The Peter Attia Drive - #204 - Centenarians, metformin, and longevity | Nir Barzilai, M.D.

Episode Date: April 25, 2022

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Nir Barzilai, Director of the Institute for Aging Research at the Albert Einstein College of Medicine, is back for his third appearance on The Drive. In this episode, Nir divulges insights into lifespan and healthspan through the lens of his extensive research on centenarians as well as the latest from the TAME trial (Targeting/Taming Aging with Metformin), a multi-center study investigating the concept that the multi-morbidities of aging can be delayed in humans. He discusses common gene variants found in centenarians, important pathways for longevity, and ultimately what we can learn from centenarians about extending lifespan while also trying to improve healthspan. Additionally, Nir goes into depth on metformin as a longevity tool for humans, including studies with positive and negative results. He discusses the impact metformin can have on exercise for both strength training and cardiovascular training, as well as future research facilitated by data from the TAME Trial. He also touches on epigenetic clocks and concludes with his take on the usefulness of NAD precursors as a potential gero-protective agent. We discuss: Insights from genetic studies of centenarians and twins [3:00]; Genes with protective variants that aid longevity [13:00]; The relationship between growth hormone and IGF-1 [22:45]; Use of growth hormone as a longevity tool [34:00]; Longevity genotypes: the role of APOE e2, Lp(a), Klotho, and CETP [41:45]; The correlation between high TSH and longevity [46:30]; Important pathways for longevity [52:00]; Insights from centenarian studies, nature vs. nurture, and more [59:00]; The contraction of morbidity that comes with improved healthspan [1:08:00]; Defining healthspan [1:13:13]; Unique perspectives and positive attitudes of centenarians [1:17:30]; Lessons to take away from centenarians [1:24:00]; Metformin overview: history, studies, and potential for gero-protection [1:28:45]; The TAME trial (Targeting Aging with Metformin) [1:39:00]; The challenge of studying metformin in animals models [1:46:45]; How data from the TAME trial could provide insights into biomarkers of aging and facilitate a future study on proteomics [1:53:30]; The search for biomarkers to identify who can benefit from treatment [2:00:30]; The impact of metformin on exercise, and finding the right indication for the use of metformin [2:10:30]; Are NAD precursors geroprotective? [2:21:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube  

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratiaMD.com forward slash subscribe. Now, without further delay, here's today's episode. I guess this week is near bar's lie. Near is making his third appearance on the podcast, the previous one being in August 2020, with Joan Manek and then originally back in January of 2019. In this episode, near and I speak mainly about two topics just in much much more detail than we've ever spoken about them before, at least publicly, centenarians and metformin. We start the conversation speaking about centenarians with a focus on what can the majority of us who are not

centenarians learn from them. We talk about longevity genes such as GH, IGF1, C-TEP, Foxo, TSHR, and APOE. We talk about whether or not environment matters at all in these individuals or whether it's all genetic. We talk about what we can learn about them from the importance of preventing diseases and we talk about what we can learn from centenarians around extending lifespan while also trying to improve health span. From there, we get into deep dive on the metformin. We talk about the tame trial. Now, this is something that we did speak about briefly in span. From there, we get into deep dive on the Metformin. We talk about the tame trial now.

This is something that we did speak about briefly in our first podcast, but we get into much more detail and I actually found myself learning some details of the study design that I didn't understand previously. Talk about Nier's thoughts on why the Rich Miller ITP program found Metformin to be unsuccessful in that model and why he thinks that may or may not apply to humans. We talk about the impact metformin can have on exercise, both strength training and cardiovascular training. Lastly, we speak a little bit about epigenetic clocks and

end with a conversation around NAD precursors. As a reminder, near is a director of the Institute for Aging Research at Albert Einstein College of Medicine, spearheading the longevity genes project, conducting genetic research on more than 500 healthy elderly people between the age of 95 and 112 and on their offspring. He is also the director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health, Nathan Schock Centers for Excellence in the Basic Biology of Aging. So without further delay, please enjoy my conversation with Dr. Near Arzalai. I'm here, it's great to have you back.

I was thinking about this when I was preparing for the podcast today. There's so much I want to cover that I don't think it's actually going to be possible. I'm pretty sure that we're going to talk as much as we talk today and I'm going to be saying to the team, all right, let's talk about when we're going to have near back because there's really just too many things I want to go through.

So anyway, thank you for making time and let's just get right into it. Thanks, Peter. I'm happy to come back, but it's you who's coming to me every week, and I'm so grateful for what you're doing for this field and for helping all of us catching this field of longevity that's going to come true. Very rapidly, I hope. Well, just thinking about the first place I wanted to start, and there's really no good one place

to start, because there's just so much I want to talk about. But let's start with centenarians. You, along with Dr. Pearls, are probably two of the people who have spent the most time studying this very, very unique subset of the population. So I think everybody knows what a centenarian is, someone who lives to be a hundred or more, but there's so much nuance about what it is about these special people. And then there's sort of the pop culture view of this, which is people love to talk about all of the bad behaviors that centenarians engage in, how much more they smoke, how much less they exercise, how much whiskey they drink, and all of those things, which are really cute. But when you study them scientifically, and when you study their offspring scientifically, as you've both done, we learn a lot of things. And if my interpretation of the literature is at least partially correct, it appears that genes play a

significant role. So genes don't seem to play a big role in people living to 70 versus 80. But boy, when you start to talk about living to 90 versus 100 relative to 70 or 80, jeans play a pretty big role. So tell me a little bit about what we understand about the role that the parents play in determining the lifespan of offspring. How fortunate were these people to pick their parents? So let me just tackle one of the things you said that there's no much genetic impacting people between 70 and 80 and it's true if you compare the lifespan of fathers and sons, okay, or mothers and daughters or sons. And let me tell you why

it's problematic. My grandfather got a heart attack when he was 68 and he died. That's my grandfather. My father got a heart attack at 68 and he had triple bypass and he died at 84. So the correlation between age of death in different cohorts is not much revealing. But let me say it now differently. Let's say it's 20%. If we understand this 20%, understand it really, we can use that in order to prevent the 80% of the environment. Well, maybe another way to think about it near, because that

example is a great example, which makes it very difficult over discrete generations to make comparison. Do we have twin data? Because it seems to me that if you had monozygotic twin data, that would be the gold standard for looking at the discordance and concordance between the role of genes in separate environments, right? Well, you would think so. So let me tell you the problems with twins. Twins are usually born

small for their gestational age. In fact, it's more true that one of the twins is small for their gestational age. Now, I've been doing studies with rats from before when you ligate the uterine artery and make them small, they get diabetes which they never get at three months. We know that twins or that babies that are born small for age develop age-related disease very rapidly. It's called the bargar hypothesis, it's observation from Holland in World War II. And we actually determined some of the epigenetic manifestation of what happens epigenetically

when you do that. So I don't think twins are the right model unless you understand that and account for that. Near this is super interesting. Can you tell me a little bit more about that? I actually was not aware of the relationship between low birth weight and the epigenetic imprint of that on reduced lifespan. And I assume health span, or is it just lifespan? Well, it's mainly health-spending humans that we know.

First thing that's obvious when you have a small,, stational age twin, there's a ketchup growth of the small baby. And those twins born in the same day in a few years, one of them is an obese child and one is a normal child. And as you know, obesity drives aging very rapidly. So that's one mechanism. The change is an imprintreating of epigenetic. I would say for now that it's more of a description than a mechanism. There are many genes that are involved and I'm

not aware of a recent paper that says this is what happens. Okay, so let's get back to the broader question, which is when an individual or when a cohort of individuals lives to 100, and we compare them with a cohort of individuals that lives to 80, what are the types of genes that seem to be offering protection to that group that lives to a hundred. What is it that the centenarians have in a polygenic sense that the rest of us schmuckst don't have? When we went to the centenarians, we had three hypotheses that we had to take care of. One is that it's all the environment, okay? It happens that they did exactly the right thing,

what the doctors tell us to do now. The second, and it's not true, as you mentioned, it's not true 60% of the men are smoking and 30% of the women, 50% of them are overweight and obese and all that, and not exercising and not vegetarians. The second hypothesis is that they have perfect genome. We know that we have a lot of genotypes that are putting us at risk for a variety of age-related disease. So maybe one out of 10,000 doesn't have that, and that's why they're flying in so gracefully.

So to be clear near part of that hypothesis is the absence of bad genes, not necessarily the presence of good genes. Exactly, that only the absence of bad genes will allow them just to get without diseases. And sorry, I took you off your track, but what was the third hypothesis? The third hypothesis that they are genes that slows their aging. Longevity genes, we call them. Okay, fair enough.

As for the second hypothesis that they have what we call the perfect genome, we took our first 44 centenarians and did the whole genome sequencing at the time, huge expense, but we only had those centenarians. We don't have had a control, but we had a great instrument we thought. It's called Cleanvar. It's an accumulation of all the genes that have shown to be causing diseases. If you had a clean variant, you're very likely to have a disease. So we simply asked, do our centenarians have any of those variants? And how many of those variants are there? At the time, there are 15,000. Now there are many more.

So just to put that in perspective for the listener, we have between 20 and 30,000 coding genes, correct? So these are variants of how many genes? Well, I don't remember how many genes are in the variants, but those are variants that we were found to be compelling. And by the way, a lot of them are not. That's another story. So let's keep it simple. We have 15,000 variants, and we asked, do our 44-centenians have variants? And the answer was, each centenarian had between five and six bad variants. Five and six out of 15,000 possible?

