00:04:04.400 me to mostly a career in virology, which confuses people. So, I spent many years working on a variety

00:04:11.180 of viruses, including HIV and herpes viruses and so on. And through that work, we ended up cloning a

00:04:17.340 family of protein called some of the first epigenetic regulators, the HDACs. And the HDACs at the time,

00:04:24.440 there was 1996, we were responsible for the cloning of a whole family of these epigenetic regulators,

00:04:30.160 ended up being important in aging. And starting in around 1995, 1996, my lab slowly shifted towards

00:04:37.340 the study of aging. And to this point today, actually, I only have one last postdoc in the lab

00:04:43.700 who's working on HIV. The whole lab is actually focused on epigenetics, immunology, and metabolism,

00:04:50.020 so that the interface between these variables. So, in some ways, it's the beauty of an academic

00:04:55.060 career, which I've just followed my interests, sometimes followed the money a little bit in

00:04:59.940 terms of funding. Now, I mean, I have another additional responsibility, which is to lead the

00:05:05.260 Buck Institute for Research on Aging. I have split my time between the lab and some more leadership type

00:05:11.240 of activities.

00:05:11.840 So, you mentioned two things there, metabolism and immunology. Talk a little bit more about how

00:05:18.840 each of those individually contributes to aging. I think most people will intuitively understand it,

00:05:24.060 but talk maybe a little deeper about it.

00:05:26.260 Well, first, immunology is central to aging in many respects. I hope we can talk about this later.

00:05:34.120 There is data showing that there are two organs that are rate-limiting in terms of your aging,

00:05:39.460 and it's the central nervous system and the immune system. And the reason for this is actually,

00:05:45.660 one could have predicted this based on the fact that both organs are distributed organs. If you

00:05:51.240 think of your immune system, it's located pretty much throughout the whole organism. And so,

00:05:56.420 its activity can influence the well-being or the functioning of every single organ.

00:06:01.940 The same goes for the central nervous system. And there's a recent study coming out,

00:06:06.700 actually, from the lab of Tony Whiskere showing that those biomarkers that measure aging in those

00:06:13.000 organs appears to be the most predictive of your lifespan. There's also incredible data showing

00:06:19.680 that if you induce a specific lesion in the immune system, for example, in mice model, if you knock out

00:06:26.820 ERCC1, DNA damage repair, only in the bone marrow so that the whole immune system is affected,

00:06:33.440 you actually induce accelerated aging in the whole organism and senescence in every single organ.

00:06:39.840 In what model?

00:06:40.880 It's been done in two different models. In mice, it's been done with the ERCC1 mutation. It's also

00:06:45.900 been done by knocking down the major TFAM, the major transcription factor for mitochondria. So,

00:06:50.680 if you induce mitochondrial dysfunction only in the immune system, you induce secondary senescence in

00:06:55.740 the whole organism.

00:06:56.140 Do you think that would be true in humans?

00:06:58.000 It's a million-dollar question. In some way, it's been shown in two different models in mice.

00:07:03.760 B6.

00:07:04.280 I don't remember the exact strand of the mouse, but there's no reason why it should be different,

00:07:08.740 frankly. And it speaks to the importance of the immune system. The second way for the immune system

00:07:12.860 is through chronic inflammation, which is tied cause and effect in the whole aging process.

00:07:19.820 And we can talk about this later as well. I find it fascinating, the whole idea of chronic

00:07:23.840 inflammation, which is induced by the aging process, but itself actually further accelerates

00:07:29.240 aging. So, there's really a lot of work that's being conducted in this area. The other one that

00:07:33.980 you were asking is metabolism.

00:07:36.140 That's a very interesting idea that two organ systems that are going to be rate-limiting in age

00:07:40.900 are the central nervous system and the immune system, both of which are distributed.

00:07:44.820 Where would you put the endothelium in that list as well? The endothelium is also quite distributed

00:07:51.160 across the organism. And do you think that there's an inevitability to basically endothelial damage

00:07:57.440 as a process of aging, which of course results in the leading cause of death, the atherosclerotic

00:08:02.880 diseases? Do you think of it the same way, or do you think of it as different?

00:08:05.900 It's not sort of defined as an organ by itself. It's a cell type. I agree with you,

00:08:10.440 has incredible importance, especially as it affects the heart and the cardiovascular system.

00:08:16.320 And the brain.

00:08:16.860 And the brain. But I think of it as not so much as an organ, but more as a principle that

00:08:22.240 maintenance of barrier function, not only in the endothelium, but also in the skin,

00:08:29.060 in the blood-brain barrier, are emerging as key areas to focus on if you want to maximize your

00:08:34.880 longevity.

00:08:36.280 Yeah. I want to come back to this in great detail, Eric, but let's, for the sake of summary and

00:08:40.920 synthesis, turn over to where you wanted to around metabolism.

00:08:44.140 So metabolism is essential to life expectancy for a number of reasons. One of them, I'm convinced,

00:08:53.400 even though that theory has been somewhat discredited, the whole oxidative stress theory

00:08:57.680 of aging, I still think oxygen is one of the major problems associated with the aging process.

00:09:04.660 We have not been able to target the oxidative stress using antioxidant. That has failed.

00:09:10.560 It doesn't mean that the whole oxidative stress theory of aging is not valuable. I think living

00:09:16.440 in an oxidative environment is one of the mechanisms that leads to aging. Not the only

00:09:20.860 one. Aging is pleiomorphic.

00:09:22.520 But just to make sure folks understand what you're saying, Eric, you're saying that the generation of

00:09:28.480 free radicals through oxygen. So I don't know how technical we want to get for people, but I think

00:09:32.820 unfortunately we might need to get a little more technical and apologies to those who don't want

00:09:36.940 to go this deep, but we have to talk about kind of what the role of the electrons are in oxygen

00:09:40.740 and why free radicals form and what they do. So maybe we do go a little deeper here and explain

00:09:46.860 what you're saying. It's a very important concept and I think we should probe it.

00:09:50.800 I don't know how much, I mean, maybe you do a better job at explaining this for the lay person.

00:09:54.900 I mean, oxidative stress is the fact that pretty much the main metabolic reaction are dependent on

00:10:01.520 oxygen, which gives its electron. It's in the so-called respiratory chain. There is leakage of

00:10:08.300 these electrons that are traveling down this respiratory chain, leakage at specific places. You know,

00:10:13.800 if the process was a hundred percent efficient, the whole energy would be transferred from metabolites

00:10:19.000 such as fatty acid, glucose, and so on. But it turns out the mechanism is actually leaky. These

00:10:25.000 electrons reacting with oxygen can generate these byproducts called radical oxygen species,

00:10:31.480 which are highly reactive.

00:10:33.260 Right. So they're not chemically stable the way we think of a normal atom of oxygen.

00:10:38.220 No. And so they tend to react with proteins, with fatty acid, and they induce lesions.

00:10:43.280 The importance of this system in terms of protection against it is highlighted by the

00:10:48.700 number of molecular systems that we have that are actually protecting against this.

00:10:53.840 And we know that as we age, that leakage increases.

00:10:57.900 Exactly.

00:10:58.200 So something about the integrity of the mitochondria and the respiratory electron transport chain

00:11:05.140 degrades as we age, and therefore we see more and more of this leakage, yeah?

00:11:09.620 Yes, absolutely. And so out of this came the whole idea, well, let's just suppress oxidative stress.

00:11:16.040 And there are chemicals, even some as simple as vitamin E, vitamin C, that you could imagine that

00:11:23.320 by chemical knowledge would be predictive to be able to quench these radical oxygen species.

00:11:31.180 Sorry to just keep interrupting you. We'll play off to each other to do this.

00:11:34.680 No, no, this is great.

00:11:34.940 So you eat, for example, an antioxidant, and as you said, it neutralizes that reactive oxygen species

00:11:41.900 with its unstable electrons, kind of like you would throw a blanket on a fire that's simmering.

00:11:47.520 Exactly. And that was the hope. So when the theory was proposed, a whole industry actually grew up

00:11:53.780 out of this, the whole antioxidant, and the antioxidant diet, and the vitamins, and so on.

00:12:00.300 You can still, by the way, that whole industry is still existing today.

00:12:03.220 Sure does.

00:12:04.040 Now, what happened is that when clinical trials were conducted in this area, they failed.

00:12:09.380 And so people who think relatively simply decided, well, the antioxidant failed, therefore the theory

00:12:15.860 has no validity. I would say not so fast, because it turns out that these radical oxygen species

00:12:21.260 also have important roles. They actually are inducing an inflammatory response, which can be

00:12:27.800 protective. And a good example is during exercise. There is some evidence of activation of oxidative

00:12:34.280 stress during exercise. And if you neutered this, for example, with anti-inflammatory, you probably

00:12:40.380 remember the data showing that anti-inflammatory drug tend to suppress some of the beneficial effect

00:12:46.040 of exercise. It's the same whole idea. And so this is one case in which these

00:12:50.900 radical oxygen species can have a protective role and actually a signaling role. So when you

00:12:57.140 suppress it completely with these global nonspecific antioxidants, essentially you're not only killing

00:13:03.180 the bad guys, but you're also suppressing an important signaling mechanism.

00:13:07.600 There's another hypothesis that I would offer, which is, is it possible that there's still a net

00:13:13.660 negative to the free radicals? So there might be some benefits, but more negatives. But it could be

00:13:19.920 that the trials were using agents that were simply ineffective, because the problem is we don't

00:13:25.500 have a great biomarker for the state of free radicals. So it's sort of like saying, I have a

00:13:31.700 hypothesis that this biological process is bad. I can't measure it really, but I think it's bad.

00:13:38.480 I have a drug that I think will tamp it down. Let's give the drug, the trial failed. Well, do you

00:13:43.720 actually know if it tamped the thing down? We don't even know if we tested the hypothesis, correct? And so

00:13:48.400 those would be kind of two distinct plausibilities.

00:13:51.440 I completely agree. And it's quite often the case. I mean, the whole story of vitamin D is a

00:13:55.620 good example. Where people will tell you, you know, vitamin D doesn't work because they conducted

00:14:00.740 clinical trials, but they didn't fix, they didn't adjust the dose, they didn't measure the level. So

00:14:05.300 it's a bit the same story. There are markers that you can actually do use in research environment,

00:14:11.520 like 5-hydroxynoninol or protein carbonylation, which are indirect markers of lipids or protein

00:14:19.080 oxidation.

00:14:21.000 How efficacious or beneficial, or I guess the word is, how complete are they in the scope

00:14:26.400 of understanding? And have we demonstrated that mega doses of vitamin E or vitamin C will

00:14:31.980 indeed suppress those markers in humans?

00:14:35.100 They're not great. They're not great. I had a colleague at the Buck Institute, Martin Brand,

00:14:39.360 who is one of the leaders of the whole mitochondrial field called bioenergetics, which is the study

00:14:44.320 of how the respiratory chain and energy metabolism happens in mitochondria. And he came up with

00:14:49.840 the idea that he identified many of the sites where these unique radical oxygen species are

00:14:56.240 generated. And he was able to generate specific inhibitors for each of the sites and was able

00:15:02.720 to show that actually inhibition at some sites was beneficial while inhibition at other sites

00:15:08.540 was not beneficial. So this project was actually supported by a pharma company, which eventually

00:15:14.060 decided to drop the program. And he's retired, which I think is a great loss because it is a

00:15:19.420 whole program that still needs to be pursued.

00:15:21.820 So if I'm understanding what you said correctly, Eric, it sounds like there's a much more nuanced

00:15:27.020 view. It's not that free radicals are bad and it's not that free radicals are good. It's like everything

00:15:33.020 in biology. It's the Goldilocks rule. You might need more of it during this circumstance in this part

00:15:39.820 of the body. You might need less of it in this circumstance at this totally different part of the body.

00:15:45.020 And as a result, any strategy that would try to globally suppress it could, even if successful

00:15:51.500 in doing it, which we haven't been able to measure, might actually not yield to a favorable outcome.

00:15:55.820 Totally correct. I get frustrated by the way that people sort of love to oversimplify

00:16:02.780 or sort of erase whole fields. I suspect we will get to talk about sirtuins because the same thing has

00:16:08.060 happened in the sirtuins. There's a lot of amazing work done. And then a few negative results or things

00:16:14.380 not working out. NAD metabolism, same thing. I always tell people, you know, once you get into

00:16:19.740 any field of study and you go deep and you start testing in humans, put on your seat belt because

00:16:25.660 it's not easy and there are no magic bullets. But I think stopping the study and saying the whole field

00:16:31.340 is BS is really, for me, not the way to go. We got to dig deeper. And eventually, you know, we'll get to that.

00:16:37.180 Tell me what else within metabolism you think is kind of a hallmark of aging. So we obviously talked

00:16:45.100 about the central part of metabolism, which is respiration and ATP generation and the leakage

00:16:50.860 that occurs there. And basically, unfortunately, that just appears to be inevitable.

00:16:55.580 Yes. We will never stop the oxygen in our environment.

00:16:59.500 I do like to tell my patients that this is

00:17:02.700 why I kind of harp on them to do a lot of zone two cardio training. So zone two, very specifically,

00:17:09.260 by definition, is the canonical exercise you would do to maximize fat oxidation, which of course,

00:17:18.460 implies the most efficient use of the mitochondria. And the hypothesis, because I don't think,

00:17:24.540 you know, we don't have proof of this, but the hypothesis is training at that level for specific

00:17:30.060 periods of time throughout the week is a way to improve the health and function of your mitochondria,

00:17:35.660 which would hopefully imply that you're reducing that degradation of function. Do you think there's

00:17:41.020 validity to that, at least first order logic? Yeah. I mean, the proof is in the pudding in the

00:17:46.540 way that we know exercising and a combination of exercise is the best anti-aging intervention we have.

00:17:53.740 But do you think part of it is through that exact mechanism? Yes.

00:17:56.060 Yeah. I mean, that's been my hypothesis. But again, we can't fully glean that in any human

00:18:00.540 clinical trial. No, hard to study. And I think your point allows me to sort of address your question.

00:18:05.740 What is it about metabolism that really is so important? I think I'm convinced that it is fuel

00:18:10.940 utilization. You mentioned fatty oxidation versus glycolysis, and I'll add ketosis to this. I think

00:18:17.180 if you think about your metabolism is able to oxidize a number of different substrates, amino acids,

00:18:24.700 fatty acids, glucose, and ketones. And lactate.

00:18:28.540 And lactate. And every one of those actually burns with different efficiency, both being car

00:18:34.620 aficionado. I think your audience probably knows also that they're different to burn diesel or to

00:18:40.140 burn 100 octane gas. And if you look at that hierarchy, I think ketones are probably the cleanest

00:18:46.940 fuel to burn in terms of, again, byproducts, oxidative stress. They seem to be really unique.

00:18:53.340 Yeah. How would you rank order from cleanest to dirtiest, inclusive of lactate?

00:18:57.660 Lactate, I would not be able to put it. I think it's probably clean.

00:19:01.180 Yeah. I think my intuition is it is as well.

00:19:03.180 Yeah. The top would be-

00:19:04.220 Beta-hydroxybutyrate.

00:19:05.260 Beta-hydroxybutyrate. Acetoacetate is present at such low abundance,

00:19:08.940 it's probably not relevant as a fuel source. Then fatty acid. Next is the worst is actually glucose.

00:19:14.620 And when you think about metabolism and aging, for me, it goes to a lot of the data that has emerged

00:19:22.620 from the ITP, for example, intervention testing program.

00:19:26.300 Rich Miller has been on several times.

00:19:27.820 Yes. I watched your recent podcast with Rich and others. One of the remarkable thing,

00:19:32.700 when you look at the drugs that have seven or whatever, 10 drugs that have emerged out of 80,

00:19:37.580 they are really targeting glucose metabolism via a completely different mechanism. Think about

00:19:44.060 acarbose, which is blocking absorption of glucose. Think about the canaglifosin,

00:19:49.580 which is targeting a protein that has nothing to do with links to glucose reabsorption in the kidney.

00:19:55.260 Think about metformin, which is-

00:19:57.340 But metformin failed.