Right. And we didn't have a control so we don't know how many the average person had. Right. But think of it, those centenarians each one of head five variants that will probably cause a disease. And none of them had that. And if you're asking, are those variants important? Well, we have two centumerians who have the Apple E4 homozygosity that puts them at major risk, one of the best genetic

risks for Alzheimer's. The textbook says they would be demented at 70 and dead at 80 and they are at 100 and not demented. Jeans for Parkinson's, for cancers, for other diseases. So basically, the centenarians don't have the perfect genome, which left us with finding genes that are protective. Right. That slows their aging, are protective even against genes that are thought at least as I'm saying it's probably not totally true, thought to most probably cause a disease. And tell me near approximately what year did you arrive at that

conclusion. This paper is more than 10 years old I think we had several papers since then confirming this and look like always there is a decrease also in bad genotypes in centenarians, some decrease, but really the majority of the study shows that it's not that, it's not the perfect genome, it's something else. So we've very easily eliminated hypothesis one, which is centenarians live to a hundred because of what they do, their behaviors, their environment. You now make a very compelling case that it's not number two either. It's not that they lack any disease driving genes. So it is, in fact, this third hypothesis. When did you actually demonstrate that? That's obviously a much harder one to demonstrate because you probably have a far smaller library

of disease-sparing variants, as opposed to disease-causing variants. So when did you start to arrive on what some of those variants were. The story was interesting because remember we started the study in 1998 and there are other parts of the studies that I didn't talk with you about, but one of the things we had is we start to establish the phenotype. And one of the phenotype that came up is high level of HDL cholesterol. Actually very high level of HDL cholesterol that actually very high level of HDL cholesterol, that was more obvious in the offspring of our centenarians, even than our centenarians. So we have offspring that have HDL cholesterol, 130, 140, falls higher than it should be. And what we could do when

the methods were poor and we were poor, we were going about genes that are involved in those phenotype. And we actually got a very compelling data on two genotypes that seems to be functional important, that are controlling lipid metabolism. One of them was a CTP genotype and one it was an APOC3 genotypes. And those genotypes increase from about 8 to 9 percent of the homozygosity in control to almost 20 percent in centenarians. And it's not only that, look, when you have people of all ages unrelated, you can look at the trend of the genotypes. If the genotype is killing you, then as you go closer to 80, 90 and above, those genotypes

will decrease. And if they are going up, and by the way, the slope that's going up is a very important statistical tool, then they are very likely to be longevity genotypes. And this is what we found and it's so interesting, it was our initial discovery and drug companies were at our doorsteps immediately, not because they're interested in aging, but they said just a minute. If we make a good drug, okay, the drug is really good. It targets exactly that with outside effects. Then we have safety because those guys for 100 years had in both cases, by the way, suppression

of the expression of those genes, it must be safe, so let's develop the drug. And isn't it amazing how big the graveyard is of C-Tep inhibitors? Yes, and I don't totally understand it. I listened to one of your podcasts. I forgot the name. Yeah, Tom Dasebring and I have discussed this in great detail. I think a lot of it comes down to not understanding the biology of HDL. I mean, the biology of LDL is relatively straightforward.

The biology of HDL, I think it's safe to say we don't understand at all. I mean, that would be putting it mildly. And I think the challenge with the C-TEP inhibitors is they raised HDL cholesterol. In one sense, they reproduced the phenotype in its most crude sense. But you can think of it very simplistically, I think, which is, how do you raise HDL cholesterol? Do you raise it by putting more cholesterol into HDL? Do you raise it by impairing HDL from conducting reverse cholesterol transport and getting rid of cholesterol? Those are two very different approaches to raising HDL. And when you look at the centenarians and examine their phenotype, you don't really know what it is. You would speculate that they have better HDL function.

But the reality of it is, we have other phenotypes that exist in nature. I'm not sure if you're aware of this, but I've seen a number of papers that examine people with HDL cholesterol that's very elevated, who have very advanced atherosclerosis. And in fact, the elevated level with HDL cholesterol that's very elevated, who have very advanced atherosclerosis. And in fact, the elevated level of HDL cholesterol they have suggests impaired HDL function and impaired reverse cholesterol transport. And so I think that's probably the issue around why a lot of these drugs have failed.

And it obviously speaks to the humility which all of us need to be able to examine these phenotypes. And it's a clever way to go about doing it. Very clever thing is look for phenotypes that are different and work backwards to find genotypes. Right, so let me add two points to the trade-offs of the Spatway are amazing. On one hand, you don't clear cholesterol on the other hand, you have high HDL. But for me,

it's not about the HDL because all the particle size are significantly bigger. So you could say it's all about high dense LDL, right? That's the phenotype that we're depicting. So I think this part is important. The other thing that was really striking, I told you about those two centenarians with Apple E4 genotypes. They both had very high HDL cholesterol and they were homozygos for CETP. So it is possible, in fact, the major phenotype for us of the HDL wasn't cardiovascular,

it was cognitive function. So when I'm saying cognitive function, maybe we're talking about physiology, we are thinking of this physiology from a heart perspective, and maybe there's a physiology of that from a brain perspective that we don't totally understand. And by the way, I did ask Merck. I said to Merck, do cognitive function, okay?

And they did, but the people they go to the study were between 50 and 70 years old, so there's no results for that. I know this up the top of your head, but even offline, I'd love to hear what you learned about the variance of clotho that those people had, especially the ones who were homozygous for APOE4. You're probably aware, but there are variants of clotho that seem to completely abrogate the effect of E4, meaning you take people with EpoE4 either hetero or homozygous, and if they have this particular variant of clotho,

they behave as though they are E3. This is so interesting. So we published on Clotto and Clotto was the example of what we call a V-shape or a U-shape genotype. Clotto basically seemed to kill 50% of our subjects by age 85. subjects by age 85, the genotype is disappeared by age 85. And all of a sudden, after that, at age 100, it was the same. And our interpretation was that those centenarians were born with clotos, but they were also born with longevity genes, which made the clot not significant. But another hypothesis is that the actual clotot that they had is a clotot that was protective in another mechanism. Yeah. So what about some of these other genes that have now come to light? So FOXO, for example, tell us a little bit about FOXO. How did you arrive at that? What was the phenotype that tipped you in that direction? Or did you arrive at Foxo through a pure genetic analysis?

Well, I didn't come up with Foxo. Foxo came out from Japan and Okinawa. I'm using you in the very liberal sense, near. I'm giving you and the field credit, yes. And me is not only me, right? It's a big team. And in fact, the research now has changed very much. The teams are really teams because you need to computational and AI people and the doctors and the physiology. So it's sweet. But let me start it differently.

Because why did I start centenarians? I started centenarians because all of a sudden, in the mid-90s it became apparent that you change just one gene in a nematode and they can leave 10 times longer. By the way the gene was bugging me because it's the insulin receptor, the IGF insulin receptor gene, and the nematodes were insulin resistant and they're also had abdominal obesity. They accumulated fat in their intestinal cell. It wasn't the right example, but the concept was right. And so I started the centenarians. I told you

about the first genes that I saw. And then I wrote a grant. Most of the grants that I wrote, the hypothesis ended up being wrong, though we found the right explanations mostly. There was one grant that I wrote, and I said, I'm writing this hypothesis knowing it's wrong, and that is that growth hormone IGF-singling pathway have anything to do with human longevity. I said, it's great, we have the nematodes, we have this and that, but this is wrong. And I was totally wrong about it. And I'm telling you the bottom line, 60% of our centenarians have genes that impairs growth hormone IGF singling pathway, including the Fox 3A. 60%. It's the most common genotype, it's not only genotypes by the way. It's microRNA, it's genotypes on the IGF receptor, it's the liations of the growth hormone receptor.

There's lots of ways to get to this, but this is very common. And sorry, just to double click on that a little bit near, I think it's worth maybe giving people a little bit of a primer on the relationship between growth hormone and IGF1. And if you want, we can talk about IGF BP3. Okay, so I said growth hormone IGF and I'll stand by picking those two, but for growth, there are actually hundreds of genes, okay? There are hundreds of genes. If you only look at what determines height, there's hundreds of genes that are determining heights. But the growth hormone is the growth hormone pathway, or the growth hormone singling pathway, that

really comes from the pituitary, controlled by the hypothalamus, but comes from the pituitary, and makes you grow when you need to grow. And it has its own actions, but also it has a specific action of binding to its receptor in liver and releasing the second important growth hormone with its called IGF1. It stands for Insulin Growth Factor 1. And so those are the hormones that we're talking about. The advantage of IGF1 is that it's measurable. Growth hormone is measurable in provocation and in young people and not much in old people. So IGF is kind of the biomarker for this action. IGF itself is really complicated because there are five actually I hear that there are seven binding proteins and there's a lot of regulation in between. But it's true to say that levels of IGF are really

very good biomarkers, even if you don't agree that they're causative for variety of health outcomes. And I want to say another thing that in nature, the dwarfs are doing better as far as longevity. The little dogs are doing better. The ponies are living longer. And in animals, everyone, no matter how you interfere, you're getting better longevity. Even the Laurent dwarfs that have deletion of the growth hormone receptor, we don't know if they live longer, but at least they have less age-related diseases, like cancer or diabetes. But they have more alcoholism and suicide,

and as you said, it's not clear that they live any longer. They just seem to be spared of some of the chronic diseases in exchange for others, correct? Right, I'm always describing it that they are still unhappy to be short. They drink, they cross the road, and nobody sees them when they're drunk, and they're being run over, right? It's not natural.

But let me tell you a much more optimistic story about that. We discovered, and when I say we, it's Gil at Smon who was a fellow and then a faculty with us, he's still involved is now in Israel, but we looked at all the pathway and we discovered that our centenarians have deletion of exome three in the growth hormone receptor. And Gil came to me and showed also the trend. Okay, and as I said, the trend is important. So the homozygosity was 3% in our population and 12% in centenarians. And I said, Gil, what's their IGF1 level?

And he showed me it's significantly lower. I said, terrific. What was their maximal height? And he said, that's the problem. And he shows me, they're significantly taller than the rest of the people, two, three inches taller. Wait, the people that were homozygos were taller than the controls?

Yes, significantly taller. And two to three inches is not subtle. What was the relative Z score difference between them in IGF? I don't remember. I'll get you the reference. It was like a 20% decrease. Okay. And what about their IGF binding proteins? There's nothing special there. No major difference. Okay.

No. But you're on the right track. So I said to Gille, what do you do with genetics? First of all, you need to do validation. The paper is not accepted to do it out. Validation. I said to Gil, what do you do with genetics? First of all, you need to do validation. The paper is not accepted to without validation. I said to validation. So Gil got three other studies from all over the world, actually. And all of them were showing the same thing. The oldest, old, false difference in their growth hormone in this deletion,

which was very compelling on its own. But still, why do they have lower IGF1? Sorry, just to be clear, they had lower growth hormone, they should have lower IGF1. You're saying, but they were taller. Why they were taller? Sorry, I meant why they were taller. Yes, yes. So, Hasiko and who's the dean of the Geontology School at USC and one of my collaborator is a growth hormone expert.

And he took the cells, and by the way, that's another thing that we have. We have the lymphoblasts of our centenarians. So if you have a genotype, you can actually look at its action with lymphoblasts. And he took this lymphoblasts and he incubated them with and without growth hormone. And something really interesting happened when they were not incubated with growth hormone. For relation of this receptor, the activity of this receptor was lower as we thought it would be because they have deletion of an exome. But when he incubated with growth hormone, it was almost like an amplifying switch.

They were phosphorylated three times as much. The same was with proliferation, proliferation was lower, and with growth hormone was increased. So what we understood that happened, although we don't understand this switch mechanism, but when they go through puberty, they are activating growth hormone. They're very sensitive. Yeah.

They're sensitive. They grow taller. And once their growth hormone decrease after puberty, they are tall, but their IGF stays low for the rest of their lives. Very interesting. What fraction of centenarians share this genotype? 12%. Okay. I want to talk more about the genotypes, and I want to come back to a question around this,

so hopefully I'll remember. So this is now another big major axis, is the genotype cluster around GH. We've already addressed the genotype cluster around C-TEP. Let's talk about FOXO, let's talk about TSHR, let's talk about some of the others. We recently published a paper because we didn't understand so well why the literature is so confusing us

with a growth hormone in IGF? We went to the UK Biobank, which has really changed our ability to validate and to learn and to get hypotheses. They have 440,000 people who have actually IGF-1 measurements. We looked at the young people that had high IGF1 level and we saw that for young people, high IGF1 was protective from variety of age-related diseases and from mortality, although not from cancer. Yeah, it was just about to say it's a very complex relationship. IGF seems to protect from everything, but cancer, right?

Right. Accepted by the way, I'll get to cancer in a second. On the other hand, people over the age of 60, it's exactly the opposite. They had more of every age related disease, except cancer. And they also had increase in mortality. Sorry, was that a linear relationship? Totally linear. It was, okay.

Totally linear relationship. What I'm describing to you is what we call the antagonistic playotrophy hypothesis of aging. The things that are good for you when you're young can turn against you when you're old. Or in this case, yeah, in order to do reproduction and to do evolution, you need a lot of growth hormone to get there. But after that, you have to switch the energy because now you're going to have breakdown. It doesn't make sense for you to expand growth in any way. And I think it was beautifully demonstrated and it also explained the confusion in the literature. It depends if you looked at young people

or old people or took care of that at all. One thing that's confusing about that pleotrophic relationship is that the cutoff is quite old. So if you really think about this just through kind of a dockens lens, you would think that that cutoff would be done by 25 or 30. But that point evolution is done with you.

You've served your purpose. Now anything that you get after that is gravy and really not under the purview of evolution. Evolution sort of stopped caring about you unless you buy the argument. And I think this is an argument that there's an evolutionary benefit to you being a caregiver beyond your reproductive capacity. So maybe there's something to be said for that, but are you surprised by how late in life we see that switch flip? Look, you made this argument. By the way, I would say, I believe in the grandparent theory, but still, if you had your kid and died the next year, the next day or survived for 100 more years,

I think it's too late for evolution. Number one, number two, one of the most interesting thing that we show and it's true around the world. People with longevity, with exceptional longevity, have less offspring. From an evolutionary point of view, you should be losing longevity genes. By the way, anybody with kids will immediately find that completely intuitive.

They just suck all the life out of you. Especially in COVID times. They're incredible. I love them more than anything, but I believe that they are indeed shortening my life on some level. I think there's ormesis. They'll come back and you'll be more resilient. But I actually wrote a paper saying people in the Old Testament are quoting Matusilla to be 969 and Moses to be 120. Maybe they were right. Maybe we had this capacity because we're losing longevity genes because of reproduction. It's really interesting. Has there ever been a

serious study about the biblical stories and if there's any way to assess any validity to some of the age-related claims that were made nearly 2,000 years ago? You know why it's problem because the orthodox people believe that every word in the Bible is true. You ask them and I ask many, believe me, I ask many. You think really that's happened? No, they didn't know how to count. They're very skeptical.

That's why I wrote the paper that I'm not skeptical. I think that's true. I want to ask you another question about growth hormone. It's a hormone that I've prescribed to patients when they're healing from injuries. So I've seen pretty good literature that says, you tear a bicep, you have surgery to repair it, growth hormone for eight weeks,

fosters rehabilitation, better than if you did nothing. So that's the very narrow window in which I've prescribed growth hormone is typically around the healing from orthopedic injuries. A couple of things I'll say, every patient I've prescribed it to, and there's hasn't been many, maybe half a dozen over the last 10 years, they all say, I've never felt better. Which then helps me understand why this cottage industry of doctors out there exists who run longevity clinics, prescribing growth hormone. I've drawn a hard line in the sand with my patients that I don't believe in the literature that would suggest that prescribing growth hormone is a pro long-jeivity tool, but if I'm being brutally honest, and I tell them this as well, I can't tell you that it's killing you either.

I can come up with theoretical arguments why prescribing growth hormone is going to make you feel better but is going to shorten your life, but I don't really see any data one way or the other. Even when you look at extreme cases, which are basically athletes who use growth hormone as the most abused drug in all of sports, because we don't have a test for it, you'd think that the morgue of athletes would be much bigger. What is your view on exogenous growth hormone as a not necessarily a pro longevity tool but as an agent that clearly helps health span but might be not as destructive to life span as I believe it could be.

I think you're absolutely right. Look, we're talking about I think you're absolutely right. Look, we're talking about chronic environment. And that has nothing to do with the fact that there could be indication for growth hormone. You mentioned one. There is a paper about growth hormone after strokes. We were actually interested in growth hormone in the brain. There are more examples like that. So I don't think those are mutually exclusive. Right. And I've often wondered, by the way, I haven't seen the literature. If you know of it, I'd love to see it. Would growth hormone be protective in stages of early cognitive decline? But anyway, putting that aside for a moment, what about this idea of the 50 year old who goes to the longevity clinic and they're being given low doses of growth hormone

every single day, typically it's somewhere between 0.4 and 1 milligram daily. I'm not going to answer you about the dose, but I'm going to make the thing that I think is very important and it's getting us back to this antagonistic pletography and it's relevant to tame and metaphor. It is possible that things that you're doing are good for you when you're young and against you when you're old. So when people are asked me on any of those geroprotectors, gerotherapeutics, vitamins, when do we start them? The answer is I really don't know. I think you shouldn't get synolytics before you're 70 or 80 years old. I think problem with forming, although we start the study at 65, most of the studies so far that

showed really large effect of metformin are people recruited above the age of 50, so I think it's 50. So I don't know to tell you for a singular patient who chronological age is 50 and biological age, I don't know what it is, you can determine it better. What do I tell them? I don't really know based on literature, based on clinical trials. So last question on this, near, based on the number of people that are taking growth hormone out there And I don't know how you would quantify this, but presumably it's not rocket science to figure it out But let's just say that there are hundreds of thousands of people in the United States alone who are taking

Growth hormone daily as part of a Giro protective regimen. Why aren't they all dying prematurely? Assuming that they're older. What we don't know. Well, that's true. We don't know it, but wouldn't we see a signal of it? I think not, because the people who are taking growth hormone are probably taking also mid-forming and exercising and doing other things. Yeah, so fair point. There's too many confounders. Yeah. I mean, again, my view is still and probably will remain for the foreseeable future that it is not a great, zero protective agent because I do have these concerns. But this is an example of something where I really wish we had data. So I want to tell

you another thing that also is a gray zone for me. Most of the negative effect of growth on an IGF in humans, we see in females, not in males, actually in animals too. So I'll describe two things. When we look at our centenarians, that's done by Sophia Milman, who's running the longevity studies now, and she measured IGF 1 in all our patients. And she looked at our centenarian, so they are already 100 years old, is IGF1 level predicts their longevity. And remember, centenarians are likely to die 30% of them are going to die each year. So those with the lowest half of IGF1, lived twice as long as those with the highest level of IGF1. And that's females only or both sexes?