00:19:58.380 Yeah. It failed, but it seems to be having very powerful effect. Well, it did not fail,

00:20:02.620 actually.

00:20:03.020 It failed unless it was paired with rapamycin.

00:20:05.020 Yes. And in monkeys, there's a study coming out that showed that it actually had an effect on lifespan.

00:20:10.220 And do you think rapamycin has any impact on glucose metabolism favorably?

00:20:14.300 Generally, actually, rapamycin is the exception to this because it seems to be having,

00:20:19.180 it's not indifferent. It has been claimed to be having an effect on insulin sensitivity.

00:20:24.860 Although I'm not clear if that's true at the doses, but anyway, yeah, we can come back to that.

00:20:29.340 I've taken rapamycin. I have not seen any effect on my blood sugar.

00:20:33.660 Think about acarbose, canaglifosin, metformin, and now the GLP-1 agonists,

00:20:39.580 which I predict will emerge as geroprotectors in the future. So I think that really speaks to

00:20:47.260 an important aspect, which is fuel utilization and how, whether you're burning a clean fuel,

00:20:53.900 whether you're burning a dirty fuel. We've put, for example, mice on a pure fat diet. These mice

00:21:00.380 never saw a carbohydrate during their life and they lived longer, which I thought was actually

00:21:04.620 quite interesting.

00:21:05.500 It is interesting, Eric, because a lot of the mouse literature, I think people don't read the

00:21:11.580 fine print very closely. They don't notice that the typical thing you'll see is these mice were

00:21:18.060 fed a high fat diet to induce obesity so that we could test drug A, B, or C against obesity.

00:21:23.660 In those studies, it's not just a high fat diet. It's a high fat, high sugar diet.

00:21:28.380 So they're making some insanely hyper palatable. The closest I can come up with is they're making a

00:21:33.900 donut, right? It's a fried dough sugar food. So they're making basically donuts for these monkeys.

00:21:42.220 And that's different than saying it's a high fat thing. So yeah, I think that's important to point

00:21:45.820 out because high fat minus the sugar might not be the same issue, right?

00:21:50.140 I agree. At least in that model. So what do you think it is about glucose metabolism

00:21:55.500 that leads to this? Because for all intents and purposes, let's just go through the metabolic

00:22:00.780 pathways. So glucose, six carbons, it gets broken down into pyruvate. You get two pyruvates for one

00:22:09.260 glucose, right? And then pyruvate, let's just assume we're doing this under aerobic conditions so we're

00:22:15.340 not in a rush. We're going to take those pyruvates. Do they turn into acetyl-CoAs? I can't even

00:22:20.780 remember to then enter the- It's actually one pyruvate and that enters the mitochondria and

00:22:25.500 becomes acetyl-CoA. Acetyl-CoA, okay, okay. So what is it about that process that is not as efficient

00:22:32.060 as when you are cleaving off carbons from a free fatty acid and those carbons are turning directly

00:22:39.500 into, I think, just a straight acetyl-CoA and then entering the Krebs cycle?

00:22:44.220 I mean, it's a very subtle difference. Why is one so much more inefficient?

00:22:47.800 You mean why is there more calories per fatty acid?

00:22:50.820 No, no, no, no, no. That can be explained by the stoichiometry. Why is one quote-unquote dirtier?

00:22:55.860 Okay. Obviously, this is a really complicated question. So I don't know that I would be able

00:23:00.680 to really tell you purely as fuels whether there is a difference. I think the biggest difference is

00:23:06.920 in terms of the whole mechanism that they elicit. And when we think about glucose, I don't think

00:23:13.000 necessarily of it if you were to study it in a tissue culture dish that one would be more toxic

00:23:17.760 than the other. I don't think there's any evidence for this. But glucose, and particularly

00:23:22.240 the form of glucose that we have not evolved to actually be exposed to, which is all the wheat

00:23:28.980 products, this fast form of glucose elicits insulin secretion. And I think insulin and IGF-1,

00:23:36.840 particularly insulin, is the culprit in this whole process.

00:23:40.600 So you're not saying that one mole of glucose, one mole of free fatty acid, we know there's

00:23:47.280 a difference in ATP generation, but you're not saying that there's a different, assuming

00:23:52.800 they're both going through the mitochondria, you're not saying there's a difference in free

00:23:55.980 radical formation mole per mole? Or are you saying that it's this way? There's another way to explain

00:24:01.640 it, which is per mole of ATP, you need to run so much more glucose through that, of course,

00:24:08.300 you're going to get more leakage.

00:24:09.580 The key difference is that the glucose is generating ATP, not only via acetyl-CoA and pyruvate,

00:24:16.540 but is also generating ATP in the intracellular plasmic components. The fatty acids do not generate

00:24:23.060 any. So I suspect that there might be a difference in terms of the amount of free radical that are

00:24:28.300 generated. There is evidence, but I would not be able to cite you the paper, that one burns more

00:24:34.040 cleanly than the other. And I suspect it's partly the cytoplasmic component of glucose. It's also

00:24:38.780 less efficient in terms of the amount of energy that's being generated per gram of fatty acid,

00:24:44.660 or per mole of fatty acid versus per mole of glucose.

00:24:48.020 And then going back to the insulin IGF component here, what role do you think they're playing?

00:24:52.800 critical. Because epidemiologically and through studies, we know that the insulin response to

00:25:00.580 your glucose. So if you do a lot of sports, I'm not a proponent of the low carbohydrate or no

00:25:06.160 carbohydrate diet, because there's very little evidence that those diets are actually beneficial.

00:25:11.220 I gave you the example of a ketogenic diet, which we did experimentally, but these are not practical

00:25:16.020 diets for anyone.

00:25:17.080 Just because of the challenge in avoiding carbohydrates in the standard world we live

00:25:22.720 in?

00:25:23.200 Yes. But socially, palatably, I mean, there's so many reasons. I went on a ketogenic diet.

00:25:29.640 And from what I remember, I think you went too.

00:25:31.860 I did for three years. I was on a ketogenic diet. So we should compare notes. I want to hear your

00:25:36.080 experience. And then I want to ask you a couple of questions about it.

00:25:38.460 It was very hard.

00:25:39.620 How long did you do it?

00:25:40.500 For a couple of years. And I did not feel super healthy, which is really kind of interesting.

00:25:47.080 I found it socially isolating. We've worked actually to remedy this on, we can talk about

00:25:52.320 this later on, novel keto.

00:25:54.040 Like a ketone ester?

00:25:55.060 A ketone ester, exactly, of beta-hydroxybutyrate. So going back to the role of insulin, there is a

00:26:01.780 lot happening that's been documented that the intensity, first, your average glucose plays

00:26:07.820 a role. Average blood glucose, this is measured by hemoglobin A1c in a whole series of complications,

00:26:13.660 cardiovascular, as you know. But perhaps more important is the intensity of your peaks. And I

00:26:20.800 think the intensity of the peaks of insulin is a reflection of your glucose intake, fast-absorbing

00:26:27.360 glucose. And that's the reason why we advocate, I advocate people to go on a CGM, continuous glucose

00:26:33.640 monitor, and to really learn to understand what spikes them. The whole idea is to mitigate these

00:26:39.580 peaks of insulin secretion. I'm just going to play this for all of our patients. We have this

00:26:44.280 discussion with every one of our patients, so it'll be nice to just play this video and let you do the

00:26:48.080 talking. The whole idea there is to, again, mitigate these peaks and either dietary or, for example,

00:26:58.280 the GLP-1 agonists are playing a role in this as well. Yeah, well, let's talk about this because

00:27:02.040 there is, at least for me, a great deal of confusion around this point. Now, we understand today the role

00:27:09.180 that the gut plays in metabolism, and we understand that a lot of it is transduced through GLP-1.

00:27:17.200 So endogenous production of GLP-1, according to Ralph DeFranzo, the world's authority on this,

00:27:23.500 is what's driving 80% of beta cell activity with respect to insulin. And therefore, when we have

00:27:31.220 insulin resistance, the GLP-1 we're making is insufficient to generate the insulin that's

00:27:36.860 required to manage the glucose. Makes sense if that's the case, that giving exogenous GLP-1,

00:27:42.620 you take a shot of terzepatide or semaglutide, you're going to put more GLP-1 in the system,

00:27:48.600 you're going to overcome the resistance at the beta cell, you make more insulin, you now have better

00:27:53.860 glucose control. Everybody wins. Now, it's not clear that that has anything to do with the weight

00:27:58.280 side of it. That's a separate issue. And I want to actually talk about that because there are two

00:28:02.240 very interesting theories as to why these things cause weight loss. But point here is, wouldn't you

00:28:08.180 expect to see higher levels of insulin in someone taking a GLP-1 agonist to achieve that better

00:28:15.500 glycemic control? Yes. And that's not what you see. And I don't have an answer for this. I've seen the

00:28:21.700 same thing, including personally, I've been experimenting with terzepatide. My insulin is

00:28:26.420 five now, which is lowest that you can possibly get it. There was a part of me that was worried

00:28:31.840 that I was going to go against my own whole theory about... Have you checked postprandially?

00:28:38.200 Have you done an oral glucose tolerance test? Because that might be something to do to see

00:28:42.420 what is happening to postprandial insulin along with postprandial glucose, which of course will be

00:28:47.200 better. No, I haven't. That would be an interesting test to do. Yeah. I've won a CGM.

00:28:51.860 My A1C has gone from 5.4, 5.5 to 5.0. And my insulin is down to 5.0 as well. So...

00:29:01.420 And did you lose any weight? I lost a little bit of weight, not a huge amount,

00:29:05.620 six or seven pounds, which was never the goal to start with. And no loss of muscle mass,

00:29:11.060 which actually is the big boogaboo that people will have you fear. No loss of muscle mass if you

00:29:17.120 are exercising. So for me, it's an experiment. I haven't decided this is something I'm going to

00:29:21.620 continue, but I just wanted to really experiment for myself to try to see, okay, what is this drug

00:29:26.140 really doing? And it's been nothing short of remarkable, I think, in some way. One of the

00:29:30.560 most surprising has been for me this feeling of satiety. You hear about satiety. I was never in my

00:29:36.440 whole life the type of person that fell full. I could always eat more. And all of a sudden,

00:29:41.480 after about two weeks on this, I just looked at my plate and said, I'm full. And I heard myself

00:29:46.980 saying this, and I just felt like, well, this is really completely different. And for me,

00:29:51.500 you know, the reason why I'm excited about these drugs is, and by the way, this is not an endorsement.

00:29:57.220 This is something to...

00:29:58.200 Yeah, yeah. This is self-experimentation, curiosity.

00:30:00.220 Self-experimentation, which is a long part of the tradition of our field. The whole idea is really,

00:30:05.660 the thinking was, one of the biggest advances in longevity medicine is this idea that a range

00:30:12.340 is meaningless. And as a practicing physician, you know this. I went to medical school and we

00:30:18.060 were told that your blood pressure has to be 130 over 90. And that was still the normal range. So

00:30:23.900 you could be 128 over 88, and you were still considered normal. The same thing, I went to see

00:30:29.860 my personal physician and told him, my blood sugar is creeping up every year that I'm doing it,

00:30:35.080 and now it's 96, fasting blood sugar. And I'm worried because soon I'm going to be...

00:30:39.720 And he said, it's below 100. It's okay.

00:30:41.700 He told me you're normal. Don't worry. And I told him, I said, what is normal? And I think this

00:30:46.480 really is where I think longevity medicine is going to make an important impact. It's really

00:30:50.760 sort of revisiting.

00:30:51.720 I can't tell you how many times I've had this argument with people about glucose.

00:30:55.540 And here's the funny thing. We have the literature. In other words, we have literature in

00:31:00.240 non-diabetics that says the lower the A1C, the lower the all-cause mortality. It's a monotonic

00:31:08.700 reduction that knows no lower limit.

00:31:11.600 I'm with you.

00:31:12.240 So we say that up to 5.6 is normal. And if you're at 5.6, you're fine. But 5.5 is better

00:31:19.360 than 5.6. And 5.4 is better than 5.5. And 5 is better than 5.4. And 4.8 is better than 5.1.

00:31:25.460 But my point is, I also find it, I don't know what the word is, maybe sad. I find it sad that

00:31:31.940 we've simplified this problem in an effort to communicate, but have lost the essence of

00:31:38.060 where is lower better? Because it's not always true in biology. When you look at TSH, for example,

00:31:43.500 when you look at thyroid hormone, much more narrow band in which we would say there's optimal. If it's

00:31:48.780 too low or too high, it's problematic. But it turns out that when it comes to average blood glucose in a

00:31:54.040 non-type 1 diabetic or someone who's taking insulin, under natural physiologic circumstances,

00:31:58.840 it's just better to be lower. And as you age, it just keeps creeping up.

00:32:03.840 Same thing for blood pressure.

00:32:04.880 Yes.

00:32:05.420 They're revisiting the number every five years in terms of making it lower. I think if your

00:32:11.120 blood pressure is at 105 over 65, you're better off than if you're 115 over 75.

00:32:16.600 That's right. Provided you're not symptomatic, lower is always better.

00:32:19.760 You know, I'm frustrated, but I'm also excited by the fact that this is now becoming

00:32:23.780 norm in a whole new field of physicians who are more aware of actually what is health. And the

00:32:29.860 same for your weight. We know that that's the thing that is really interesting in the whole

00:32:34.440 aging field is this idea that everything is a J curve. So there is a sweet spot where you want

00:32:39.560 to be. And quite often it's broad enough that you can maneuver this in a way to optimize people's

00:32:44.620 health.

00:32:44.900 What do you think is the relationship between, I mean, body weight is so crude, but maybe we can

00:32:49.760 even talk about it through adiposity, body fat and longevity once correcting for metabolic health.

00:32:56.840 So it's obvious that so much of the relationship we see between body fat and poor health is really

00:33:04.080 just a proxy for something that's harder to measure, which is metabolic health. It's very

00:33:07.580 easy to measure body fat and we estimate body fat from BMI. And so that's why we have all these

00:33:11.640 population data from BMI. But if you have the luxury of working with actual patients, I couldn't tell

00:33:17.520 you the BMI of one person I take care of, but I know everybody's body fat, everybody's visceral fat,

00:33:22.080 and everybody's oral glucose tolerance tests. We know what we know and we know what matters.

00:33:26.100 Are you convinced that adiposity per se is problematic? Or do you believe that a person can have

00:33:34.540 excess body fat, but be metabolically healthy and confer the same longevity benefit as a metabolically

00:33:43.140 healthy lean person? We know there are people who are considered overweight who are metabolically

00:33:48.980 healthy. Yes. Easily 20% in my experience. Yes. And these are facts. No one can dispute them. You can

00:33:56.360 be overweight and metabolically healthy. What I worry about is the long-term effect. Do you mean from an

00:34:02.140 orthopedic perspective with the other complications that come from excess weight? Or are you saying that

00:34:07.520 they're basically increasing their probability of eventually going off the metabolic slide?

00:34:11.760 Both. Honestly, I don't know what the data says, but my worry would be that you might be

00:34:17.920 metabolically looking healthy when you're 40. But if you sustain this for 20 years, clearly visceral fat

00:34:25.180 is highly predictive of everything. The other thing I'll say also, the BMI itself is that my BMI is at

00:34:32.320 the border of being overweight. I am overweight by BMI, I think. I'm four pounds. If I lost four pounds,

00:34:37.680 I would get down to a BMI of 25. And I have 11% body fat.

00:34:41.760 So I don't worry about it because I know all in all, I'm metabolically healthy. My numbers are good

00:34:47.300 and all this. So in some way... It's not a particularly helpful... I mean, it serves its

00:34:51.200 purpose at the population level, but it can't be used to make a decision about an individual at all.

00:34:55.720 Exactly. But it can also sometimes become a confounding variable. And when people do studies

00:35:00.620 and they use these numbers and they make predictions or they draw conclusions that are really not based on

00:35:06.300 the fact that high BMI fraction of the population is heterogeneous in terms of metabolic health.

00:35:12.840 So my colleagues at the Buck, Nathan Price and Lee Hood, I've actually published a paper.

00:35:18.160 Wait a minute. I didn't realize they were at the Buck.