That's females only. Okay. Males, the ratio of female male centenarians around the world, is there 85 females for every 15 men. We have better results because a lot of the female centenarians have never got married, none and other things, going back to your problem with your kids. But we need people with offspring, our studies based on offspring because the phenotype you capture in offspring and not in centenarians.

In centenarians, the phenotype is going down already. Those women also have better cognitive function, and as far as muscle function, it's not different. In other words, I think a lot of our problem when we come from sports, we're trying to preserve muscle. I'm not sure that low IGF is the best way to preserve muscle. I think maybe it's making the muscle biology better, but it's not making the muscle any better. Sorry, just to be clear, you're saying that the women in the bottom quartile, say, of IGF, are no more likely to be sarcopenic than the women with higher IGF, but they do tend to live longer. And smarter. They have better cognitive function. Right. With male, there is a trend, but it's not significant. So I think that if you have male, and that's my way out of

that, a lot of it is males that are taking it. I haven't convinced myself in my study that it's not a major sex differences, the sensitivity to growth hormone. Yeah, I'm just reflecting on the few patients in my practice who do take growth hormone. It is prescribed by other doctors. I've made it clear that I'm not thrilled about it, but they feel strongly about it and it's their choice. I think it's an equal, it's a very small number,

it's an equal mix of male and female. And which again, gets to a question that we are going to talk about today, which is health span, lifespan trade-offs. So let's continue down this path of double clicking on the centenarians and their bucket three genes. That is to say, their good genes, rather than their absence of bad genes,

are centenarians more likely to have Apo E2 than non-centenarians, which is the protective variant of that gene. That's the most common general longevity genotypes that we have. An apoe2, either an allele frequency or the homozygosity of apoe2, is the most validated longevity genotype that we have. First of all, it's the truth if you measure genotype. It was hard for me to accept it and it's only recently that I convinced myself.

And the reason is that apoe2 genotype is also associated with diseases too. It's not so simple. I thought for a long time that what we have actually, we have a problem, it's a statement by us that to our study, we don't get people with Apple E4 because they are demanded and they're not getting to our study or to any study, so that we increase the proportion of other genotypes. But what convinced me is that it should have been equally distributed between apple E2 and apple E3 and it's not.

It's really an apple E2 phenomenon. And so although I don't understand totally the mechanism, I'm convinced myself that there is something true in this and that apoe2 by mechanism that I don't totally get is a longevity genotype. Presumably, this is backtracking a little bit on something you said. I'm guessing centenarians have less LPA genotype.

So LPA genotype is really interesting. Remember, we talked about how we are losing clotos with age. Until we regain it, yeah. Right, we are losing a little LPA and regaining that. Now, what we've done with computational biologies, the system biologies, we interacted every one of those bad genotypes with the longevity genotype. And actually the centenarians with high LP little A, they're homozygous for the CTP genotype.

So they have some protection to counter it, and by the way, they might be getting some benefit from LP little A. There may be something that LP A, because you have to think, LP-A is common. It's about 10% of the population. So 10% of the population over-expresses this thing. 10% of the population has an elevated phenotype for LP-little-A. And it's true that evolution wasn't selecting against atherosclerosis,

but there are arguments to be made that LP Little A could have played a role in managing infections, for example, that this could have been a manner in which we fought oxidative stress. So it begs to at least question the idea, do the centenarians who have it get some benefit from it while having genes that offset some of its negatives. Yeah, but you have to explain on a population base how all of a sudden at age 85 you switch and this genotype becomes protective. Yeah, is that really necessary or is it just a denominator problem where at 85 you've really eliminated so much of the population that you're now concentrating

the people who were never harmed from it. In those people, they've never been harmed by the gene, and now they are disproportionately rising to the surface because the population around them has withered away so quickly. So those are the two explanations, either what you just said or that they're protected by other longevity gene and it makes it irrelevant what this LP delay doing. Although I don't think those are mutually exclusive, I think the latter is an explanation for the former. It's the amplifier of it. It's what lets them get there in the first place. Using C-TEP as an example, they happen to have a C-TEP mutation or a C-TEP variant that offers remarkable protection against atherosclerosis of which an interesting but kind of irrelevant phenotype is high HDL cholesterol, and that's offsetting the damage of their L-P-little A. And then eventually at some point when everybody else has died because of their L.P. L.A., they're still standing and they might even be getting some benefit from L.P.

L.A. that everybody gets, but in other people's cases, it's so dwarfed by the damage of L.P. L.A. Again, total hypothesis or speculation, but it's plausible. It is. Okay, tell me about T.S.H.R. I've never understood that one fully. So the thyroid story is interesting because we found a correlation between high TSH and longevity. As an endocrinologist near maybe give people the two-minute story on what TSH is and how it functions. Sure. My sisters are listening to you and I promised I'm going to be so simple. You won't need to call me again and ask me, what did you mean?

And now I'm falling into... I know, I'm doing a bad job of this. I'm sorry. So, TSH is really your control of thyroid function in the sense that if you become hypothyroid, then this TSH, this hormone from the pituitary will increase in order to get those thyroid hormones to be normal again. And they might fail and then you'll be hypothyroid, but there's an effort to get those thyroid after your glands.

Okay, so that's TSH. So when we see a high TSH in a normal person, we ask the first question, is there thyroid gland not making enough T4 and or converting enough of that T4 to the active hormone T3, which is the feedback loop that tells the pituitary how much TSH to make. So what you're saying is we see a higher amount of TSH in long live people. And their children. Yeah. So maybe suggesting a subclinical or potentially

a clinical degree of low thyroid function or hypothyroidism. Is that a safe summary? Correct. And I'll tell you our discovery has led to several papers and to change in the thyroid association recommendation of what to do with old people. You know, the endocrinologies of the thyroidologies are looking for business. So once the SH was above 10 and then they said, it might be subclinical at seven and we went to five and now if you're three and symptomatic which we are always because we're tired. So that's where the science came and we pointed out to the fact we did it in our study then we did it in a national study and we said you have to leave those older people because maybe this is a physiological way for them to be well. And tell me how high you're seeing the TSH. What is the difference when you age match

them between centenarians? It's like 5 to 8. Wow. So normal is like until 5. Yeah, or even 4.2 on our lab. Yeah. Yeah, and changing baseline. And look, the thyroid hormones themselves are normal. It's really only the TSH. So normal free T for normal free T3, but they walk around with the TSH of 5 to 8. Now here's the kicker, and this is where I'm hoping the offspring can help us. Do you know what their TSH would have been in their 30s and 40s? Would they have also had a TSH of 5, 6 or 7? Well, I think that's why we have the offspring and I don't have the answer for this yet, but that's why we have the offspring because we want to see the effects of those longevity gene as they get old and to see really what phenotype

and what measurements are changed throughout. I don't have the answer, but a lot of them do have high TSH when they're 60. So they're youth thyroid high TSH patients. Right. Right. What's the hypothesis for that? Is this simply a bio marker of something else that is unrelated to thyroid function? Or does it suggest that these people live right on the edge of hypothyroidism without actually becoming clinically symptomatic? And that there's something protective within running a lower RPM, running the engine a little bit lower, a little bit slower. So by the way, the growth hormone deficiency models are also hypothyroid. It might be part of the physiology of what we're seeing anyhow. Have you looked at prolactin in these people and other pituitary hormones that tend to move with TSH? We have prolactin. I'm not sure that we looked at TSH. This TSH paper came

years ago. I don't remember that we're doing anything. It's a good question. I have two endocrinologies that are looking at our data and analyzing it. I'll be happy to come again or have them talk more about the endocrinology of those people. But we're just looking and I don't have association with others, but the hypothesis was that their metabolism is maybe slow and although they're compensating by higher TSH, still their metabolism, you know, it's like insulin resistant. You don't totally normalize the glucose, although you have enough insulin for that, that there's a metabolic advantage.

I'm saying it like that because I don't know that it's true. I don't really think that our data supports low metabolism necessarily, but I do think as an endocrinologist that if an elderly person comes by incidental finding has TSH between 5 and 8, you don't have to go and treat it straight away. Has anyone done Mendelian randomization on any of these clusters of genes? Because we haven't really established a causal relationship here, have we? In these genes?

No, by the way, Peter, you just said another word that nobody knows. Okay, sorry. You want to explain him in delian randomization? Well, I don't want to go long into that, but because we have so much genetic data, and by the way, genetic data is disappointing because they're not so predictive most of them. You can find lots of genes for obesity and you'll be lean for lipids and you'll have normal lipids. But we have lots of genotype

and we try to integrate those genotypes in order to assess how much they're increasing the risk of us of getting a disease. And usually it's not by much. What we're trying to do, we're trying to have an instrument that will do Mendelian randomization to longevity, okay? So we can see what's your genotype that fits longevity more than anything else that's

in evolution now. But otherwise, look, I have to tell you, the reason this is not good is very simple. We're doing something so stupid in genetics. We do lots of genotypes and we take each one of these genotype and we ask, is this associated with obesity or diabetes or not? And we found many things and in order to make them statistic significance without increasing their power much we just need to get 100,000 more people in the study, okay? But we're not built with van Genotype at the time, we're built with numerous Genotypes. What we've started doing lately

and that's our latest nature paper was to say just a minute, we're looking at the difference between centenarians and people with outlawn Jeviti. And we're going to take all those rare genotypes, less than 1%, because to be centenarians, one out of 10,000, so we need to find rare genotypes. And by the way, there are 80,000 rare genotypes just in our population. Then we take those genotype and put them in pathways and look at the enrichment of the pathways rather with their specific genotype. And then we get really important information. And by the way, the important information that we got in the study in

Summary statement is that the genetics of longevity in humans is exactly what we learn from animals It the insulin singling pathway. It's the amtore singling pathway. It's the map kindness in pathway It's exactly the same genotype that distinct Centenarians and other people. And I think this is really very important for us because people have blamed us that our animal models, animals models are not good. Yeah, they're not good for diabetes, they're not good for Alzheimer, they're not good for other thing. But for aging actually, our models are really good because it's so conserving evolution. All our animals, their skin, their hair, their skeletal, their get cancers, they get diseases. So this is the same, but it's really

the same pathways. And the first that comes out is the IGF insulin signaling pathway. All of this really points towards the importance of polygenic risk scores. And when I talk to someone like Richard Isaacson, who is so focused on understanding Alzheimer's disease, and Richard and I work so closely on this, because it's obviously one of the most important things we think about in our practice. I think of the evolution that we have had in our thinking over the past five years. In fact, we're working on a paper now that's looking at this polygenic assessment of risk in dementia. You brought up earlier, ApoE4. Obviously, any listener to this podcast is no stranger to it.

We've spent so much time talking about it. One of the things that I would say is 10 years ago, we thought that being homozygous for E4, so being in that roughly 1% of the population that has two copies of the E4 gene, that was a death sentence, as you noted earlier, that's a person who's going to have Alzheimer's disease by 60 and they're going to be dead by 70. There's no way out of that. Their risk is deemed at about 20 fold that of the general population. And then five years ago, we looked at the data again and said, it's still awful, but it's not 20 times the risk of the E3, E3. It's 12 times the risk. Then we look at the data again

two years ago and you know, it's still bad, but it's maybe it's five times the risk. And now we are looking at patients who have E4, E4, not only do they not have Alzheimer's disease more importantly, they don't have any of the early signs of it based on really, really advanced cognitive testing that shows very subtle signs decades before. And we're starting to look at other genes that are abrogating some of the effects of this. And so now the focus has been less at looking at ApoE4 and making it a determination, and it's looking at E4 plus Tom40 plus mitochondrial haplotype plus cloth though plus a whole bunch of genes and taking a polygenic approach

to risk. It seems to me that this would be the most logical way to do the same thing with respect to longevity. I think this is true with cardiovascular disease. LPA is part of this story, but it's not the whole story, right? Absolutely right. You described the problem and the solution absolutely right. I would just tell you that looking for those longevity genes that we just published, 12 of them are associated, we're funded for that, but they are associated with resiliency to Alzheimer's. And I think that not enough of the genetics is explaining not only the genetics but the resiliency or looking at the genetics of resiliency, which is what we're calling longevity in this

case, but the resiliency to diseases, which happens to diseases that you get in young age too, not every genotype causes this disease. So I think you're right. Would you put Foxo in that category is kind of a general resilience gene that is less disease specific and more broadly protective? Yeah, I actually count Foxos 3a as in the insulin IGF signaling pathway. We can argue about it, but that's my bucket. What are the genes that you would put in the general resilience pathway, not necessarily a disease specific or system specific as in the endocrine system?

Well, I think we mentioned a lot of them now, but I think more important to realize that we have 750 centenarians in our study. Now they're all Ashkenazi Jews. Why is that? Not because religious is important, but because Ashkenazi Jews are a genetically homogeneous. They went through a bottleneck, an expansion, and then a bottleneck, and very few survived, and they lived in isolation and intermarriage, and their genetic pool is much more homogeneous. In fact, we can measure it.

It's genotype specific, but we need between 20 and 50 times less people in order to get the same data. So think about it that not 750, but few thousands, but it's still not enough to find all longevity genes. And one of the things that we realize is that there are 50 ways to live your lover. There are 50 ways probably to get to longevity. It's possible there's only one person who's 150 years old somewhere and if we knew his genotype, he will solve the problem for anyone. And the genotypes we are discovering are things like that.

We have 20 genotypes in centenarians and one in control. But those for geneticists who are dealing with 400,000 people in study, they say, well, in 750 centenarians, this can change any minute. So what can we do? Well, what we can do is look at the function of those genotypes. And you know our friend, Yushin Su, that's what she's doing with our studies. She takes those discoveries and either takes the lymphoblast of our patient or she does construct and express those genes in cells and see how resilient they are to injury.

So, there are a lot of genes and I think the biggest news for me now is that American Federation of Aging Research has gotten contribution from a single guy at $2.8 million to recruit guy at $2.8 million to recruit 10,000 centenarians across the United States and their offspring and control. And I think that this will give us such an acceleration of understanding longevity and such an acceleration of getting drugs that probably are likely to work and also things that we don't know yet, like who knows, some of the things that we discovered are in pathways that we're not in our longevity lexicon. Near, that's interesting. Only $2.8 million is required to recruit 10,000 centenarians

plus their offspring's plus appropriate controls. Well, let's see. Let's see where we get. That seems like a very high ROI for that donor. Well, we hired two companies who have approaches and actually there's a preliminary study to see what's the best way to approach these people, because it's all going to be basically web-based, so we need their children and grandchildren, and we're going to send them a swab so that they can do it with help and we'll get the swab, at least on the first pass, and be able to rapidly do the genetics and post it, by the way, just immediately post it so people can start looking at it and making sense of the data.

And you're going to do whole genome sequence or exome. Both. We're going to do mainly exome sequencing and maybe switch as the whole genome sequencing price comes down, which it does rapidly. What's the current price of whole exome? I don't totally remember that. The reason I don't remember is that our genotypes was done by Regenerone, and they paid for that.

So I don't remember how much it is now. So let's talk about a thought experiment. You mentioned something earlier, which is what made me think of this. You said there's somebody out there maybe who's gonna be 150 years old, one person that will concentrate all of these genes in perfection and they'll get to be 150. And if we could look at that person's genes,

we might have an answer, I would push back and say, or not, it might be that we're discounting the stochastic nature of this. And even if you found that 150 year old person, and even if you identified which genes played a role, the likelihood that you'll identify which environmental factors turned on those genes or amplified some and attenuated others,

seems very low. It begs this thought experiment, right? If you took 10,000 identical people with whatever program you have of the perfect genotype. So this is 10,000 people that have as many of the good genes as possible and as none of the bad genes, we put them in a time capsule and we let them live their lives, but now we randomize them to I'm making this up, but three groups. One group is the base case. Go and live a normal life. One group is the do everything bad that you possibly can. So I want you to start smoking when you're 15. I want you drinking three drinks a day, never exercise.

You're only allowed to eat it McDonald's. And then the third group becomes the do everything right. We do the opposite. Give me your prediction of how long each of those three groups lives. So Peter, I was trying to do things simple and you complicates me again. And I'm taking back

First of all when I said 150 I think the maximal of human lifespan as a species for us is about 150 years Even if we argue even if there's one 22 somewhere and we die before the age of 80 So we're talking about 35 years that we can realize it's a lot of years we should realize that but I think aging will improve by other methods and mechanism that can break eventually this 115 years and maybe get us to 150. When people are asking when will we leave 150? I said, oh, in 150 years, because even if we start the experiment now, it'll take 150 years to get there, right? We wouldn't know. I'll tell you what I'm getting out in the experiment. I want to understand how in the perfect genetic makeup, how much can environment hurt or better? What is already a genetic lottery?

I totally understand and I would take you back to and I meant to ask you that when you described that Apple E4 was a 24-risk and became smaller and smaller, well became smaller at whom and how their lives were different than those that we knew 20 and 40 years ago that have the upper E4 genotype. Yes, it gets back to the point you raised about your grandfather versus your father versus you. Right. The environment, both in what we do, both in medical treatment and surgery and all those things. Absolutely. And so you're right. We think that there are master switch to longevity and some of them we're doing with exercise and food. So you don't really have a sense of how much longer group three could live than the group one when you basically put amazing genes in everybody. Yeah, I, you know, it's not the things that I'm doing predictions on.

No, it's interesting to me because it where I'm really going at a macro level is most people don't have these genes. So the only interesting question is the contrapositive of that, which is once you have a sense of what that could be now for the rest of us, the 9,999 of us who don't have centenarian genes, how much does environment make a difference? I know the answer is significant, but I'm curious as to how much you think it is. For me, some centenarians are coming to me and said, okay, what can you do for me? And I'm like, you're eat. I don't do anything for you.

So for me, the question, if those centenarians are willing and I'm starting to exercise them and to change their diet, am I going to kill them or help them? That's how I'm thinking about it. And I don't know the answer. Fair enough. So Thomas Pearls has written quite a bit about this idea of dividing centenarians into buckets. I think we have the escapers, the delayers, and the survivors. Are you familiar with that terminology?