00:35:19.680 Yeah. Both of them.

00:35:20.780 They were up in Seattle before, weren't they?

00:35:22.220 Yes. We recruited both of them actually in the last two years.

00:35:25.220 Oh, congratulations.

00:35:25.840 Yeah. Thank you. I think this is transformative for us.

00:35:28.620 Fantastic, guys.

00:35:29.260 And really exciting. Lee is still partially in Seattle. So he's partially at the Buck.

00:35:34.920 We've established a collaboration with Phenome Health. And Nathan was at Thorne and still a CSO

00:35:40.840 at Thorne, but faculty member at the Buck. And they're really helping us to do something really

00:35:45.240 exciting. Along these lines, for example, they had a paper describing this BMI, but biochemical BMI,

00:35:51.660 based on biological markers that essentially assess your metabolic status. So I think that

00:35:57.480 those tools are available and it's a question of educating the physicians.

00:36:01.800 And do you know what makes up that biological BMI?

00:36:04.940 No. I'll give you the paper.

00:36:07.340 Okay. We spent a little more time on metabolism than we did immune health and the immune system

00:36:12.600 overall. I'd actually like to go back and talk about it a little bit more. I think,

00:36:16.200 again, the listeners of this podcast are very familiar with the metabolic stuff. We haven't

00:36:20.140 had as many discussions on the immune system. Talked about it at length with respect to cancer.

00:36:26.200 Had Steve Rosenberg on a few years ago. That was a fantastic discussion explaining the role of the

00:36:31.220 immune system in cancer, which I think we're going to have to talk about here because I certainly feel

00:36:36.440 convinced that a big part of why cancer incidence goes up exponentially with age is the declining

00:36:43.500 immune system, not just the accumulation of mutations, although I imagine they both play a

00:36:48.260 role. But I will tell you something else, Eric, which is, you know, I wrote a book a couple of

00:36:52.420 years ago about the space. And in the book, I talk about these things called the four horsemen.

00:36:56.980 And I describe them as the four things that are basically coming for us all. If you manage to

00:37:02.360 outlive youth, this is not to diminish the role of trauma and other things that are deadly. But for

00:37:07.420 many people living in OECD nations, it's going to come down to ASCVD, cancer, dementing and

00:37:14.520 neurodegenerative diseases and metabolic diseases. And people often say, Peter, is there anything you

00:37:19.620 wish you'd written in the book that if you go back in time, you would do? And I say, yeah, there are

00:37:22.900 probably many things if I thought about it. But the first thing that jumps out is I really should

00:37:27.060 have added a fifth horseman, and that is immune health and the types of infections that ravage

00:37:34.160 people in old age that a young person would laugh at. Thank you for bringing this up. Immunology and

00:37:40.380 aging have been not really mixing very well. One problem is that immunology is an extremely complex

00:37:45.860 and advanced field, along with neuroscience, one of the most complex. So when you go to an aging

00:37:51.120 meeting, there is no one talking about immunology. You go to immunology meeting, there are very few

00:37:56.520 people talking about aging. We try to navigate, even the nomenclature is being used differently.

00:38:02.280 People in immunology talk about immunosenescence, meaning aging of the immune system. They don't

00:38:07.920 mean senescence the way we talk about it in the aging field. So that yields all kinds of crazy

00:38:12.800 communication problems. Yeah, because if you're in the aging field, then you hear immunosenescence,

00:38:17.120 you think of SASPs and things that are being secreted by T cells. It just means aging of the immune

00:38:21.960 system. Now, the reason why I think this is a tragic failing for both fields is what happened

00:38:29.700 during COVID. It became obvious that your risk of infection was not linked to your age. The virus

00:38:35.000 infected everyone across, but the outcome could be completely different with 84-fold excess mortality

00:38:42.060 if you were above 75, 84-fold. Now, when this happened, and we can go in terms of trying to

00:38:49.220 understand why did this happen, what are the reasons for this? I went and started to look

00:38:53.860 at the literature. Influenza, it's exactly the same thing. RSV, same thing. So all of these viruses

00:39:00.560 that you can contract in later years will kill you with really significant rates. Influenza, I think

00:39:06.860 30,000 people die every year from influenza. The mortality in terms of COVID was really highly

00:39:13.240 segregated into the older part of the population or in that part of the population that showed

00:39:18.220 accelerated aging, obesity, and so on. Do you think that most of the mortality,

00:39:25.140 anytime we saw a gap in mortality, whether it was young versus old, whether it was obese versus non-obese,

00:39:31.920 diabetic versus non-diabetic, anytime you looked at that, you saw a difference in mortality.

00:39:35.760 Do you believe that it was always a difference in immune function? I mean, with young versus old,

00:39:40.660 it's very obvious, but do you think that was also true in the other comorbidities?

00:39:44.100 I would say so. And it comes from two reasons. One is there are two broad immune systems,

00:39:50.300 what we call the innate and the adaptive immune system. I don't know if you want me to-

00:39:54.160 I would. I actually was going to say, I think it is worth going full bore on this. I think it is time

00:40:00.060 for people to roll up their sleeves and understand arguably the most interesting system in the human

00:40:05.820 body. I am biased. I spent two years at the NCI doing immunology, but I think this is such an

00:40:11.700 interesting field.

00:40:12.440 Our immune system is built to recognize foreign elements. That really is why it evolved. It has

00:40:20.600 two lines of defense against microbes, bacteria, viruses, fungi, all of those. We are constantly

00:40:27.240 bombarded by those. It is actually amazing because, I mean, the evidence of this is if your immune

00:40:31.940 system doesn't function, the bubble-

00:40:33.780 It's incompatible with life.

00:40:34.780 It's incompatible with life. So we are colonized with bacteria in and out,

00:40:38.420 on our skins, everywhere. So we constantly respond to them in an appropriate manner.

00:40:43.280 And we survive everything, including disruptions to the barriers.

00:40:47.700 Absolutely. Absolutely. So we have two lines of defense in the immune system. First,

00:40:52.420 the so-called innate immune system, which is your macrophages, your dendritic cells,

00:40:56.960 but also pretty much every cell has a whole series of mechanisms that are not pathogen-spoken,

00:41:03.780 specific. That is, they will recognize an intruder, be it a virus, be it a fungi, be it bacteria,

00:41:11.160 and it will activate a first line of defense. Those line of defenses are nonspecific, and therefore

00:41:17.200 they're less effective. And they give time to the so-called adaptive immune system, which

00:41:23.440 is the second part, which is made up of T cells and B cells. And both of those cells have

00:41:30.140 highly selective defense mechanisms. The B cells make antibodies, which will go recognize a bacteria

00:41:37.100 or a fungus or virus, and the T cells, which are able to actually kill the infected cell itself.

00:41:44.740 So it will recognize when the cell is colonized by a foreign pathogen and will kill it. So the time

00:41:52.020 course of these is that once you encounter a pathogen, you will activate your innate immune response.

00:41:57.980 Typically, it can be fever, it can be all kinds of symptoms, but activation of this defense.

00:42:03.620 And this gives the whole organism a couple of weeks to actually build the defense

00:42:07.680 for the specifically recognized disorganism.

00:42:11.000 Let's talk a little bit about memory within that system.

00:42:13.780 So the innate immune system does not really have a true memory. It will always react in the same way,

00:42:19.360 no matter how many times.

00:42:20.300 If your kids are ping-ponging the same respiratory virus at you from school,

00:42:25.040 your innate immune system has the same playbook. Fever, you're going to get red.

00:42:31.260 Inflammation.

00:42:31.780 Yeah, you're going to get sore.

00:42:33.020 Yes.

00:42:33.160 All of those things are going to happen regardless.

00:42:35.340 Exactly. Yeah. And that's in contrast to the adaptive immune system, because once the initial

00:42:41.140 response has been generated, either via an infection or a vaccination, this is what a vaccination is,

00:42:47.200 presents you with a given fraction or the whole virus or a part of it. Your body will mount a

00:42:54.000 response, and this will lead to the amplification of a subset of cells that are selective. So think

00:42:59.760 about your T cells or your B cells. None of them are the same. We have a process by which we generate

00:43:06.560 so-called diversity, which is billions of different forms of antibodies or T cell receptors that are

00:43:13.600 recognizing, in principle, every chemical structure or every protein from a microorganism.

00:43:20.400 Now, what happens during the initial encounter, either being a vaccination or an infection,

00:43:26.660 is those B cells or those T cells that have a receptor that is able to recognize the pathogen

00:43:33.740 will become amplified, and they will turn out a large amount of the antibody or the T cell clones.

00:43:40.500 Once the job has been done, they will contract, but they will not contract back down to the same

00:43:48.420 level. They will become what we call memory T cells or memory B cells. So that if you encounter the

00:43:54.500 same antigen in the future, the reactivation process is shortened, the maturation happens faster. So

00:44:02.160 eventually, the whole idea of the vaccination is to sort of get yourself ready with a subset of memory

00:44:07.940 T cell clones or B cell clones that once the true virus will come, you will be able to mount a response

00:44:14.860 within a few days or up to a week. And so that's how vaccination works. Now, what's interesting during

00:44:20.640 aging is, and people are not aware of this, if you're above 70, most vaccinations do not work. So people then

00:44:28.600 will ask, actually, your immune system has aged and your vaccination rate really decreases very strongly.

00:44:35.040 From what I remember, this might be different in different populations, but vaccination rate

00:44:39.940 success is close to 30% if you're above 70.

00:44:43.960 During COVID, what was the risk reduction for a person over 75 who was vaccinated versus not vaccinated?

00:44:52.540 It was almost complete reversal of the effect in terms of the protection.

00:44:57.520 Meaning it was highly, highly protective.

00:44:59.760 Yeah, it was protective.

00:45:00.820 So how do we reconcile those two facts?

00:45:02.820 That's true. To be honest, I don't know how this has been studied. I would be happy to read about

00:45:08.500 this.

00:45:09.200 Because the COVID vaccine seems to have had a remarkable risk reduction in very old people.

00:45:16.760 Didn't seem to have an impressive risk reduction in younger people because the absolute risk was so

00:45:21.420 low. It didn't seem to matter that much. But boy, did it matter in older people.

00:45:25.300 But did it matter at the population level or at the individual level? This is what I'm not sure about.

00:45:31.460 I certainly don't want to go on record saying something. I think we can find the answer and

00:45:35.140 put it in the show notes. My recollection, which could be wrong, is that the older a person got,

00:45:42.980 the greater the benefit they got from COVID vaccines with respect to mortality. So I guess the question

00:45:49.880 is, let's maybe talk about other vaccines. Is that not the case with influenza? Is that not the case

00:45:56.020 with pneumococcus or any of the other vaccines that are used primarily in older adults?

00:46:01.900 In general, and I'm not a vaccine specialist, but the thinking is that there is a dramatic decrease

00:46:08.700 in the efficiency of vaccination against influenza, against RSV, against all of those as you age.

00:46:15.520 The thinking then is, how does it work at the population level? And this is where the whole

00:46:20.000 concept of herd immunity works, is that if you limit the spread of the infection in a family,

00:46:25.400 for example, you're much less likely to infect grandpa. So that's been my understanding of how

00:46:31.560 most of these viruses, these vaccines work.

00:46:33.660 Yeah, I'm asking a different question. That's an important question. I guess I was asking,

00:46:37.760 obviously they didn't probably do a randomized control trial, so you've got all these confounders in

00:46:42.880 it. But I wonder if they just looked at all comers to the hospital, vaccinated versus non,

00:46:49.540 let's try to control for all the confounders. If the hazard ratio is 1.2, it means nothing or 0.8.

00:46:56.020 But if the hazard ratio was 0.2 or 8, well, you'd say even with the confounders, there must be some

00:47:04.300 high degree of protection that came from that. So anyway, I'm sure someone listening to this knows

00:47:09.540 the answer to that. We'll try to find the answer and put it in the show notes. But let's go back

00:47:13.240 to the why. Why is it that as a person ages, they're less likely to respond to a vaccination?

00:47:19.880 Is it because A, their immune system, the adaptive immune system is less able to recognize the foreign

00:47:26.320 pathogen and build up a high enough reserve of T cells and B cells that will respond? Or is it B,

00:47:34.340 that they can do that, but the ability for those cells to stay in a memory state and be reactivated

00:47:42.600 is somehow impaired?

00:47:44.000 I think it's both. Isn't everything aging? But there's one aspect which is really unique,

00:47:50.380 at least in terms of T cell, which are really instrumental in terms of most vaccine response,

00:47:56.580 is the fact that these T cells are generated, the diversity of the T cells is generated by the

00:48:02.720 thymus. And the thymus, a small organ behind the sternum.

00:48:07.580 How big is your thymus and my thymus right now?

00:48:10.400 I'm 68. So it's probably very, very embryonic and it's probably not much left after age 50.

00:48:16.780 And most people, you find it very small.

00:48:19.640 Whereas when you're young, it's actually, you can see it on an imaging study. And I would imagine

00:48:24.020 if you and I had a CT scan of the chest, you'd barely be able to pick it up.

00:48:27.880 Exactly. And it's replaced by fat actually in most people as you age. Although there is some

00:48:32.780 somewhat controversial evidence that there might still be some clones that can be reactivated,

00:48:38.080 even in older people. And human growth hormone, as you know, is one of the interventions that has

00:48:43.680 been shown to actually re-induce thymogenesis.

00:48:47.020 So let's talk about that a little bit. Are you referring to that Fahey paper from about

00:48:51.320 seven or eight years ago that looked at growth hormone with metformin and DHEA or something

00:48:56.380 like that?

00:48:57.520 That's one. But that Fahey paper was actually inspired by work of a colleague of mine when

00:49:03.880 I was at the Gladstone Institute who did this, actually Mike McCune and colleagues did this

00:49:10.000 in patients with HIV who are chronically infected with HIV where they lose a lot of their CD4 T cells.

00:49:16.700 And there was an interest. So there's a big lesion initially in infection. And there was

00:49:23.400 an attempt to actually try to see if you could regenerate these populations to bring them back to

00:49:28.220 our normal. Because even though we had great drugs against HIV, they could not bring those patients

00:49:34.220 back to normal. There was a remaining original insult. So they did a trial with human growth

00:49:40.360 hormone that were able to show some degree of thymogenesis and increase in naivety cells in

00:49:47.080 these patients. And I believe the Fahey trial actually tried to reproduce this. I think there's

00:49:52.760 a second Fahey trial that is ongoing or, but I haven't seen the results.

00:49:57.360 Yeah. I mean, the first one was, I don't remember the results. The cocktail was a little suspect.

00:50:03.100 Right. So the GH made sense, if that's your hypothesis. I believe, I've never spoken with

00:50:08.980 Greg, but I believe reading the trial, the metformin, which was really given at a homeopathic

00:50:15.200 useless dose. I think it was only given at 500. So apologies if it wasn't, but I think it was only

00:50:20.040 given at 500, was meant to offset the glucose metabolism disturbances of GH. Do you remember why

00:50:26.820 the DHEA was given? No. There was some reason for it that made sense on paper, but didn't make sense

00:50:34.040 physiologically. Now, the more important question is, my take on that trial was it was a single

00:50:39.640 active agent, which was growth hormone. Like I don't think DHEA does anything. I don't think 500

00:50:43.480 metformin does anything. So the question is, and it was a very small trial and I think it was open

00:50:47.800 label. I have a significant problem with the readout of that trial. So that's what I wanted to ask you

00:50:52.820 about. Remind me of the readout. The readout was one of the clocks. Ah, that's right. This was,

00:50:58.980 Steve Horvath was the other author on that paper. Exactly. And actually this whole story sort of

00:51:03.600 pushed us into a whole project that we've published down on what we call entry and clock,

00:51:08.060 because there was in the experiment, in the patients, they'd indeed observed some increase

00:51:13.600 in the fraction of naive T-cells, which tells you and me that something worked. The fraction of naive

00:51:20.740 T-cells increased with respect to the memory T-cells. The naive T-cells are the ones that are

00:51:26.020 generated in the thymus. They're naive because they have never met their cognate antigen and they sit

00:51:31.640 there waiting for something to happen. So the whole idea of treating with human growth hormone was to

00:51:36.840 induce thymogenesis and to restore the pool of these naive T-cells. So I think to some degree it

00:51:42.620 worked at low level. Then they used the clock on the whole blood. And my worry when I saw the paper,

00:51:48.940 which is a worry that actually existed, predated this, and was also a worry when people were using

00:51:54.680 telomere length, is the idea when you sample the blood, as an immunologist, I know this is a highly

00:52:00.760 dynamic organ. Think about the blood as an organ. We enumerate at this point today with the best

00:52:06.840 technology, more than 500 different populations of cells in the blood. Suppose that these cells vary

00:52:13.880 in response to any intervention and that these cells individually have a different epigenetic age,

00:52:20.900 you would have the impression that you are rejuvenating, which was the claim of that Fahey

00:52:26.600 paper that they had rejuvenated people. But in effect, what you would do is simply change.