Yeah, yeah, of course. I'll tell you two things about it. First of all, Tom Pearls and Paolo Sebastiani are, did terrific job and we're collaborating a lot and they've been great and I don't hear Tom talking about it because this is the point average life expectancy is 80 some people are going to be 81 80 to 83 It's not that 100 years old is any special you're picking at one time People who actually aged before or will age later. And what we've done together to kind of overcome that and that's very important thing. We looked at our data in

both studies and harmonized them and asked what is the health span of centenarians versus by the way cohort that lives now. It's not their cohort, their cohort died before. And the answer is that it's not only that they live long, they get a variety of age-related disease 20-30 years later. There are control groups between 60 and 80, accumulate lots of diseases, and 80-only 10% of them don't have a disease. In our centimarians, after the age of 130% don't have a disease in our centimarians after the age of 130% don't have a disease and are not treated with anything.

But there's a 20-30 years of health spend. This is not really the important part. The important part that the end of their life, they get sick and die. Some of them don't wake up in the morning. But they have such a compression of morbidity. They are sick for months at the end of their life, unlike us that are sick for years at the end of our lives. And I think this is really the boundary. So first of all, there's an example of humans that can live healthy and long and have contraction

of morbidity. And for me, it really says it's not that they didn't get older. Of course, they got older, but they had great life. They have great health. And at some point, they're checking out much quicker without diseases at the end of their lives. And this is what we're trying to imitate. Completely agree, although I'll throw a wrinkle into it near, which is, could it be that the average person has their first heart attack at 70, languishes with congestive heart failure for five years and dies at 75? The Centenary has their first heart attack at 101, and they die six months later.

Could it be that the reason that the first guy languished for five years is he really technically had more resilience given that he was 25 years younger. And if so, you can now do a very grim thought experiment, which is we could easily replicate the contraction of morbidity in non-sentinarians with a rule that says the moment you get a disease, you get a pillow over the head. The moment you get your first heart attack, we're not going to cath you, we're going to kill you. Right? A thought experiment, please, let's be clear.

But you would immediately square everybody's longevity curve for the most part. You would contract that period of morbidity to replicate that of the centenarians, but you would dramatically truncate lifespan as well now. And now you would even widen the gap between the non-centenarian and the centenarian. So in my mind, it's very difficult to disentangle the objective for someone like me, which is, I do want to lengthen lifespan. I do want to delay the onset of chronic disease, and I want to compress the period of morbidity not by having you die quicker, but by having you live better longer. If that makes sense.

It absolutely makes sense, Peter. And, of course, your point is very important, but it's like the podcast last week on the COVID. You had scientists and the advocates. Which by the way, our mutual friend David Allyson, he was really the one who I think made me first realize. We need to talk about these two things totally separately. Absolutely true. And what you did, you really stopped me from being advocate because you're absolutely right. I think that the reason that centenarians are dying so fast is because they're already frail. They

are aging and so they are less resilient. But on the other hand, without diseases, I mean, some of them are working as hedge fund managers until 107. Some of them are painting. As long as they have no pain and mobility, their life is good, not like when they were 20, but their life is good. So I totally agree, but as an advocate, I wanted to hide that, Peter, I didn't want to. But you're right, why they're dying. But you know what? I think it's still important for people, and I think this concept is probably true. If you prevent aging and age-related disease, you're going to compress morbidity too. One of the biggest challenges I have with health span is I don't think that we have great ways of describing this in medicine.

I think there's several issues with it. The first is our definitions, I think, are not wonderful. We talk about freedom from disability and disease, but that doesn't really with it. The first is our definitions, I think, are not wonderful. We talk about freedom from disability and disease, but that doesn't really capture it. I can tell you a lot of people who don't qualify for having disability or disease, but their health span is still poor. And by the way, this completely excludes a very important element of health span, which I think is emotional health. So let's put that aside, because it's not particularly the age dependent,

and it's outside of the purview what we're talking about today. But if you just limit it to physical and cognitive, in fact, if you just limit it to physical, you can have people who can still carry on activities of daily living, but one of them has a VO2 max of 50 mills per minute per gig,

and the other is 30 mills per minute per gig. By the way, neither of those people would ever qualify as disabled, because whether you're at 30 or 50 in VO2 max, you can still do any activity of daily living. But one of those people can clearly get more out of life. You can take someone who has the grip strength to hang on to a bar for 30 seconds, versus hang on to a bar for 30 seconds versus hang on to a bar for two minutes. Both of those people will see no immediate difference in their day-to-day activities, but one person can do far more should they choose to.

One person can sit on the floor for half an hour and play with kids and feel nothing. Another person, their back will ache for the rest of the day. Neither of those people are debilitated or disabled, and therefore, by traditional health span metrics, they're both equal, but they're nowhere near equal. So that's problem one that I have with the way we, as a community talk about health span. The second thing is, nothing that you or I learned

in our medical training, even remotely prepares us for how to help people be truly stronger, late in life. It just wasn't part of our training. There's nothing about that. So I guess my point here is it's hard for me to really interpret the data and get at something I'm very interested in, which is do centenarians truly have better health span or are they just dying later and for the most part they have this period of compressed morbidity so it looks like they have better health span. But do we really know that I mean I think they do based on the literature, like I think

a 90-year-old who will become a centenarian is functioning more like a 70-year-old who will not, but it's still very difficult to quantify. I don't think we have great metrics here. Do you disagree with me? No, I don't think that health spin is well-defined, definitely. So there are two comments that I will make. For the NIH, back to 10. For them, what is aging is if we can prevent diseases.

That's their measurements, which is not satisfying, not to geratrician and not to physician. But that's how you get drug approved. For the economist, there are two issues. One is what we're counting as the medical cost of the last two years of life. By the way, in Centenarians, the CDCS data, in Centenarians, that last two years life are third the cost in 100 years old and when you die in 70. Of that is fascinating. I mean, to me, that is something that speaks to what we're really aspiring to. And actually, that statistic captures much more

about the quality of a person's life. Right, but Andrew Scott had a paper in nature. I think I sent you guys, right? I read it. Yes, you sent it to me, yep. He describes an economical term that's called the value. And by the way, it's very hard. If you want to know more about this paper, we should talk. I had to sit with him in order to understand what he was saying, but basically

saying, Hey, if you increase the health spend of someone, it's not only medical cost because this guy is going to travel and spend money traveling and buy gadgets and buy houses for his kids. Their value of the person life is going to be increased. And some of those people, by the way, are going to still work. They're not just playing golf. Right. So the economical value is huge. So you can do it economically. And the third thing I wanted to tell you is this story. The real story about economically. And the third thing I wanted to tell you is this story. The real story about this 102 year old guy that I met and I'm sitting and talking with him and he's the nicest guy I've ever met. He's so considerate, he's thinking about life in such a nice way,

nothing bad about his daughter-in-law, right? And so I'm spending time with him, I'm going out of the room and I'm bumping into his son, who's 80 years old. And I'm telling this 80 years old, what I'm telling you, you know, your father is just the nicest guy I've ever met. So he looks in my eyes and says, you should have seen the son of a bitch when he was my age. He was a terrible, terrible person. So then I realized, and you'll see why it's connected to what you just told me, then I realized that because we wrote paper about the personality of centenarians and you have to be positive and stuff like that, but apparently he became positive only when he was under the years. Not when he was 80 years old. And then you see papers like in University of Pennsylvania, they took two groups of people, young and old people and show them bed slides, cockroaches in pizza

and good slides like islands in the Caribbean. And they asked them to repeat what they've seen. And the young people knew, remember the lot from both bed and good. The old people remember less but mainly the good things. So I'm waiting for this part in my physiology that I remember. Only the good thing. But what I'm telling you is that think of the complexity now because your brain age, you also retired, you lost your spouse, you moved from independence or you moved to somewhere else, you moved several times,

you get to 100 years old. So apparently, there's changes not only in your environment, but in your physiology where life can still look good to you. Is this wrong? Actually, that's such an interesting point near. I know you mentioned already that a number of the centenarians in your cohort were not married. What fraction were married? No, my centenarians have to have offspring. Okay, so all of them, at least at a partner,

at least married for a while. Okay, and then what fraction of them have lost their spouse? Most of them. And sorry, one other question here. What fraction of them have also lost children? Also a lot of them. This gets to something very interesting. Someone asked me once at a dinner party, if you could wave a magic wand, how long would you want to live?

And I said, not that long, truthfully, because unless I could wave that magic wand for the people around me, I think it would be an awful life. Could you imagine if I waved a wand and said, near, you have immortality. And not just immortality, I'm going to let you preserve your quality of life today. So as smart and healthy and able as you are now, I'm going to let you do this for the next 500 years. I would view that as an awful curse. You'd have to watch your wife die, you'd have to watch your children die, your grandchildren die. Sure, you could remarry and do it all over again, but then they're going to die. That's a silly thought experiment, but I also think it gets to something I've

never really considered with respect to actual centenarians, which is the price of being a centenarian is giving up and losing most of your friends. And how many funerals do you go to? The most common thing that centenarian tells me, the thing that underlined their age is when the children of their friends were long gone. The children of their friends started to die. That's for them kind of what's going on. We're losing now the second generation. What's coming next? You're absolutely right. I'm thinking about it for immortalists. So immortalists, they have 12 billion years. We don't know, but one of the estimates, 12 billion years for this planet. I'm a little tired from some of the shit now. Really 12 billion years, January 6th, wars and stuff. It's true, but what I try to tell you in

a different words is that those centenarians have been adapting not only because what got them to be centenarians, but because of physiology of aging that allowed them to harbor and maybe to put in compartments lots of their stuff. Yeah, lots of grief. And it's not that you come to centenarians and they want to tell you first of all about the spouse that they lost.

That's not how they are talking to you. They're talking to you about where they went and what they do and they're going to concert and their grandchild is coming to visit them. At least the Centenarians in my study. So it's not all Centenarians in the world. Look, I think living to a hundred with preserved health span would be a wonderful thing. And even if it meant you lost a spouse, a child, it means you probably have three generations of people. You know, one of the questions I love asking my patients is how many of your great-grandparents

can you name? So we all have eight great-grandparents, and I say, tell me the names of them. I've only had one patient who could tell me two of them. Most people can't tell me a thing about one. I can't. I didn't even meet two of my grandparents. They died so young. So if you think about that for a moment and the reason I ask my patients this by the way has nothing to do with living longer, it's more about living better. It's basically, it's a way to remind everyone, myself included, that we're not that important.

Like, my point being is my great-grandchildren will never know who I am. Maybe in the age where they have video, they'll see a video of me or something, but like, I'm not going to be an important part of their life. Meaning, the only people who I matter to are very narrow and close to me now. So So let's not lose sight of that. But these centenarians have a gift which is their great-grandchildren will know them and When you use this example when you can go to concerts with your great-grandchildren That's amazing when you could take a vacation with your great-grandchild And you're not only able to give them money for college, but you go to their graduation? Think about the implication of how much of their life you've been a part of. So the flip side of everything I just said is, I've never really met somebody who's

dying at the age of 75, and that's a phenotype I've seen an awful lot in my training, who didn't wish to have another year of life if it could be had at a higher quality. Which now brings this whole discussion full circle. 9,999 out of 10,000 of us will not live to 100, directionally speaking. But if we want to live an extra year, or five years, what is the most important lesson we can take away from the centenarian that we can actually do something about. So, first, I want to start with what you mentioned before, one of my darkest day in research, when Jay Leno in the tonight show said, there's those people at Einstein and they said, the secret for longevity is don't exercise, don't, you know, be obese.

And you know what he said, if you die, you don't care anyhow. And that was the wrong lesson from the Centenary and Study. If you're going to be Centenary and maybe it's not important, by the way, it could be important for Centenarians. I mean, this woman that I have that smoked for 90 years and died at 110, I just wonder, wouldn't she be the next Madame Clement without smoking? So, the lesson for most of us is still exercise and nutrition, whatever it means to everyone and everything else that you give. That's the lesson and it's not the lesson from

centenarians. The lesson from centenarians is that there are longevity genes that could be translated into drugs, and I believe that they could afford years of health spend, however we want to define that. And that's really what I'm trying to say that is not an emotional part, but a clinical part. Would you agree with my takeaway from this cohort? Because the single most important lesson I glean from everything we've said, in addition to lots that we haven't said that you and I have talked about elsewhere or that my own work has pointed me to based on my study of this problem. Their superpower is simply delaying the onset of bad things. Bad things just happen to them 20 to 25 years later. It's not that

they don't get heart attacks. They just don't get them when they're 65. It's not that they don't get cancer. They just don't get it when they're 60. It's not that they don't even get dementia. They just don't get it when they're 75. And the last time I looked at the distribution of death for centenarians, it was shockingly similar to that of non-centenarians with a couple of differences. They tended to have a little more atherosclerosis, a little more heart attacks, a little less Alzheimer's disease, and I think a little bit more pneumonia. But directionally, they had the same actuarial table of death as people dying in their

80s. It was just a time shift. In fact, I reviewed the paper from Germany where they looked at pathology. It's a pathological. They looked at thousand centenarians that over the years died in their homes. And they're right, because in the hospitals, we kill them in other ways. So, they're hiding their homes and they're right because in the hospitals we kill them in other ways, right? So, I think their homes versus thousands, I'm not sure about the numbers of other people that died at their homes. Basically the paper was funny because the title was like there's nothing special about the centenarians. They're dying for the same thing. But 30 years later, okay? They missed the point. It was like a negative study, but you're right.

They're kind of dying from the same thing much later on. So, you can look at it about what you said, the resiliency that go to them there, the resiliency for anything that detect them to get them there, or the fact that their aging was slow. And so, what's the takeaway for us? To me, the takeaway for us, as physicians or people who want to have an extra five years of life, or 10 years of life, even if we can't have an extra 20, is nothing matters more than prevention of chronic disease.

And by the way, you don't get to prevent it once you have your heart attack. Secondary prevention is not prevention. We're talking ultra ultra ultra primary prevention. And if health span is something that the medical system hasn't been poised to teach, ultra primary prevention is also something that we haven't really been prepared to teach. So let's pivot to another topic that we visited last time, but I think so much has happened in the interim, which is metformin. I probably get an equal number of questions near about the following three things. So the frequency of this would be several times a week. A patient or a friend is asking me about metformin,

rapamycin, or some combination of NR, NAD, or NMN. Somehow those three things seem to rise to the level of everybody's curiosity when it comes to zero protection. Let's talk a little bit about all of them, but let's focus on Metformin. So for folks coming to this who have heard of Metformin, because I think at this point, many people have, but don't know much more than that, can you give a brief background of what Metformin is, how long it's been around, what it's historically been used for, and of course, we'll talk a little bit more about why we're going to talk about it.

Oh, so boring. I also get those questions. What's the distribution, by the way, what do you mostly get asked about while we're on that subject? So, the most common question is, I hear you're doing a bit of a form in study. Can I volunteer? Can you assure me I'm not on placebo? Yeah, it's just about to say. You sure you want to volunteer? Okay. Yeah. By the way, I'll tell you something really interesting because I'm leading this study. I'm not pushing me to form. Again, the difference between advocate and scientist. I'm doing this study. Okay, I believe in that, but I'm doing this

study. So I cannot tell you that it's good. So I'm not this study, okay, I believe in that, but I'm doing this study, so I can not tell you that it's good. So I'm not going to prescribe to anyone, even to my friends, I'm not going to prescribe. But I have a method that works 100% of the time. There are two papers that I wrote, one I think in 2016, about 16 about metformin and tame and the clinical data and one in 2020 about actually the mechanisms of action that was in both of them were in cell metabolism, but the mechanism of action the fact that metformin actually hits all the hallmarks of aging miraculously. I'll explain it later. And I'm saying to those people, send it to your doctors and say ask the doctor what do you

think about me taking metforme and there are one of two things that always happen one could be that the doctors reads the paper and said oh shit I should be on metforme myself of course I'll give me a medforming or the other is the doctor said, unbizzy, but you know, mid-forming is a safe drug and stuff. Let me just give them a mid-forming and that's the end of that. And that's 100% success. Everybody can get mid-forming.

Now I know that I'll get emails asking for those papers. I'll put it in your box. We will absolutely link to those papers in the show notes, yeah. But I think what people don't realize is that metforminism extracts of the French lileg. Some people say it's nutraceutical. It is modified and it is a drug. The three best drugs in the world are nutraceuticals. Rapamycin, statins, metformin. There you go. Right, but you need prescriptions.

But also, look, one of the modification was fenforming. It's an early form of mitforming that kind of was little too potent. Too potent on the mitochondria and cost the trouble, but we're over that for 80 years. But mitforming was used initially to treat the flu and malaria and inflammatory diseases. And it's at that time that people noticed that people with type 2 diabetes have lower glucose when they took them at forming. So the whole metformin moved to diabetes. And that was about the 1950s or 60s, interestingly, in the United States it was approved only in 1993 or so. I came as a fellow to Ralph DeFronso at Yale and my mission was to describe the mechanisms of action of metformin in humans. I did insulin clamps and I'm the first to describe that metformin decreased the patex loose production rather than increase insulin sensitivity. In the periphery,

it's serendipitous. I didn't think about it as aging. I came to Ralph DeFroncen. I did aging in another way to insulin resistant and aging, but not metformin. But point is, there are billions, billions years of use. Remember, every patient takes it for years, and there are people on metforming who are 90 years old. I actually know them. So, there are billions years of use of here, and I cannot think of a drug with better safety record. If there are any side effects to metforming, they happen usually in the first week of use, and that's even if you didn't take them the way you should, which is small doses with food. And when I say with food after the first bite, when your stomach is full.

And then usually there is no side effects, but 3 to 5% of people and maybe more with elderly have diarrhea that doesn't stop and we basically stop metformin in those people to stop diarrhea. By the way, in tame study, we're going to follow those patients that were sensitive to metformin and see if there's something unique about them. That's one of the things we hope to do. Well, we're definitely going to talk about tame. So let's pick up the story 10 years ago. All of a sudden, people start to notice things. People start to notice that diabetics who take metformin when compared to diabetics who don't take metformin do better. And when I say do better, I mean they have lower mortality from all causes and

lower mortality from very specific causes. And if you look at it in some extremes, if you compare the patients taking metformin to the patients taking insulin, the difference could be 50, 80% difference in mortality. Is that a fair assessment of where curiosity began to peak that this wasn't just a good diabetes drug, but it might have some protection against aging? Yes, absolutely. We should just know that's the base of gerotherapeutic. It has to be a drug that has effect beyond its disease. Whether it's on other diseases, whether it's on overall mortality, not a disease-specific mortality, that's when you have to think this drug

is a gerotherapeutics, and that's exactly where metforming fell. I would just add one thing, look, some of those studies are association studies, but some of the studies were clinical studies. The diabetes prevention program, the DPP, is an NIH funded study where metformin was one arm, there was also an arm of lifestyle changes. Both of them were preventing diabetes in about 30%. And by the way, the study was stopped early because it was significant