00:52:31.260 Yeah. It's like you're on a sine wave that goes like this and you take two sample points. They could

00:52:36.880 be here. They could be here. They could be here. And by the way, as you probably know, Matt Caberlin has

00:52:41.740 famously purchased, I think, four or five of the commercially available aging clocks. He bought

00:52:48.360 them in duplicate and did all of them, sampled them all simultaneously. Two of this, two of this,

00:52:53.840 two of this, two of this, simultaneously take 10 samples. And not only do all the clocks disagree

00:52:59.340 with each other, but even within the same clock, there was disagreement, significant disagreement.

00:53:05.360 So yeah, I mean, I want to actually come back and talk about clocks in some detail, but given that

00:53:09.820 that study was done years ago with an older clock, I think the clock part of it is not even remotely

00:53:15.600 interesting. I think the more interesting question is, was there genuine thymic regeneration? If so,

00:53:22.020 how do we reconcile a very pressing and vexing question within gyroscience, which is the role of

00:53:29.200 growth hormone? So I've never taken growth hormone. I've never, I shouldn't say I've never prescribed

00:53:33.480 it. I've prescribed it in very rare circumstances for injury healing, but I've never prescribed it for

00:53:38.240 longevity benefits, but a lot of people are out there doing so. And as such, I've had lots of

00:53:44.040 patients who come to my practice who have been taking or are on growth hormone. And I will say this

00:53:49.960 to a person, every single one of them has said, I feel so much better when I take growth hormone than

00:53:56.080 when I do not. I mean, across the board, 100%. And I can't actually point to evidence that tells them

00:54:04.420 it's bad to take. I can just say it doesn't make sense to take if our goal is to reduce the risk

00:54:10.660 of cancer. And if our goal is to slow the aging process. So what is your take on that? Just your

00:54:17.680 intuition, or is there any data you're aware of that would lead one to think that, well, maybe we

00:54:22.560 could pulse a little bit of growth hormone here and there. If we get some thymic regeneration, we don't

00:54:26.600 have to be on it all the time. I mean, how would you think about that?

00:54:28.560 I do worry about it. I'm not a specialist on growth hormone itself. It induces diabetes.

00:54:35.500 It induces glucose intolerance. So from that angle, I do worry about what it would do chronically,

00:54:43.000 especially in someone young. It's a bit like increasing your protein intake. There's clear

00:54:48.380 evidence that increasing your protein intake, especially as you age, becomes beneficial. And

00:54:53.260 the people who have higher protein intake actually do better in terms of muscle mass and so on.

00:54:58.560 So in someone who is 65 to 70, who is starting to feel the effect of manifest some form of

00:55:07.080 sarcopenia, there might be a benefit for that person to actually increase muscular mass and all the

00:55:13.740 benefits with this, especially if it's not done continuously.

00:55:16.240 But I mean, I would argue there's no doubt that there's benefits, but you're going to get far more

00:55:20.380 efficacy from testosterone or anabolic steroids when it comes to mitigating sarcopenia. Growth hormone

00:55:27.600 actually is not remarkable at inducing muscle mass. It's nowhere near as effective as testosterone.

00:55:34.120 It's more effective at eliciting fat loss. But I wonder if there's something that goes beyond that.

00:55:38.880 Because I think when people tell me they feel better on it, I think they're talking about less aches and

00:55:43.760 pains. Joints just feel better. I don't think anybody's saying they feel better because their thymus is

00:55:49.540 more plump. But I wonder, that to me would be a reason to potentially consider a schedule,

00:55:56.440 an intermittent schedule of something. If it's, again, going back to my macro thesis here, which is

00:56:01.480 I've been harping on these four horsemen, four horsemen. Well, if we introduce a fifth horseman,

00:56:06.900 what is the strategy? Because I can give you chapter and verse the strategy for how you will mitigate

00:56:13.120 heart disease, cancer, all of these other conditions. What is our strategy for mitigating

00:56:18.440 immune decline?

00:56:19.960 I would say the same as a strategy that would mitigate decline in every other organ. There's

00:56:25.580 clear evidence that the effect of exercise on immunology is the same as in every single...

00:56:29.940 So I'm not familiar with it. So tell me a little bit about that. I don't know

00:56:32.820 specifically how exercise impacts the immune system.

00:56:35.540 I cannot speak to specific papers. Clearly, there's evidence that people who exercise actually

00:56:41.880 respond to infection better, respond to vaccination better. So that's all been documented.

00:56:46.960 I cannot speak to specific studies.

00:56:49.000 Do you have a sense of mechanistically why that's the case?

00:56:51.580 It is so complex, I would say. I would not be able to tell you. But that being said,

00:56:57.740 I think the whole line of investigation to induce thymic rejuvenation, I think is an important

00:57:04.440 one area, especially if we're thinking about increasing lifespan further for what we are

00:57:09.720 doing now. That's in the future, it will become one of these rate limiting steps. It's a bit

00:57:14.100 the same situation as the ovary, where the ovary and the thymus, we call them the canary in the

00:57:20.620 coal mine. I mean, there really are specific organs that show accelerate aging way earlier than

00:57:26.040 other tissues. Now, the question is, why is the thymic involuting so early? I think it's probably

00:57:31.860 because evolutionary, we were never meant to live this old. And so that really is one of the

00:57:37.240 thinking that goes on. That's going to be, in the long term, one of the problems that we have to face.

00:57:42.820 And this is something we're actively studying. And the lab is trying to, we just completed a study

00:57:47.160 where we are looking for novel biomarkers that are predictive of whether you will respond to a

00:57:53.320 vaccination or not. And there's something done in collaboration with Mark Davis at Stanford,

00:57:57.560 using the 1000 Immunome Project, which is one of the largest studies studying aging and immune system

00:58:03.860 only in humans. So we've been able to, studying people to identify some metabolites that are

00:58:09.700 associated with poor response to vaccine. And so those are not only markers, but they could also become

00:58:15.540 tools that we include as adjuvant or as a pretreatment theory. I'm sure you're familiar with the work of

00:58:21.940 Joan Manick. Of course. Yeah. I was going to ask you about Manick and Clickstein in a moment. Before

00:58:26.420 we do, I want to go back to this point here, which is biomarkers are so important. When I think about

00:58:33.120 cardiovascular disease, and even though it's the leading cause of death, why I tell my patients,

00:58:38.700 it's the one you need to be least afraid of if you're willing to be proactive in management.

00:58:43.780 And it comes down to the fact that we just have such a clear understanding of how the disease works

00:58:48.280 and we have exceptional biomarkers. So we can measure the things that are causing the disease.

00:58:54.780 We can measure inflammation. We can measure ApoB. We can measure VLDL cholesterol, LP little a.

00:59:01.960 We can measure blood pressure. We can measure metabolic health. And we know how to address

00:59:06.740 those things. And we know that when we address those things, we can measure whether what we're

00:59:10.760 doing is working. Okay. So problem solved, basically. When it comes to the immune system,

00:59:16.460 we're going to talk about Manick and Clickstein in a moment, but as we saw from their paper 10 years

00:59:22.160 ago, they gave a rapamycin analog to people, people who were in their sixties, vaccinated them

00:59:28.160 and demonstrated that, oh boy, you got a much better immune response. Okay. They were able to

00:59:33.900 demonstrate that using laboratory techniques. I'm sure they used flow cytometry or something like that

00:59:40.140 to measure it. How close are we to being able to do that sort of thing commercially?

00:59:45.460 By commercially, I mean over the counter.

00:59:48.800 Not close. I think in that study, they actually measured antibody titers.

00:59:53.260 So even more complicated than flow cytometry.

00:59:55.660 Yes.

00:59:56.020 Okay.

00:59:56.440 In that case, they definitely showed an enhancing effect with a known gyroprotector.

01:00:02.140 A suspected gyroprotector, at least in humans.

01:00:04.620 Exactly. A rapalog. And they showed not only increased titers, but also protection,

01:00:10.100 increased protection. Eventually the clinical trial failed for a whole series of other reasons,

01:00:14.660 which were in part due to the way that the FDA imposed the trial to be generated. I think it

01:00:21.000 just complicated the whole picture. Yeah. By the way, for folks listening to us who are confused by

01:00:25.680 that, Matt Caberlin and I had a specific discussion because it wasn't the 2014 trial. It was a later

01:00:33.180 trial. It wasn't the RAD001 trial. It was the other trial that failed. And I actually don't remember

01:00:39.860 the reason, but Matt explained it. It was very clear that it was a tragedy of bureaucracy.

01:00:47.200 It is.

01:00:47.940 And it shouldn't be viewed as a black eye on that molecule.

01:00:51.080 Yeah. Matt is more of a specialist in the whole rapamycin. So I will defer to what he said.

01:00:55.880 We'll link in the show notes to where Matt and I had that discussion.

01:00:58.200 Yeah. What I've heard from anyone that I've talked to, including Joan, is that

01:01:01.540 this was in some way bungled, which is sad because sometimes things like this can put a field back

01:01:07.980 for a number of years and discourage investors. We have a startup that originated at the Buck

01:01:13.940 called Eovian, which has raised $50 million. Again, coming up with rapalogs, novel rapalogs that

01:01:19.600 are going to be, I think, revisiting that whole picture. So we're quite excited. The field is far

01:01:24.440 from being dead. Will we ever be able to measure this in people the way we measure hemoglobin A1c or

01:01:30.220 things like that? Or is it going to be one of those things where it's a bit of a leap of faith

01:01:33.240 and you're going to have to look at the clinical trial where the outcome was there. And then you're

01:01:37.560 just going to have to say, well, even though there was probably massive heterogeneity amongst the

01:01:43.120 participants in the trial, we're going to dose this thing individually. I mean, it's a little bit like

01:01:47.560 you brought up vitamin D earlier. I mean, one of the problems with the vitamin D trials

01:01:51.300 is that they're all garbage because they all just give people a given dose. They don't measure the

01:01:57.180 response. They don't measure compliance. A vitamin D trial should be done based on target level,

01:02:03.400 not target dose. And we run the risk here of the same thing in a much more complicated system.

01:02:10.620 Agree. That being said, measuring pathogen-specific titers is done routinely in the clinic. I don't know

01:02:18.820 if you did this, but I just had my measles titer measured. I was born in 1957, which is right the age

01:02:25.980 before 1957. Everyone was exposed to measles. So you're typically safe, but you should measure

01:02:34.400 your titer to determine whether you need to be revaccinated. I found out that, yeah, you can do

01:02:39.400 this very easily. You get a titer. But would the titers by themselves tell you, so what would you

01:02:44.340 predict? If I measured every titer right now? Yes. If I measured polio, shingles, did a pan titer on you

01:02:52.060 and then started you on rapamycin for eight weeks and then stopped it and then remeasured your titers

01:02:59.420 without vaccinating you, what would you expect to see? I would not expect them to change.

01:03:03.680 Yeah, exactly. So how do we know we're improving your immune system if indeed we have?

01:03:08.400 Oh, I see what you're saying. So in terms of if we were to start you on rapamycin,

01:03:13.060 what would happen? How could we measure the improvement in immune function?

01:03:16.980 By the way, the manic trial showed that first they did a one-month treatment with the rapalogue

01:03:23.520 before vaccination. They demonstrated not an effect on existing vaccinations, but only demonstrated on

01:03:30.760 de novo vaccination. That's right. Yeah.

01:03:32.360 And I think what would be the effect on existing titers against all of the other pathogen? I don't

01:03:37.580 know. I don't think this has ever been done.

01:03:39.760 Yeah. Interesting. You want to just say a little bit more about that trial? So that was at least

01:03:44.080 for me, a pivotal moment in my journey in this space and in understanding this world. So that

01:03:49.560 was December of 2014, that paper came out. And if I recall, roughly 300 plus participants divided

01:03:55.540 into four groups. So placebo group, a group that got one milligram every day, a group that got five

01:04:01.620 milligrams once a week, and a group that got 20 milligrams once a week. Two people were pulsed,

01:04:06.580 one much higher than the other, and then one given daily, and then a placebo.

01:04:09.760 I believe they were all over 65. I think the study was done in Australia. And as you said,

01:04:14.180 they were put on their, whatever treatment was for four weeks, immunized. I think it was another

01:04:21.040 four weeks and then a six week washout. And then the titers were checked. The best response I think

01:04:27.820 was in the five milligram pulse and the 20 milligram pulse. The one milligram daily still had a better

01:04:33.680 response than the placebo, but not as strong as the two pulse doses. But the five and the 20 weekly

01:04:38.940 were nearly identical, but the 20 had much more side effects. I don't remember perfectly. So

01:04:44.500 correct me if I'm wrong. You remember pretty well.

01:04:46.300 The takeaway was basically five milligram pulse was the sweet spot. You get all the benefit without

01:04:51.080 the side effects. That's how I remember that trial as well. Although I'm always impressed by

01:04:55.280 how you remember all of the details of these clinical trials. What was remarkable about that data

01:05:01.020 was the fact that this is from a drug that is supposed to be an immunosuppressant and it's been

01:05:08.560 a long road for the longevity field to try to get our colleagues who are actually using a rapamycin as

01:05:15.080 an immunosuppressant to have them believe that this actually has an effect on immunity and not only

01:05:20.720 not immunosuppressive, but actually a promoting immunity. How do you reconcile that? Not their

01:05:25.980 disbelief, which is warranted, but how do you reconcile that one molecule? So if you think

01:05:31.340 about the doses we used to give rapamycin, it's not actually used that much, by the way,

01:05:35.820 today in the transplant clinic. So FK-506, I'm blanking on what FK-506's real name is,

01:05:42.260 but anyway, whatever. It's largely displaced, sirolimus, which is rapa. But that said, when we

01:05:47.140 used to give it out, we were giving two to four milligrams a day. Now let's just assume that it was

01:05:54.280 indeed contributing to prevention of organ rejection. Do you think it was doing so because

01:05:59.340 that's a high enough dose of constitutively giving a drug that it suppresses the immune system? Or do

01:06:04.480 you think it was only suppressing the immune system because it was being given in combination with two

01:06:09.200 other drugs and it was only as part of that sea of other drugs that it has the immunosuppressive effects?

01:06:16.760 I think there's clear evidence it is immunosuppressive by itself. I can tell you that for the period when I

01:06:22.820 was on rapamycin, I would take either four or six milligrams a week, every morning, once a week.

01:06:29.920 The biggest difference between the immunosuppressive and the geoprotective effect is really the amount,

01:06:35.120 the frequency and the amount. The reason why people adopted this once weekly dose is to

01:06:40.740 first not have any immunosuppression and second, to mitigate the secondary effect,

01:06:46.680 which are thought to be caused by inhibition of mTORC2, which is the second complex.

01:06:51.320 Yeah, the glucose effect. And that seems to be working largely. What was, in my case,

01:06:56.740 remarkable is that every time I took my dose, not two, I only did two for a couple of weeks,

01:07:02.820 but either four or six, the next morning I would have a pimple on my nose. So I was immunosuppressed,

01:07:08.640 clearly, every single time.

01:07:10.220 For a day.

01:07:10.600 Yeah, for a day, for a day or two. I sort of made peace with it in the fact that if I had a really

01:07:16.340 heavy workout, I would have exactly the same thing. Exercise is immunosuppressive. If you go all out,

01:07:21.800 you can get a cold. You're temporarily fragilized after a really heavy exercise. So I think

01:07:26.960 the difference really between these two worlds, the immunosuppression, which clearly has been

01:07:32.340 documented by clinical trials, it is immunosuppressive by itself, versus the beneficial effect on the

01:07:37.940 immune system. To me, it's a question of dosage and frequency.

01:07:40.700 And yet, I cannot reconcile the unambiguous success of the interventions testing program,

01:07:48.760 where those mice were eating rapamycin in every single bite of food they took. In fact,

01:07:56.580 they were consuming it more continuously than even the most immune-compromised patient.

01:08:02.140 And without exception, every single ITP study of rapamycin, whether they started in old mice

01:08:10.140 or young mice, rapa alone, rapa with another drug, it just doesn't matter. It always worked.

01:08:16.660 How do we reconcile that?

01:08:19.040 Well, I don't have the answer, but I can sort of talk about it. There's something that worries me about

01:08:25.100 our reliance on the mouse as a model system for aging, for studying aging, and how relevant it is to

01:08:32.000 us as species.

01:08:34.000 Even mice, because we would all admit that the ITP mice are the best, they're the Ferrari of mice.

01:08:38.960 Exactly. The ITP is the best way to address this question, because they're using mice that are

01:08:45.400 crossed. So it's not-

01:08:47.160 Not inbred, yep.

01:08:47.960 Not inbred. When you're using Black 6, you're essentially doing the experiment on N of 1.

01:08:52.840 And the whole world, I mean, 80% of the work that's being done in mice is done on Black 6.

01:08:58.460 We're all studying the same person. So obviously, when you go and try to transfer this to a human

01:09:03.760 population with all of its variation. So the ITP did the right thing. That being said, and this is

01:09:08.920 not an attack on ITP. I think ITP is a great program and should be funded, and should continue

01:09:13.800 to study this. I just worry about the over-reliance on ITP alone. And I think we should have another

01:09:21.800 system that studies primate interventions with drugs. There are a number of primates,

01:09:26.860 non-human primates that are actually much closer to us. The reason I worry about mouse is something

01:09:32.120 that actually Steve Ostad, you've had on this podcast as well. Steve is a good friend, and he

01:09:37.160 came up with something called the longevity quotient, which I think is something that people do not pay

01:09:42.640 attention enough. So the longevity quotient is this idea that if you look across the animal kingdom,

01:09:48.600 the larger you are, the longer you live. Okay? So you can take 1,000 species and you can,

01:09:55.140 on the x-axis, you have their size, on the y-axis, their life expectancy.

01:09:59.560 It largely rises to the right.

01:10:01.040 And you can see a monotonous curve. Now, there are exceptions to this. One of them is

01:10:07.460 naked mole rats, for example.

01:10:10.160 They punch above their weight. Dogs tend to punch below their weight.

01:10:12.820 Exactly. Although in dogs, again, this is between species. Then when you look

01:10:18.480 intra-species, it gets even more complicated, which is the larger dog lives shorter than the

01:10:24.220 smaller dogs, the Great Dane versus the Chihuahua. And that is down, actually, that's driven mostly

01:10:29.160 by growth hormone, which is, again, another reason why we should look at taking growth hormone as an

01:10:35.880 anti-aging drug with some degree of circumspection. Because in dogs, the more growth hormone you have,

01:10:41.900 the larger you are, and the shorter you live. We know also in humans, the larger you are, the taller

01:10:46.920 you are, the shorter you live. So are these effective growth hormone? Yes. Are they only

01:10:52.180 important while during the growth phase? That's a possibility, but it's something that really gives

01:10:57.140 me pause to go back to our discussion about growth hormone. So going back to the longevity quotient,

01:11:03.160 mice are also an exception. They punch below their weight. So they live shorter than they should based

01:11:09.180 on their size. And humans is the biggest exception. We live about five to six times longer than we

01:11:15.780 should based on our size, which tells me that we aren't a naked mole rat of primates. We do

01:11:22.520 incredibly well, which means that we already have optimized a lot of these pathways that are

01:11:28.080 promoting aging. I suspect the mice is exactly the opposite. I don't know that someone has really

01:11:33.740 compared sort of intrinsic TOR activity in mice. Are they, for example, living? Mice are, especially

01:11:39.720 laboratory mice, are engineered to reproduce and grow as quickly as possible. They have large litter

01:11:45.460 size. They do everything very quickly. Now we know all of these activities are requiring a lot of

01:11:52.040 anabolic strength, which is driven by TOR. So the question is, are the mice examples of animals that are

01:11:59.740 maximizing TOR activity to do everything they do very quickly? And we are maybe at the other end

01:12:05.500 of the spectrum where we have low basal TOR activity. So that's where I worry when people just

01:12:11.100 transfer everything we know from TOR from mice into humans and saying it's going to show and work in

01:12:16.720 humans. I don't know if you heard- Such an interesting point.

01:12:19.600 Yeah. And this is frankly why I stopped taking rapamycin. I thought I did not really see anything

01:12:24.860 in terms of anything. Metabolically, physically, muscle strength. I could not. In contrast to GLP-1

01:12:31.900 agonist, where I saw all of my numbers get better and functionally strength, all of this, I saw

01:12:36.780 everything getting better on GLP-1 agonist. With rapamycin, I never could tell whether I was taking

01:12:41.900 it or not. Yeah. Although it's not just that. I would say where rapamycin acts, I don't know that

01:12:49.480 we would see anything getting significantly better. Because if we think that the main places that

01:12:55.440 rapamycin is going to act would be on autophagy, well, there's no way you're going to measure

01:13:00.960 autophagy. You're not going to feel autophagy. You're not going to see it or measure it. Does it

01:13:05.320 tamp down on certain subsets of senescent cells? That's certainly plausible. Again, I don't know how

01:13:11.440 we're going to see or measure or necessarily even feel that. Does it reduce some of the tonic,

01:13:16.800 low-grade, unhelpful inflammation? Probably. But again, if a person doesn't have much to begin

01:13:24.320 with, it's going to be tough to measure. Conversely, GLP-1 agonists act directly on a

01:13:30.840 thing that is so easy to measure, which is glucose metabolism and body weight for those who are losing

01:13:36.460 weight as well. So it might not be a fair comparison. I guess the other thing I would add

01:13:39.780 to this interesting observation is that, of course, the mice and the ITP are still in a relatively

01:13:44.640 sterile environment. And it might be that even if they incur some immunosuppression, it's not going

01:13:51.160 to be as maladaptive as it would be if they were wild animals as we are.

01:13:55.640 They live in a sterile environment. They live grouped in a cage with no ability to move,

01:14:03.540 to exercise. They eat a diet which makes the American diet look like the most healthy thing ever.

01:14:11.760 I mean, have you ever seen the pellets that these mice are eating?

01:14:15.440 Do the ITP mice eat the crappy pellets as well?

01:14:18.180 I suspect they're eating...

01:14:19.600 Okay. I don't actually know what their diet is.

01:14:21.120 Yeah. I don't know what their diet is. I can guarantee you they're not eating salad

01:14:24.360 and fruits and vegetables. So in some way, they are an incredibly artificially bad sort of

01:14:32.300 environment. These mice are actually doing everything that is conducive to a poor health.

01:14:37.220 And so the fact that we see something that works in that system might have some value for

01:14:42.420 a fraction of the population that has a very poor lifestyle. I do worry about transferring this to

01:14:48.520 someone like you and I who are exercising or trying to eat well or trying to sleep and all of this.

01:14:54.500 I take these observations with some degree of caution. And frankly, when people ask me,

01:14:59.440 should I go on rapamycin? I do worry. Now, this is a different story if someone,

01:15:04.100 a patient comes and sees you at 40 years old and tells you, I think, I want to go on rapamycin.

01:15:09.260 I would strongly argue that you should not do this because even in the studies that have been

01:15:13.640 conducted, they still saw an effect in mice that were the equivalent of 65 to 70 years old.

01:15:18.700 Now, if you're 75 years old and you have the feeling you're chronically inflamed and you have

01:15:22.920 the feeling that things are not doing well, there are a number of anecdotal cases where people have

01:15:27.680 described really feeling a lot better and a lot stronger very quickly.

01:15:31.720 On rapamycin.

01:15:32.520 On rapamycin. But I would predict it would be the same thing with a growth hormone or

01:15:36.380 some of these interventions. So I've really put those in different categories. My argument to

01:15:40.800 people is today we have one intervention that is very profoundly anti-aging and it is physical

01:15:47.540 activity exercise in all of its forms. Once you have optimized this, I think let's talk about doing

01:15:53.580 something else on top of that.

01:15:54.900 Yeah. Earlier, you brought up the Sirtuin story and NAD. I'd love to spend a little bit of time

01:16:00.180 there. I was at a talk recently and as always, I get asked questions about stuff like that. And I

01:16:06.700 got asked the question about NAD and I said, look, this is one of those things where if I tell you the

01:16:12.240 following facts, I'm going to tell you three facts, NAD is completely ubiquitous throughout the body

01:16:19.980 and it is absolutely essential for the most important chemical reactions that happen in the

01:16:26.720 body. You cannot undergo redox reactions, metabolic reactions without NAD. That is point one.

01:16:32.860 Point two is a class of proteins called Sirtuins rely heavily on NAD as the substrate in the process

01:16:43.160 of repairing DNA. That is fact two. Fact three is as you age, NAD levels decline precipitously.

01:16:52.260 Okay. Those are three facts and I don't believe, is there any dispute to any of those facts?

01:16:56.480 No controversy.

01:16:57.080 Okay. Armed with those three facts, how could it be that supplementing NAD does not lead to

01:17:06.160 a longer, better life or some health benefit? That's a logical conclusion, right?

01:17:11.180 Well, not completely because it depends also what is the reason why NAD levels decrease and it depends

01:17:18.820 also what supplements, how you remedy and decrease. And this is something I'd love to talk about CD38.

01:17:24.600 So it could be that NAD levels go down because their consumption goes up. As we age, there's

01:17:30.380 more DNA damage, there's more consumption, the Sirtuins need more of it and it goes up. And then

01:17:34.000 of course the question would become, is the current level of NAD that we have rate limiting to that

01:17:38.680 reaction? If not, then all the extra NAD in the world should have no benefit because you're just

01:17:45.360 adding more substrate to a reaction where it's not needed. Conversely, if NAD levels are going down

01:17:51.520 because there's a production issue and if you provided more of it, you could actually do more

01:17:57.160 good, well then it could be the exact opposite story. So let me pause there for a moment and have

01:18:02.240 you fill in the edges of everything I just said so that we can go deeper into this discussion. So

01:18:06.460 maybe explain a little bit what NAD is, explain what it means in Redox. And obviously let's talk

01:18:11.320 about Sirtuins and the role that NAD plays there.

01:18:13.300 Lots to unpack there. It could be a two-hour podcast. It's one area that we've worked on for

01:18:19.300 the last 25 years. We were responsible for cloning the human Sirtuins actually after Lenny Guarante

01:18:24.980 published his paper on Sirtu and yeast. We were the graduate student-

01:18:29.740 Matt was the first to publish this, wasn't he? Cable and-

01:18:31.940 Yeah, actually Matt and Brian, I mean David, I mean that whole gang was the original gang along

01:18:37.060 with Lenny Guarante were paved the way for a lot of what we know. One thing that I would just start

01:18:42.700 by saying is that it pains me in some way in a field that is so rich and has generated so much

01:18:49.060 data that there's a whole cloud lying on top of Sirtuins and NAD. There's nothing there. I just tell

01:18:56.280 people it is an incredibly studied system. We are still juggling the complexity and I would argue that

01:19:04.180 any field where the same degree of investigation will be conducted will have the same controversy.

01:19:09.900 This is the nature of science. The beauty of science is that it's incredibly messy on the way

01:19:14.600 up, but eventually things are getting clarified. And I think in the terms of the Sirtuins,

01:19:19.820 we're still right in the middle of it. So there's some complete garbage.

01:19:23.820 Yeah. And by the way, I'm not completely dismissive. What I will say has made this field complicated

01:19:29.280 is that the leading proponents of it have all opted for a commercial pathway.

01:19:34.560 And therefore they have opted not to study this in a rigorous way, but to study it in

01:19:40.460 a commercial way. And I mean, I understand why you would do that. Like that's the nature

01:19:44.660 of it. And this is not a molecule that you're not going to generate intellectual property in

01:19:48.880 the same way that you would around a novel drug. And so it poses a limitation to how these

01:19:53.920 things can be studied. But unfortunately that coupled with the resveratrol fiasco, unless you

01:20:01.420 think otherwise, Eric, we don't need to talk about resveratrol. I remain completely convinced

01:20:05.240 that resveratrol had zero benefit whatsoever. I think it is an absolutely useless molecule.

01:20:10.680 So I think that resveratrol debacle, the overhype complete debacle of that, coupled with the fact

01:20:17.160 that all of the participants in the NAD landscape are doing it through their own commercial enterprise

01:20:22.460 with their own proprietary blend, has resulted in this inability to drive forward in this field.

01:20:28.640 I agree. You've identified the problems, the hype and the commercialization. I mean, commercialization

01:20:34.140 can be helpful if the companies are actually willing to invest in clinical trials and so on. I always

01:20:40.300 use the example of timeline, urolithin A. I mean, we've worked with them. They do clinical trials,

01:20:45.560 rigorous. They publish them in the best journals. And at the end, you know what you're measuring.

01:20:50.320 That being said for the sotuin, so let's try to maybe step back. And given the controversy,

01:20:55.540 I would say I would encourage your listener not to just discard it all. We're still in the middle

01:21:00.060 of it. And I think there's something interesting will emerge out of it. So NAD is a critical

01:21:05.400 intermediary metabolite. It has two big roles. First is it plays a key role in redox reactions. Again,

01:21:12.700 we've talked about these reactions, reduction oxidation.

01:21:15.260 Anytime electrons need to move around.

01:21:16.920 Exactly. So it exists in two forms, NAD and NADH. And it's critical to intermediary metabolism.

01:21:24.220 There are more than 600 of these enzymes that use NAD in the whole metabolism. So it stands to

01:21:30.780 reason that if you're losing NAD levels, you go below a certain critical level, these enzymes are

01:21:36.020 going to suffer. Your whole metabolism is going to go down. And we know, by the way, that decreasing

01:21:41.440 metabolic efficiency at all levels is one of the hallmarks of aging. So in addition to these

01:21:46.620 enzymes that utilize the NAD and NADH couple, there's a whole series of other enzymes that

01:21:52.280 actually are digesting, cleaving NAD. And these would be the PARPs, polyADP, ribos, polymerase.

01:21:58.900 So these are enzymes mostly involved in DNA repair. So it plays a critical role.

01:22:03.460 Sirtuins, seven sirtuins, all doing different things within the cell. And we can go back and dig

01:22:09.200 into this a little bit in terms of what are the sirtuins doing. There's also another two enzymes

01:22:14.820 called CD38 and CD157. These are also NAD hydrolases, and we are studying them a lot.

01:22:22.940 So that's, I guess, the background of what these enzymes are doing. One thing that your listeners

01:22:29.040 should know about NAD levels and why the decrease in NAD levels are relevant to aging with respect to

01:22:36.560 the sirtuins. Because sirtuins have a relatively narrow range of KD for NAD. So if the NAD levels

01:22:45.220 change, as we know they do during aging, it will lead to a change in the activity of the sirtuins.

01:22:52.740 And I think this is something that was proposed by Lenny Garante back in the days and showed,

01:22:57.680 for example, even during fasting, your NAD levels will increase and this will activate sirtuins.

01:23:03.800 So I think this is something that's really unique to the sirtuins. And we know this in a really acute

01:23:10.060 way because there are sirtuins that are present in the cytoplasm versus in the mitochondria versus

01:23:15.080 in the nucleus. And the NAD levels in each of these organs are very different. For example,

01:23:19.980 much higher in mitochondria. It turns out that SIRT3 has a KD for NAD, which is much higher than SIRT1.

01:23:27.260 And so variations, that really is the indication that they are sensors of NAD levels, which goes back

01:23:35.320 to the initial model that you mentioned, NAD levels change during aging. Therefore, we can expect

01:23:40.040 the activity of the sirtuins to change. Now, what else have I not addressed in your initial batch of

01:23:47.720 questions? I think we're now ready to then move on to, if we believe with some conviction that

01:23:57.520 restoring NAD levels in an aging individual is beneficial, we now have to deal with the same

01:24:04.860 problem you deal with any small molecule or large molecule for that matter. How do you get it in the

01:24:10.160 body? So what are the ways in which you could get NAD into the body directly or indirectly?

01:24:15.600 So that brings me to maybe another element of the biochemistry. So one thing that has emerged

01:24:20.860 is this idea that the question as to why do NAD level decrease? And there's been lots of theories.

01:24:28.620 Activation of the PARPs, that seems to be happening in C. elegans. In mammals, this is the work of

01:24:35.220 Eduardo Cini, was the first one to show that CD38 appears to be the major driver of the decrease

01:24:42.320 of NAD during aging. And the way that he's demonstrated this, and we've actually repeated

01:24:47.340 some of his results and published on this as well, if you study a mouse that's knocked out for CD38,

01:24:54.280 you find that NAD levels actually do not decrease during aging. And that's pretty much across all

01:24:59.500 organs. And I think what this does is really brings the whole question in terms of what should

01:25:04.920 we be targeting?

01:25:05.660 Did we talk about what CD38 is doing specifically?

01:25:08.800 Yeah. So CD38 has a membrane-anchored protein. Some of it is facing outward on the outside of

01:25:16.000 the cell. Some of it is facing inward. For example, in T-cells, it's mostly facing outward. In macrophage,

01:25:22.140 it's mostly facing inward. And it is in a dehydrolase. Now, what is it doing in the immune system? Why do we

01:25:29.440 have it? Not entirely clear. One idea is that because it is present in T-cells...

01:25:34.880 Is it on non-immune cells?

01:25:37.080 Endothelial cells as well. One idea, at least for the immune system, is that it might come up and

01:25:44.120 eat up all the NAD that's local in the extracellular fluid, although there's not much of it, and limit

01:25:50.220 the abilities as part of the innate immune response and limit the ability of bacteria and other organisms

01:25:55.920 to actually access these micronutrients for their own growth. That's one thinking. But I think it's

01:26:01.860 a lot more complicated than this. And we're really in the middle of it. I have a good part of my lab

01:26:06.180 actually studying the role of CD38 in the immune system and in endothelial cells and in the brain

01:26:11.700 as well.

01:26:12.740 Now, you mentioned a moment ago that the CD38 knockouts do not see a decline in NAD with aging.

01:26:18.380 Zero. And they live longer.

01:26:19.660 I was just about to say, what is the phenotype of a CD38 knockout? What deficiency do they have?

01:26:23.760 Nothing that we can tell. And they live longer.

01:26:26.860 How much longer?

01:26:28.220 15%.

01:26:28.660 That's comparable to rapamycin.

01:26:30.700 Yeah. It's pretty significant. This has been published by Eduardo Cheney.

01:26:34.760 Do you think that that is true, true, and unrelated to the increased pool of NAD?

01:26:40.300 Now, CD38, that's a key question. And that's one that's not been answered. And I would say,

01:26:46.760 if I had to go on a limb, I would say it's not linked to the NAD decrease.

01:26:50.840 Just to make sure everybody understands what you're saying, your belief is that the CD38

01:26:55.220 mouse, the knockout, does not live longer because he has more NAD. That's just another

01:27:00.580 issue we're seeing and that there's something else about that mouse.

01:27:03.800 Yes. Or it might be partially the NAD and partially the other mechanism I'm about to discuss.

01:27:09.000 One thing that's remarkable is that as we age, us and mice, we see an increase in CD38 level

01:27:16.040 across the organism, especially in the immune system. We've published a paper showing that

01:27:20.600 the SASP from senescent cells is a very powerful inducer of CD38 expression in macrophages. So

01:27:27.800 that's one mechanism by which we're linking senescence and the SASP to increase CD38,

01:27:34.060 leading to a depletion of NAD and other effects.

01:27:36.780 And yet we have no idea what it's doing other than hydrolyzing NAD.

01:27:40.840 It has a cognate receptor on other cells. They don't seem to be immune deficient. It's really

01:27:46.220 one of these players that people, there are hundreds of papers.

01:27:49.340 Do you think it plays a role in inflammation, a negative role in inflammation?

01:27:52.920 One idea about it is that it plays a suppressive role in the immune response because we see it being

01:27:58.940 induced latish in the immune response and the idea it comes down to tampen down.

01:28:04.120 So it's actually the exact opposite. It's so pro-anti-inflammatory that it can be

01:28:09.240 harmful in that way, as opposed to contributing to sterile inflammation,

01:28:13.720 which is the more typical problem we see in aging.

01:28:16.340 Yeah. We did not discuss this. The other side of the immune system is that

01:28:20.320 it has to be incredibly balanced between reacting appropriately towards exogenous pathogen,

01:28:27.720 but not reacting against the self. As you know, as a physician, there are so many conditions

01:28:33.960 that are a manifestation of an excess of immune response against the individual. All of the

01:28:39.780 autoimmune diseases, which by the way, increase during aging. So-

01:28:43.420 Except for type 1 diabetes.

01:28:44.740 Yes. That's the one young.

01:28:46.680 I know that you used to study that. Why do you think that is?

01:28:49.080 It's really an interesting question. Although there's something called LADA that I'm sure you've

01:28:54.760 heard about that is emerging that we might have been diagnosing some type 2 that were actually late

01:29:00.400 type 1. The thing that is really unique about type 1 is the fact that I remember a number of papers that

01:29:08.700 highlight the fact that there might be something happening during development that exposes the

01:29:14.840 immune system to the developing beta cells, and that might trigger more autoimmunity at that time.

01:29:21.540 It could also be linked to the fact that there's been for many years a discussion of the role of

01:29:25.980 viruses, infection, and molecular mimicry between some of these viruses and beta cells. So it could

01:29:32.000 be that a subset of infections that happen during childhood actually puts you at risk of activating

01:29:38.040 your immune system inappropriately. That's the whole idea. But there's clearly an increase with

01:29:43.440 autoimmunity throughout life.

01:29:45.600 By the way, CD157, do we see the same effects? Do we have a CD157 knockout?

01:29:50.080 No. Much less studied. There is some interesting effect also, but CD38 is garnered.

01:29:55.680 Most of the attention. If you think about it, I'll go back about CD38 in terms of what it's doing.

01:30:02.420 It's taking an AD and cleaving it into ADP ribose, which is sugar, and nucleotide, and nicotinamide.

01:30:10.920 Nicotinamide is a precursor to an AD. And so this nicotinamide, which is generated by CD38,

01:30:16.240 but by the sirtuins, by the PARPs, normally gets recycled in a two-step reaction all the way back to an AD.

01:30:23.600 Now, what's really interesting is if you block this, it's called the salvage pathway for nicotinamide.

01:30:30.660 If you block it, within a few hours, your NAD levels go down to zero. So the system...

01:30:36.500 Wow. Heavily dependent on recycling.

01:30:38.640 Incredible, actually. And there's a specific inhibitor of this enzyme called NAMPT. You can add it to cells.

01:30:44.600 We've done the experiment. Within four to six hours, NAD levels down to zero, the cell dies. So

01:30:50.360 there's an incredible churning through that whole pathway, which is a reflection of the activity of

01:30:55.780 sirtuins, CD38, CD157, the PARPs, and so on. So you have a situation during aging where CD38

01:31:03.820 increases. You increase the degradation. So you decrease the pool of NAD.

01:31:09.260 But you're increasing, in theory, the metabolites.

01:31:12.280 You're increasing the metabolites, nicotinamide. Now, one important thing is nicotinamide

01:31:16.680 metabolism is either salvage, back to NAD, or methylation by an enzyme. And this is important

01:31:24.180 for supplementation, because it turns out CD38 not only cleaves NAD, but it also cleaves NMN,

01:31:32.020 which is one of the two precursors, NMN and NR. So when you actually have increased CD38 activity,

01:31:37.960 and you take NMN, you churn through this pathway, and actually you increase your nicotinamide,

01:31:43.800 and you increase its methylation.

01:31:45.180 So NMN is also cleaved by CD38?

01:31:47.520 Yes.

01:31:47.840 Into what?

01:31:48.880 Into what?

01:31:49.340 Nicotinamide plus something that's not ADP ribose.

01:31:51.740 Yes, exactly. Yes.

01:31:52.480 Okay.

01:31:53.260 And so when you do this, you're increasing your level of nicotinamide to the point that

01:31:58.840 it's shunting to methyl nicotinamide starts depleting your one carbon cycle. So what you see in a number

01:32:05.440 of people actually on NMN is their homocysteine level going up, including me. I stopped taking

01:32:11.640 it when I saw this. I thought this is not, I was taking about a gram of NMN for a while,

01:32:16.680 and then I saw my homocysteine level going up, I think as a reflection of this pathway,

01:32:22.680 and basically stopped it.

01:32:24.940 Now, why is it, Eric, that the increased pool of nicotinamide preferentially goes down

01:32:30.440 a methylation pathway as opposed to the salvage pathway to give you more NAD?

01:32:34.100 Yeah. I don't think it goes preferentially. It just depends how much.

01:32:37.500 It's just the more you put in, even if it splits stoichiometrically or stochastically even,

01:32:43.840 you're going to take away one carbon.

01:32:45.280 Yeah. And I do not know what the relative proportion is, but clearly the more you drive

01:32:50.020 the system with NMN, the more you're going to yield these.

01:32:54.520 How much did your homocysteine go up, by the way?

01:32:56.700 Up to 15.

01:32:57.940 From?

01:32:58.340 From typical seven.

01:33:01.140 Wow. That's a big jump.

01:33:03.240 And then how long did it take to resolve once you stopped the NMN?

01:33:06.220 I measured typically every three months. After three to six months, it had gone back to normal,

01:33:11.140 seven to eight.

01:33:12.460 What about NR, nicotinamide riboside? How is that treated by CD38?

01:33:16.640 It's not metabolized by itself. NR eventually, in the cell, has to make it back to NMN,

01:33:23.740 which is on the salvage pathway that we talked about. So NR is less bulky, less big than NMN,

01:33:30.240 so it is able to get into the cell, but eventually it makes it into nicotinamide NMN and then goes

01:33:36.520 back into the same pathway. So eventually they all come back to the same.

01:33:40.240 So do you think that there's no difference between the same amount of NR and NMN?

01:33:44.840 No, there clearly are some differences, especially in all the really complex biochemistry that happens

01:33:51.080 in terms of getting them into cells. The problem with NR and NMN is that if you think about what

01:33:56.920 the approach is, you essentially, you have a pool of NAD, which is a sink. Think about a sink full

01:34:03.000 of water. It's leaking. That's your CD38. That's the leak at the bottom of the sink. And you keep

01:34:09.040 pouring more NMN, more NR inside of it. You're just going to accelerate the leak. You're not going to

01:34:16.280 solve the problem, basically. Maybe you'll reestablish the level at a normal, semi-normal,

01:34:20.740 but the churning through is problematic. Now, why is the churning through problematic? Because

01:34:25.780 some of the byproducts of CD38, for example, are cyclic ADP ribose. So there's two forms of ADP

01:34:32.880 ribose, non-cyclized and cyclized. Cyclized activates calcium signaling. And so there's a whole

01:34:41.080 aspect of the biology of CD38 that's linked to calcium signaling. So I think I do worry about the

01:34:48.960 supplementation with the NR and NMN. I do worry about it. I'm not discounting them. I think

01:34:55.180 clinical trials are ongoing. There's dozens of clinical trials. So we will soon identify

01:35:00.020 something in which it has a benefit. Again, if you think about the metabolism of these metabolites,

01:35:08.000 it's incredibly complicated. There are effects on the microbiome. There are effects on different

01:35:13.520 absorption by different cells, just literature, hundreds and hundreds of papers, I think way

01:35:18.960 beyond what your audience probably wants to hear. But I would say at this point, most of what you can

01:35:24.960 buy a supplement have doses that are so low. This is where there's an important discordance also.

01:35:30.920 When we do experiment, we've seen amazing things in laboratory animals in terms of supplementing with

01:35:36.400 an RN and NMN. This is where the excitement comes from. But typically, these animals are getting

01:35:41.180 10 times more than what you're buying as a supplement. And the reason is I think grass

01:35:46.560 status is given to these companies to give a small amount.

01:35:50.800 Grass meaning generally regarded as safe, the FDA's criteria for giving something that is naturally

01:35:55.380 occurring, but doesn't require it to go down the IND pharmacologic pathway. Eric, if you were taking

01:36:02.620 one gram a day of NMN and your homocysteine went from seven to 15, I guess two questions would be,

01:36:08.280 has that been reported elsewhere? Is that a known phenomenon in the trials that are testing NMN? Are

01:36:13.300 they measuring homocysteine to see if that's... I must have read it somewhere because I was...

01:36:18.940 You were looking for it. I was looking for it, yes. And then the second question is,

01:36:22.440 how would you then tolerate 10 grams of NMN? I mean, if one gram is doing that,

01:36:26.720 you would deplete all one carbon. Does that mean you wouldn't even be able to alter your epigenome

01:36:32.040 in ways that might be favorable? You run all kinds of risk. And a number of people that I've seen the

01:36:37.200 same thing and start taking trimethylglycine to try to supplement this, I do worry about this.

01:36:42.860 I think for me, I want to reiterate the fact that I think the data and non-animal models of some of

01:36:48.260 the things that we've seen with some of these precursors is really interesting. And this is why

01:36:52.700 there's so much interest. Did you ever try using TMG to see if it would offset the...

01:36:56.700 No, I didn't.

01:36:57.600 Okay. That would be an interesting little self-experiment.

01:36:59.280 Okay. What about intravenous NAD?

01:37:03.380 So that is one of my pet peeves. I try in everything to remain open-minded to things

01:37:09.640 that I don't know and don't understand. My prediction is that first, NAD is not

01:37:16.820 an extracellular molecule. NAD does not exist, almost does not exist at all in your plasma.

01:37:24.780 It is an intracellular. And as I mentioned, high concentration in mitochondria, much lower

01:37:30.500 in the cytoplasm in the nucleus. So the whole idea of injecting intravenous NADs, first, it's

01:37:37.020 too big to be absorbed by cells. So what is the body doing with it? There is a famous paper

01:37:41.820 by Joshua Rabinovitz that showed that if you inject it actually intravenously, you actually

01:37:47.760 get it mostly catabolized by the liver into nicotinamide. Nicotinamide is one of the fraction

01:37:54.280 of niacin. You can buy this at the pharmacy for very cheap. You can go into an IV clinic

01:38:01.020 and get a $700 injection of NAD. Very few studies, one or two. I've read both of them. They're

01:38:09.200 interesting. My opinion is that NAD intravenously is not something that should be done. The same

01:38:16.620 thing for subcutaneously. I've seen another company that sells it subcutaneously. Really

01:38:21.740 no evidence for doing this. Now, that being said, I've heard, and this is where I try to

01:38:27.480 remain open-minded. Obviously, we don't know everything. I have heard anecdotal evidence of

01:38:34.060 dramatic effect in some patients with Parkinson's. People really describing not a miraculous but near

01:38:40.960 miraculous effect right after the infusion having increase in motor performance that you can really

01:38:46.900 assess in someone who's a severe Parkinson's. So, not studied systematically.

01:38:52.040 Mechanistically, is there a reason you could explain that through dopamine or something else?

01:38:56.960 There's a whole literature on the effect of NAD precursors and so on on Parkinson's,

01:39:02.840 mostly animal models. And I think there are lots of clinical trials going on in Parkinson's as well,

01:39:08.840 but more using the standard NR and NMN. The thing that I've described is more as a couple of friends

01:39:14.000 who've told me, I've seen this. Not enough to make a product, but enough maybe to question. Maybe

01:39:19.980 there's something more to it than what we truly know. But the proliferation of these intravenous

01:39:25.020 clinics, frankly, is- How complicated is it to produce a bag of intravenous NAD?

01:39:29.800 I don't think it's very complicated. I mean, I've never made it. I know making NMN purity took some

01:39:35.960 effort to scale it up. And for some of the companies that have been doing this right now, there's like

01:39:39.820 one major supplier out of China that pretty much everybody uses. But in terms of NAD, I don't

01:39:45.000 think this is an industrial process. I can tell you it's not $700.

01:39:49.500 Yeah, I'm sure it's not. So, if a person was going to supplement with one orally,

01:39:54.360 do you think there's a case for NR being superior to NMN?

01:39:58.140 I would say no. I would say take them both. If you're going to do something and you want to

01:40:03.320 a bit of an insurance, I did this for a while. I'm not doing it right now. Take 250 milligrams of

01:40:10.140 each and you'll have a half a gram. You are in a relatively safe dose. Follow your homocysteine.

01:40:16.580 If you are 60 or above, you could make the case this could be part of a stack. Although this is

01:40:22.660 the same thing that we see with so many of these supplements right now. Which one do you take?

01:40:27.460 Which ones are beneficial? There's one little bit of a dark cloud linked to NAD supplementation. It's

01:40:33.660 the demonstration that the SASP is actually dependent on NAD levels. And so, when you are

01:40:40.700 actually increasing NAD levels, you might be increasing these pro-inflammatory markers.

01:40:45.400 Let me make sure I understand why. Because the SASPs, which for folks listening, these are the

01:40:50.600 soluble products made by the senescent cells that effectively are doing all the bad things that we

01:40:56.280 don't want to see senescent cells doing. So, now they are dependent on CD38 to some extent.

01:41:02.520 So, as CD38 goes up, they go up. And are you saying as you give more NR and more NMN?

01:41:10.600 You might churn it up.

01:41:11.900 You might be churning up the SASPs.

01:41:13.580 Yeah.

01:41:14.160 You finish your point and then I want to make a broader point.

01:41:16.180 There's also some worry about the fact that supplementing with some of these precursors might

01:41:21.380 also accelerate tumor growth. So, this would not have an effect in you and I who don't have a

01:41:26.500 cancer. But if it's someone out there who has an early form of a cancer, this could lead to an

01:41:31.560 acceleration. This is something that's been shown in animal models that giving some powers to some

01:41:36.560 people in terms of recommending this to be taken over by everyone.

01:41:40.380 The folks who make this have strenuously denied that there is any validity to those animal models

01:41:47.080 that have suggested that. And some of this has been done in vitro as well, correct? I'm not very

01:41:52.780 familiar with that literature. I remember seeing one study. It was very small. My take on it was,

01:41:59.100 I guess if you had cancer, this might be a bad idea to take. But I didn't find it that convincing.

01:42:03.860 I agree with you. It is a general consideration for our whole field of longevity research. It's

01:42:10.280 better as the enemy of good. It's something that was sort of drilled into me as I went through

01:42:14.860 medical school. We have a term in French which is sort of like therapeutic, overdoing it,

01:42:21.480 doing too much. There's such a thing as overdoing it for your patients. In this case,

01:42:26.400 the whole longevity field is embracing a whole series of these interventions. I mean,

01:42:31.040 there's not a week that doesn't go by that I don't see a new supplement being touted online and so

01:42:36.620 on. And I read about all of them. The question is, which ones should you be taking? Which ones are

01:42:42.040 actually risky? Which ones are not? And to me, this is part of the whole balance of the equilibrium

01:42:47.040 that I'm trying to reach. There's something that really has a beneficial effect. You want to be on it

01:42:51.520 as soon as possible. If not, why take the chance?

01:42:55.580 Yeah. That's the point I was going to make at the outset. You've said it so much better.

01:42:58.660 Let's pivot a little bit to a couple of the things I want to chat about quickly. Let's talk

01:43:02.240 about interleukin-11. Big trial last fall that looked at blocking interleukin-11, which is a

01:43:10.660 molecule that's made by immune cells, plays an important role in inflammation. And this was done

01:43:15.100 in mice and those mice lived longer. What do you make of the study?

01:43:19.200 I read the paper like you. I don't have sort of an inside knowledge about, of course, when the paper

01:43:24.460 came out, it was like interleukin-11. I mean, as an immunologist, you talk about one, interleukin-1,

01:43:30.120 two, four, six, seven, but 11, never heard about it. It goes up to like 30. So I went and read the

01:43:38.100 paper. It's an inflammatory marker. So again, it could be-

01:43:41.980 No, I would say probably not. So it came out of the left field, but it sort of makes sense in the

01:43:50.280 context of what we know about the inflammatory response linked to aging. And maybe this is

01:43:56.460 where I can add one point is when we think about the chronic inflammation of aging, sort of

01:44:01.820 inflammation, it is both cause and effect. We talked about how the immune response helps you to protect

01:44:08.540 yourself against the innate immune response, against pathogen as a first line of defense.

01:44:13.340 The innate immune response also has another important role is that it recognizes damage,

01:44:17.900 any kind of damage. If you cut yourself, if you have a wound inside of your organism-

01:44:24.620 Coronary artery.

01:44:25.480 Huh?

01:44:25.720 A coronary artery.

01:44:26.640 A coronary artery. This will act any kind of damage, unfolded proteins. There's all kinds of things.

01:44:32.620 So the innate immune response will be triggered and will activate itself. So as we age,

01:44:38.540 and as damage slowly accumulates, because aging is a slow, irreversible accumulation of damage,

01:44:44.640 eventually your immune system responds to this by becoming chronically activated. And so the problem

01:44:52.020 is that you might think, well, this is great because you're actually repairing all of this damage.

01:44:56.060 The problem is the activation of the immune response by itself becomes problematic because

01:45:02.580 these cells, macrophages, for example, are powerful tissue remodeler. The immune system in this

01:45:08.120 case is Dr. Jekyll and Mystic Hyde. It's helping, but it's facing an unsurmountable amount of damage.

01:45:15.020 And eventually its activation leads to an AD depletion. That's one of the things that it does,

01:45:19.340 but many other things, stem cell dysfunction and mitochondrial dysfunction.

01:45:23.120 So the whole idea here is that 11 might simply be, is one of the key markers of this chronically

01:45:30.880 activated immune system. So this is not something I imagine you're going to give to a 20-year-old,

01:45:35.220 but in someone who's getting really in the part where chronic immune activation is present could

01:45:41.480 really play an important role in the future. And what the paper showed was, again, in mice,

01:45:46.600 but from what I understand is already an existing molecule. And they actually recently was contacted

01:45:52.140 by a company that has another novel inhibitors of IL-11. You could imagine this to become part of the

01:45:58.340 whole armamentarium that we have against aging. And then how do you see playing that off something

01:46:04.560 on the other side of the spectrum? Because we're really trying to deal with two sides of this system.

01:46:08.660 We want to tamp down the part that's overactive, and we want to ramp up the part that's underactive.

01:46:14.680 So we've got basically the only example we have over here is rapamycin. This one does this. And then

01:46:20.860 we now have IL-11 inhibition, or use knockout mice, but block this. That's a good thing. So

01:46:27.360 is this one of those things where you need to do both? By the way, maybe you have growth hormone

01:46:30.640 over here as well, right? Yeah, IL-1 there also. Anti-IL-1 as well, which has been shown to-

01:46:35.680 Yeah, block IL-1, block IL-11, give growth hormone, give rapamycin. I mean, here's the problem.

01:46:41.000 You get into this reductionist state, which is like the whole NAD world of NR and NMN. Hey,

01:46:46.260 it sounds great, but what if there's unintended consequences we can't see? Like, even as much as

01:46:51.640 I love thinking about this and want to do all of these things, I start to think, man,

01:46:59.740 what is the probability we're going to get this right?

01:47:02.660 I agree. The immune system is an incredibly tenuous system, which is in really delicate

01:47:08.760 balance. So the balance is too much immunity. You might say, well, this is good protection against

01:47:14.880 cancer, protection against microbes. Right, but then you get autoimmunity.

01:47:20.000 But then you get autoimmunity. Not enough immunity while you run the risk of being

01:47:24.380 killed by a pneumonia or some kind of infection. But at least you don't have too much inflammation.

01:47:29.360 Yes. Yeah. So this is a very fine balance.

01:47:31.780 This is why I wish we had a dashboard. What are the biomarkers we can use for these things? Because

01:47:36.740 we don't have this problem with blood pressure. We don't have this problem with thyroid hormone.

01:47:41.780 We don't have this problem with so many things that we treat because we can measure what we care

01:47:47.740 about. That's a good point. And the question is, the immune system is so complex, there's not going

01:47:53.460 to be one single marker. My colleague, David Furman, is this thing called I-Age, which is an immune

01:47:59.340 aging set of tests that you can actually conduct. That was the first attempt at trying to measure

01:48:04.920 immune aging. What do they actually measure? Is it all serum biomarkers?

01:48:09.080 Yes. Serum biomarkers and mostly cytokines.

01:48:12.360 Validated how?

01:48:13.260 Been validated in clinical studies.

01:48:15.620 I-A, immunoaging?

01:48:17.160 Yeah. Yeah. I-Age.

01:48:19.220 Oh, I-Age.

01:48:20.160 Yes. So this was developed and pioneered by David Furman and Mark Davis. So David Furman is with us

01:48:26.260 at the BAC. Mark Davis is still at Stanford.

01:48:28.900 I guess this brings us to clocks.

01:48:31.720 Yes.

01:48:32.360 I don't even know if I have the energy to talk about this. Okay. Where do you want to begin?

01:48:35.640 There are so many of these things out there. Some of them are commercially available. Some

01:48:40.780 of them are just tools of research at the moment. Some of them aim to tell you an actual

01:48:47.320 age, an actual number that represents your biologic age as opposed to your chronologic

01:48:51.860 age. Some of them don't aim to tell you that at all. They just want to tell you a rate of

01:48:56.040 aging. Some of them look only at the epigenetic signature. In other words, they look directly

01:49:02.020 at the methylation sequence. Others look at a host of markers, including some very simple

01:49:09.420 serum biomarkers like glucose levels and vitamin D levels and things like that. So how do you

01:49:14.360 make sense of all of those tools?

01:49:17.520 Right now, we don't. First statement is they are not ready for prime time in terms of patient

01:49:23.160 management. There are research tools.

01:49:26.500 Which is interesting because they're far outside of research labs at this point.

01:49:29.920 Yes. They are available commercially. I've done the same thing. I don't remember who

01:49:34.440 told, you told me someone actually, was it Matt?

01:49:37.120 Matt Caberlin.

01:49:38.180 Measured his clocks. I do the same thing. Actually, I measure them every three months.

01:49:42.280 It's just a scatter plot.

01:49:43.580 It's a scatter plot in a way, you know, I'm between 25 and 68, which is, of course, I like

01:49:48.820 the clock that show me to be young. But that being said, we know that we're learning. So we

01:49:54.360 know that, for example, you alluded to the fact that they can vary the same clock. There's

01:49:59.200 circadian variation, for example, five years. So your age can vary by five years using some

01:50:05.460 of the clocks, depending on when you measure.

01:50:07.520 What time of day?

01:50:08.260 Yeah, what time of day. That's biology. That just tells you the epigenome is something

01:50:12.620 that's highly dynamic. And so that's something, as we learn, obviously, the companies will

01:50:17.660 encourage you to measure it, you know, to draw the blood always at the same time. Now, the

01:50:22.980 whole field right now is pretty much focused, almost completely focused on DNA methylation.

01:50:29.160 Steve Horvath has done beautiful work. I mean, it's really pioneering work identifying all

01:50:34.540 this. And Morgan Levine and others have gone on. Dan Belsky, I think, with denadine pace,

01:50:40.640 which is another epigenetic clock that measures the pace of aging. By the way, I think this is

01:50:45.140 probably my favorite because it really seems to be responding to interventions. If you change

01:50:50.920 your diet or if you do something, you will see your pace of aging changing. So I think that one,

01:50:55.900 to me, seems more promising. We don't know really how to use these tools clinically. That's the

01:51:01.300 problem. They're nice gadgets to buy. The companies are selling you supplements and then they're selling

01:51:06.620 you the tests with it. I don't know what to make of it. Personally, I think this is not ready for prime

01:51:12.680 time. It's something that should be done in the future. It might become in the future.

01:51:17.480 Would you agree with my stern words on this? Because I've made a lot of enemies by saying

01:51:24.560 that if as a consumer, you encounter a company that is selling you a test, especially a test that

01:51:34.020 is not validated in any clinically meaningful way, and then in the same breath, selling you a

01:51:39.380 supplement to fix the result of that test, you need to run. I agree.

01:51:45.280 I don't have the patience for that kind of behavior.

01:51:49.020 Someone told me actually recently that one of these tests actually that you can measure,

01:51:55.440 almost everyone who gets their result is low. And of course-

01:51:59.440 Low being good or bad in this test?

01:52:01.000 It's bad.

01:52:01.580 Bad, yeah.

01:52:02.080 It's insufficient. The next step is the recommendation. You have to buy this

01:52:06.340 supplement to solve the problem. So yes, again, it's the same thing with the sirtuins and the NAD.

01:52:11.380 Let's not throw out the baby with the bathwater. There is a whole series of these players. I'm not

01:52:17.680 disputing their honesty or their good intention. From what I've seen, I think it's too early.

01:52:23.560 And what do you think is the biggest problem? Is the biggest problem the biologic noise in the

01:52:29.520 system, which means even if you had the absolute perfect tool to measure and you knew exactly what

01:52:36.500 to measure the movement of that thing is so great that the probability that you're capturing a

01:52:42.440 meaningful value is irrelevant. In other words, imagine that there's a variable that moves like

01:52:47.040 this, but on the small level, it's moving like this. I'll give you an example. Imagine you were

01:52:53.560 measuring heart rate, but you could only sample it milliseconds at a time. And what you were actually

01:52:59.120 measuring was heart rate variability instead of heart rate. It would be useless. It's too noisy.

01:53:04.120 I agree. Do you think that's the problem? No, I don't think that's a problem. I'll speak

01:53:07.820 personal experience. I work with True Diagnostic. They use the Epic Array and you get not one clock,

01:53:13.780 you get dozens. So I get all of them. And they tend to be reproducible every three months unless I make

01:53:21.020 some interventions. But in general, there is some consistency. I'm not the only one who has seen

01:53:26.800 this. So my advice, if you really are determined to use them, use all of them. They all are different

01:53:33.800 mirrors of your reality. The problem of the methylation clocks is that there's a very

01:53:39.960 tenuous link between the change of methylation at any given site and the biology. Typically,

01:53:46.180 each clock would rely on about 500 different methylation sites, but they're not attached to

01:53:51.660 a specific gene. So you don't really know what it means. But how are they even doing that? They're not

01:53:56.880 measuring with point arrays. They do this with arrays.

01:53:59.620 They're doing this with an array?

01:54:00.940 Yeah, they have about 20 million methylation sites that they're assessed. But each clock

01:54:04.620 uses a subset, four or five hundred.

01:54:07.760 Sorry, just to be clear, you're saying they're actually measuring point of methylation?

01:54:12.780 Yes. Okay.

01:54:13.080 Yes. They're quantifying the level of methylation at each of these sites. The problem with the

01:54:17.960 clocks is also where do you obtain them from? Typically blood, as I mentioned, it's a heterogeneous

01:54:24.360 compartment. As you age, for example, you know that your fraction of naive T cells decreases

01:54:30.620 down to close to zero. If you're 80 years old, your memory T cells increase. So we did

01:54:35.960 a very simple experiment. We sorted all of these different T cell subsets, memory, naive, central

01:54:42.840 memory, TEM rather terminally differentiated, and measured their epigenetic age using several

01:54:49.740 of the clocks. 20 to 25-year difference between the naive and the central memory T cell.

01:54:57.580 In the right direction, the direction you would predict.

01:55:00.180 Yes, the naive and much longer.

01:55:01.040 Yeah. That's somewhat interesting.

01:55:03.120 That was really interesting for me because it means also any conditions where you see a

01:55:07.580 shift in the relative proportion of these cells. For example, you get an acute COVID infection.

01:55:13.000 What happens? You have a massive expansion of your memory T cells. So it looks like you're

01:55:18.660 going to, and then you sample. And given that these cells look much older than the other

01:55:23.880 ones, you're going to look like you're aging. And there's a whole literature that talks about

01:55:28.720 accelerated aging and rheumatoid arthritis and COVID and HIV, all of these conditions that

01:55:35.520 are all associated with chronic immune activation. So that's another confounding variable. So what

01:55:41.360 we did to do this with a student in a lab, we made a new clock in which we eliminated all of these

01:55:48.920 methylation sites that are linked to differentiation. Okay, so now this clock that we've done does not

01:55:55.820 vary, actually, as a function of the types of cells that are in the blood. As a T cell goes from being a

01:56:03.340 naive T cell to being a memory T cell to being a TEMRA, the methylation patterns change. That's part of the

01:56:08.760 epigenetic regulation. So we eliminated all of those sites, made a new clock called entrant clock,

01:56:14.320 which actually is impervious to your level of immune activation. And what's interesting is that

01:56:18.980 that clock doesn't change anymore during COVID. It doesn't change very little during HIV. It doesn't

01:56:25.420 change during a whole series of conditions where people have talked about aging acceleration,

01:56:30.640 including the story that we talked about earlier on growth hormone.

01:56:34.340 What does change it then?

01:56:36.860 What does change it? Cancer, senescence, which is really interesting.

01:56:42.140 What about short-term interventions that might be beneficial? So if you took an individual who

01:56:47.660 is insulin resistant, and you put them on a GLP-1 agonist, and three months later,

01:56:53.880 they're 20 pounds lighter and their insulin resistance has resolved, how does that change on the clock?

01:56:58.380 I would not be able to tell you specifically for individual clocks, but Dan Belsky's Dennett & Pace

01:57:05.340 clock is the one that repeatedly people have shown seems to be responding to interventions, which is

01:57:12.240 the two qualities that you want in a clock is one to be predictive, and the other one to be

01:57:18.020 predictive of ultimate income, sort of life expectancy or the occurrence of disease. But also,

01:57:23.780 you want it to be modulatable, responsive. And reproducible.

01:57:28.480 And reproducible, yes. Reproducible, I think, is more a question of the laboratory that's doing

01:57:34.400 it. So there are no- But also potentially the biologic noise still.

01:57:37.560 Exactly. So biologic noise and laboratory conditions speak to reproducibility. I agree with

01:57:42.800 what you said. I mean, I've often made this case when people ask me about clocks is my gripe with the

01:57:47.880 age clock. So again, the pace clock is different because it's just trying to give you a rate of aging,

01:57:51.720 and I agree with you. I think there might be more there. But these clocks that spit out,

01:57:55.600 hey, Eric, congratulations, you're 25. I say to someone who says, isn't that wonderful? I say,

01:58:02.120 maybe, but do you actually believe that you're 68? You're 68 and your clock said you're 25.

01:58:10.680 Should I expect you to live another 55 years? Yes.

01:58:14.340 In other words, is it a better predictor of future life than chronologic age? And the answer

01:58:21.180 is, to my knowledge, no. There is no clock that has a better ability to predict lifespan

01:58:27.860 than chronologic age does. And until that's the case, I worry that the biologic clocks are creating

01:58:35.560 a bit of a distraction, at least this subset of clocks, and that we maybe ought to focus better on

01:58:42.220 clocks where the readout state is more about, is this intervention good or bad? Or is this a net

01:58:50.000 positive intervention or a net negative intervention? I agree. As we mentioned earlier,

01:58:56.100 the field initially focused on the epigenetic clocks because this is Steve Horvath's pioneering

01:59:01.420 work, so it got everybody to start thinking we can generate these tools. But the field is now moving

01:59:06.740 into proteomics clock. So what makes up Dan's clock? Dan is a methylation. It's also methylation.

01:59:13.540 Why do you think it's doing a better job than maybe Horvath's clock at the moment? Typically,

01:59:18.920 it really depends on what the variable, what the cohort, what the question was. I don't know. I mean,

01:59:25.460 I think that Dan's is the only one that's doing it in this way. Why is it working better? They're just

01:59:30.520 looking at it in a completely different way. How much is AI facilitating this at this point?

01:59:35.280 Machine learning is the key instrument. Essentially, what these clocks are is a regression analysis on

01:59:40.940 to start with a variable, which is your age, and you regress each methylation site onto the age. You

01:59:47.520 do this on enough people of different ages, you find an average. I wonder if that's the wrong way to

01:59:53.760 do it. Wouldn't it be better to get biobank data and instead of mapping it onto age, map it onto number

02:00:01.460 of years remaining in life? Because if you'll know that in a biobank.

02:00:05.300 They've done this. They've done this. They've done this in terms of life expectancy. They've done

02:00:09.680 this in terms of morbidity. So this is like the third and fourth generation of these clocks now

02:00:15.240 are looking at regression. The initial one- Was just chronologic.

02:00:19.260 Yeah. And Steve used to go around saying my correlation coefficient is 99. And I was like,

02:00:24.540 well- That's because that's what you built it on.

02:00:26.160 Yeah, exactly. And I can look at a calendar. I don't need an epigenetic clock to tell me how

02:00:30.900 old I am. But the next generation clocks actually had a bigger spread. Of course,

02:00:35.440 you have an average- That's right. Because they started to build it on a different variable.

02:00:39.100 Exactly. So what really excites me right now is the whole idea that the field is moving on to the

02:00:44.800 next stage, which is non-epigenetic clocks. Because I'm still frustrated as a biologist trying to

02:00:50.880 understand what are these clocks- It should be everything. It doesn't make any sense to me that we

02:00:54.920 wouldn't look at the metabolome, the proteome, and the epigenome. There's no excuse today with the

02:01:00.440 compute power not to do that.

02:01:01.660 We have clocks based on fundus. We have clocks based on skin. We have clocks based on facial

02:01:08.180 recognition. So the clocks are going to be measured using dozens of different biological variables.

02:01:15.440 Any biome, a small company in the Bay Area is using the tongue, a tongue picture, the old doctor

02:01:21.160 looking at your tongue. So you can actually use machine learning to recognize patterns of

02:01:25.840 discoloration. And another exciting really story was, I don't know if you're familiar with a Tony

02:01:31.000 Wiscore's paper using proteomics. He has shown, for example, proteome in plasma changes throughout life,

02:01:38.900 pretty dramatic manner, which is really completely mind-boggling for me just to see that you can be

02:01:43.760 so different as you age in terms of your whole blood proteome.

02:01:48.220 Why? If the epigenome is changing, then gene expression is changing. If gene expression is

02:01:53.520 changing- No, no, you would.

02:01:55.060 Yeah, yeah, yeah. Okay.

02:01:56.140 But that it would change to such a degree. Tony has a beautiful slide which shows all of the proteome

02:02:02.780 in the blood and how the colors change across age.

02:02:06.280 And do you think that most of those changes are post-translational?

02:02:08.780 No, most of them are probably expression level.

02:02:11.920 It's expression.

02:02:12.520 Yeah, it's expression. People are building transcriptomics clock. And so Tony now has a

02:02:17.360 study that is, I believe, in press or coming out soon where they've gone back using this proteomics

02:02:24.120 clock and they've done this on a UK biobank, more than 40,000 different people. And this is the study

02:02:30.180 we started this discussion on identifying. What Tony did was actually remarkable. He looked at each of

02:02:37.320 these proteins that are in the blood and selected some that were predictive to be coming from unique

02:02:44.780 organs. Imagine what you know about how you measure a tropomyosin for heart attack. So they did this.

02:02:51.900 They went and looked in every single organ and said, okay, what proteins are specific of this organ

02:02:56.800 and which ones actually can be measured into the plasma? And using this, they were able to generate

02:03:02.720 what they call an organ-specific clock. Simply from a blood draw, they're able to really determine,

02:03:08.400 do you have a frailty point? When I look at you, is there like suffering happening?

02:03:13.940 And this is Tony's work through the proteome?

02:03:15.860 Tony Wiscore. It's a new startup called Vero. For disclosure, I've joined the board of this

02:03:20.260 company, but I only joined the board because I was really excited about what they're trying to do.

02:03:25.200 And I think it really brings a whole new dimension to these predictive biomarker, which is more aligned

02:03:32.440 to what you and I have seen as physicians. Kind of simple-minded. As the protein is released into

02:03:38.240 the blood, it shouldn't be there. It might be indicating some suffering. And I discussed with

02:03:42.900 some colleagues who have used this clocks and have identified some abnormal aging in a unique organ,

02:03:50.700 only to go back and find that there was indeed one problem without going into what the issues were.

02:03:57.260 The reason I tend to be a slow adopter of these things is, even if that's the case,

02:04:03.420 the question is how much noise is in the system. I go and do that test on a patient and it comes back

02:04:09.140 and says, oh my God, there's something wrong with your liver. Your kidney's a bit too old. You're this,

02:04:13.380 you're that, you're this, you're that. So I have two fundamental questions. The first is,

02:04:17.160 could I have figured that out another way? So if it's telling me your liver is angry,

02:04:20.700 or something's wrong with your liver, how do your transaminases look? If it's telling me

02:04:25.380 something's wrong with your kidney, could I have picked that up on a urinary analysis,

02:04:29.380 looking at creatinine clearance or cystatin C or something else? In other words,

02:04:34.040 is it giving me information that I can get elsewhere in a more reproducible, more validated

02:04:38.960 fashion? The second thing is, let's say it tells me seven things are not perfect. And by the way,

02:04:45.460 everything looks perfect. I have my standard assays. Everything looks awesome. This test says,

02:04:50.120 oh my God, these six or seven things are problematic. And I go poking around,

02:04:54.800 poking around, poking around, and I find out one of them is indeed not working,

02:04:58.700 but the other six were perfectly fine. So now we have this huge false positive situation.

02:05:03.840 That's a whole MRI.

02:05:05.440 Yeah, exactly. It's the same problem we have with cancer screening, which is buyer needs to beware

02:05:09.660 of the Pandora's box you open. And at least with MRI, you're dealing with imaging,

02:05:14.460 but this sounds like exciting. And yet it's a bit of a black box.

02:05:18.960 Agreed.

02:05:19.520 Where it's going to spit out, oh my God, there's something wrong with your left testicle. And what

02:05:24.100 do I need to do? You know? And...

02:05:25.620 That being said, I think the assays are generated in a way that there are multiple. It's not like

02:05:30.780 one single protein, like a tropomycin. We know that's a clear indicator. There's something cell

02:05:35.520 death in terms of your heart. In this case, the clocks are generated in a way that there are

02:05:40.400 multiple sentinels for each organ, many. The story I was talking about early days, okay? We totally

02:05:46.940 agree with this. It's a startup. I think they will deploy it. And obviously, it's going to take,

02:05:51.920 again, a group of physicians who are able to look at these tests. This is what research is. This is

02:05:56.380 what startup. I can't blame them for trying because I think it has a potential, for example,

02:06:01.180 to highlight a frailty point, which is, in aging research, to me, is really critical. You could have

02:06:07.220 the best mind and the best heart in the world if something else is going to fail that you are

02:06:12.820 completely unaware of. You want to know as soon as you can. My prediction is, I'll share the paper

02:06:18.280 with you if you're interested in looking. It's quite exciting in terms of where this is leading.

02:06:23.020 But I agree with you early days. Yeah. I will probably maintain a shockingly high degree of

02:06:28.260 skepticism and probably enjoy some experimentation with it. But again, my experience in the real world

02:06:35.540 is that that's just not how it works. There aren't people walking around that are insanely,

02:06:40.860 remarkably healthy, where everything looks amazing, but they have some time bomb they don't

02:06:45.640 know about. With the exception of a few things, I'm not sure it would pick up. For example,

02:06:50.400 cancer is always that thing. And of course, there's an entire field of medicine that's going around

02:06:55.380 with liquid biopsies that's exactly trying to solve that problem. You could reword the liquid

02:06:59.600 biopsy industry through the lens you said, which is, it's looking for that weakest link,

02:07:03.060 which in this case is the earliest signs of cancer. And it could be that a cancer will manifest itself

02:07:08.840 also in local organ suffering. And again, leaching, it might actually point along with a liquid biopsy

02:07:15.460 that tells you you have some cancer cell. It might tell you, it might point you to one place where

02:07:19.720 actually this is actually happening. Yeah. It's interesting. The case that I've made about MRI is

02:07:25.620 the same. I have a whole bunch of physician friends. I get a yearly MRI and they tell me, why do you do

02:07:31.420 this? I say, well, because I would rather know. He said, well, you're going to find all kinds of

02:07:35.680 things. I said, we did find something. I had a tumor behind my jaw and a mass. It was not a tumor,

02:07:42.180 but it took me six months of worrying about what it was and decided not to biopsy and anything.

02:07:48.580 My sense of all of this is that these are novel ways to practice medicine.

02:07:53.200 I'm criticized heavily for being too much on the forefront of doing that, but probably not nearly

02:07:59.540 as far as some. At the end of the day, I think about every time you do a test, one, you never do

02:08:05.820 a test unless you're willing to act on an outcome or you have a sense of how an outcome will change

02:08:10.840 your behavior. We don't order tests for the sake of information. We order tests to make decisions.

02:08:16.200 Therefore, you must at a minimum understand the full suite of outcomes that can come from the test

02:08:24.280 and how many of them will pose huge trouble for you. 20% of my patients opt not to do whole body MRI.

02:08:32.480 Yes.

02:08:33.140 And I fully endorse that decision. And I try to talk patients out of it. I really try to

02:08:37.860 highlight how many times we find thyroid nodules that we have to put needles into that ultimately

02:08:43.120 end up being nothing. And all we do is subject them to that risk and the anxiety that comes along

02:08:49.580 with it. So I'm eager to look at this because I do think that the proteome offers a lot, but I'm

02:08:54.280 always worried about going a little too far on the clinical implication of a test.

02:08:58.920 I'm with you in terms of being careful. I view this as another attempt. For example,

02:09:03.900 we talked about the data showing that the two organs that appear to be rate limiting in terms of aging,

02:09:10.500 the immune system and the brain. That came out of that story. That's actually the title of the

02:09:14.880 paper, essentially, that identifies the brain and the immune system. So they have a whole series of

02:09:19.880 immune markers that are predictive of some degree of immune activation and so on.

02:09:26.520 Well, Eric, there's a lot of other things I wanted to chat about, but I think what we'll do

02:09:29.220 is we'll have you come back out to Austin for another day of driving a COTA, and then we'll justify

02:09:35.160 it by doing another podcast where we dive deeper into some of these topics. We really take advantage

02:09:40.140 of the fact that we have the best race course in the country here in our backyard. So I think

02:09:44.540 you're going to have fun tomorrow and you'll be like, let's come right back and do it again every

02:09:48.580 month. I'm looking forward to this. Thank you, Eric. Thank you.

02:09:51.580 Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash

02:09:59.700 show notes. If you want to dig deeper into this episode, you can also find me on YouTube, Instagram,

02:10:05.780 and Twitter, all with the handle peteratiamd. You can also leave us review on Apple podcasts or

02:10:12.300 whatever podcast player you use. This podcast is for general informational purposes only and does not

02:10:18.520 constitute the practice of medicine, nursing, or other professional healthcare services, including

02:10:22.900 the giving of medical advice. No doctor patient relationship is formed. The use of this information

02:10:29.000 and the materials linked to this podcast is at the user's own risk. The content on this podcast is not

02:10:35.400 intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should

02:10:40.500 not disregard or delay in obtaining medical advice from any medical condition they have, and they should

02:10:45.700 seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts

02:10:52.040 of interest very seriously. For all of my disclosures and the companies I invest in or advise, please

02:10:57.940 visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.

The Peter Attia Drive - August 04, 2025

#359 ‒ How metabolic and immune system dysfunction drive the aging process, the role of NAD, promising interventions, aging clocks, and more ｜ Eric Verdin, M.D.

Episode Stats

Length

Words per Minute

Word Count

Sentence Count

Misogynist Sentences

Hate Speech Sentences

Summary

Transcript