after four years, although the study was funded for five years. Now, I do want to talk about that study near. And some of this, of course, you and I have already talked about, but I think it's just good for people to be able to hear our discussions on this. One of the challenges of these studies, and I think this is frankly true of every single study I've looked at for metformin, is when you squint your eye at the study, there's always a problem. And in the case of the DPP, the problem is,

the patients in the metformin arm could easily fall out of that arm and therefore not be counted. So if they progressed to a need for medication beyond metformin, or if they couldn't tolerate metformin, or if they were not medication beyond metformin, or if they couldn't tolerate metformin, or if they were not compliant with metformin, they were no longer counted. And this is true, not just of the DPP, but of course, when you compare the metformin patients to the other patients who are taking other diabetes drugs, you always have this potential

confounder, which is you are disproportionately selecting the healthiest people, which are the people who A, can be compliant with medications, which might say much more about their behaviors outside of medications, whose diabetes is maybe just mild enough that it's always kept at bay with metformin,

never requiring other medications including insulin. So am I correct in saying we don't to date and tame we will talk about in a moment, but we don't to date have any clean example of a study that demonstrate metformin's zero protection in humans. First of all, you're right. You can say it on many studies, but it's certainly true with diabetes. Diabetes is a problem because it's a progressive disease, no matter what. And you can go back to the data and show whether the people were

met forming from the beginning versus other have done better and whether it stops. And there's a lot of things. But first of all, you're right. You're also right about, we had this discussion about the mortality data. And you pointed out that maybe the control, we're not controlled enough for getting them out for some reason. You watch them all the time. You're absolutely right. even the clinical studies are not perfect studies. But they are still enough of clinical studies or small studies that gives you the confidence. For example, there are two studies on people with mild cognitive impairment that were treated with metformin 1 for half a year and 1 for one year and some of the outcomes have changed.

And there is no different in how they were treated. In other words, they didn't have diabetes, so it's not that they switched to other medication. So there are lots of examples like that, but you are right, if this was compelling on its own, you could argue we wouldn't have to have tame even. And really, tame is not that there are not studies for each one of the diseases, but there is no studies to be agnostic of the diseases. We don't care, look, we're targeting aging, we don't care what disease you have, and we don't care which disease you're going to get. If you're obese and your mother's diabetes, you're going to get diabetic necks. We have to think in neuroscience that aging is going to drive

your next disease and therefore it's the cluster that is going to come and we're counting the clusters. By the way, we had this discussion about mortality. Mortality, you get a point for mortality just like you get a point for a disease. The important thing of the cluster is that we cannot do tame study. Imagine we do a tame study. And in two years, cardiovascular disease comes up as significant. as in significant reduction of cardiovascular mortality. Yeah. And the FDA will say, Hey, we have to stop the study because we cannot go with the study when with placebo and it will ruin it for us. So the whole problem of the statistics of tame is to make sure that we're not getting to any significant in any disease, just to

trans. By the way, the one way to stop the study is if mortality is significant. That will trigger a stoppage of this study. Otherwise, what will stop the study is the integral approach of the cluster of disease. So statistically, your biggest mistake here is overpowering the study for mortality and therefore appropriately powering the study for subsets of mortality. Yes. Substance of mortality, you mean diseases. Disease-specific mortality is what I mean, yes. Yeah. Well, let's talk a little bit about tame. This is something you and I spoke about God, two years ago. So this is a study that is going to look at people

who do not have type two diabetes. Right, it's an exclusion criteria. And they are over the age of 65. 65 to 79. Okay, so 65 to 79, no type two diabetes, any other exclusion criteria? Yes, but it's not important for our discussion. So if you have cancer in the last year,

things like that, you know, very specific. Yeah, okay. But again, these people are gonna be taking statins, they're gonna be taking medication for blood pressure, some of them will be overweight, some of them will be normal weight, presumably. Right, the point them will be overweight, some of them will be normal weight, presumably. Right. The point here though is that look, we don't want to recruit a bunch of centenarians to

be in our study. Yeah. You don't want to recruit future centenarians here. You're not going to get an answer. So they have to have something. For example, walking speed less than 6 meter per second is an inclusion criteria. You have to have something that shows you age. I see, so you don't want exceptionally fit people in this group.

Right. You know, it's almost like you want to take the patient population that Predamed started with because this was a primary prevention study for cardiovascular disease that found a statistical significant difference in under five years. I think it was four and a half years. They expected to go for seven. You're really looking for that type of population. You really do want people who are gonna, I mean, it's morbid to say this,

but you're looking for people who's risk of death in the next five years is high enough that you're gonna move the needle. Now, the risk of that is you get a negative study, which means there is no difference in all-cause mortality, or even disease-specific mortality. And the counter argument might be you started too late. That's like applying the brakes on a car that's driving towards a cliff when it's only 20 feet from the cliff. Should this be a longer study where you start this at people when they're 50,

and your five-year mortality expectation is very low Again, I'm not saying this can be done because that's a very expensive study, but it is a risk here correct There are two arguments here. First of all, we needed to do Look to start a study at 50 where you have to show mortality is a 20-year study we cannot afford it So we needed to start it when people are starting to accumulate disease in order for us to have lots of events. Our hypothesis is that the aging part of your biology

doesn't stop working when you had your first disease. It's still going to get your next disease. If we think biologically like that, we should be able to intervene as we do with animals quite late also. That's one thing. The second thing is there are metformin studies which included elderly people. For example, the DPP, the DPP by the way, got 20% funding from the NIA in order to include 20% of the subjects over the age of 65, which they didn't. They had 20% over the age of 60, but there are still people over the age of 65, and their results were similar in prevention diabetes to younger

people. It's an example, but we have several other studies that tells us that metformin will still target aging, even if you started it. It's not that the first disease canceled. Yeah, it just means that you have a lower period to apply the brakes on, and it suggests that if tame shows a reduction in all-cause mortality in a subset of people so old

in quotes, when I say so old meaning in five years is really what I'm saying. It would suggest biologically that there would be a benefit to starting sooner, but of course then the question goes back to our original discussion how soon? So Peter, you said an endpoint of mortality in tame. There could be only trend of mortality in time. There could be only trend of mortality. So I'm sorry, I misunderstood. What is the primary outcome of pain? It's the cluster of bunch of cardiovascular, cancer, cognitive, and mortality.

It's the cluster. You get one point for each one. I see. So let's define them again. So you get one point if each one. I see. So let's define them again. So you get one point if you die. Right. You get one point if you have a major adverse cardiac event. One point if you have a cancer occurrence or recurrence,

except skin cancer, right? Okay. An MCI or dementia. Got it. Do you have any points for health span outcomes such as frailty, falling, breaking hips? This is in the 70 million program. for health span outcomes such as frailty, falling, breaking hips. This is in the 70 million program. Let me explain.

We would like to start longitudinal study where we capture a lot of the other health spend issues, hospitalization and function and depression and all that. We are still powered to do it at the end of the study or as the study goes on. We probably wouldn't have money to do it longitudinally through the whole study, but we have power at the end of the study to see if there are difference in frailty, etc. Just a statistical question, why is mortality given equal weighting to disease occurrence? Is there a reason that mortality wouldn't be three points to one point for MCI, Mace, and cancer? Well, it was questioned for each one of them, and we decided just that we cannot rationalize that.

Everyone is an outcome. We basically said, those are the outcomes. We don't know which one you're going. You're going to get an outcome. You're going to get the point for that. By the way, it's the time until, of course, you're moving health spend. Now earlier you spoke about how animal models are not really great for Alzheimer's disease, cancer, and cardiovascular disease, which I think any listener of this podcast is well aware of those limitations. But you note that, look, animal models are pretty darn good for aging given how conserved it is. And yet, one of the challenges Metformin has had

is in animal models. Now, Rich Miller was on this podcast a while ago. We spoke about the ITPP where Metformin was successful in the ITP when combined with rapamycin, but alone was not. Again, I think the ITP is a very rigorous type of experiment. I know you've probably thought a lot about this. What explanation do you think exists for why Metformin

did not succeed in isolation in the ITP study, which I'll just take for a moment to explain to people the ITP. If you haven't listened to that podcast with Rich Miller, you should go and do so. We'll link to the appropriate section here. But these are studies that are conducted using a particularly good model of mouse that is kind of less troubled by the usual difficulties my studies have. It's also done independently at three separate laboratories concurrently. And then the final thing is they look at all cosmortality. So tell us why you think that we could be misled by the ITP.

So let me make a big picture statement now. It is possible that some of the drugs that had mild effect in ITP will have much bigger effect in humans and the other, maybe Rapa Mycin is going to be not as effective in humans as it is in animals. We just have to accept that. Rich Miller, if it's not in true in mice, it's not true. Well, I don't think Rich says, by the way. I've never heard Rich say that. Rich just says, this is what it is in this model. I'm kidding. He started saying that initially and he took it back, of course.

I think one of the problems with animals is the dosage that they're using. The dosage in animal where, if you look back, as 0.1% in a solution to 1%, 1% is deadly because listen, mit forning, after all, is a weak cyanide. It binds to a complex in the mitochondria. It probably affects complex 1 and also complex 3. It's not totally clear, but if you give too much, there is a trade-off. So you have to give right. And I think that the studies in animals, except by the way, mice, it's not true for nematodes and there are several other fish, there are several other

animals that live longer and healthier with mid-forming. But I don't think that 0.1 percent healthier with mid-forming. But I don't think that 0.1% is really the appropriate dose. What do you think is the... So you think? I don't know. I don't know. There's no dose response. So you're saying 1% is clearly problematic. Yeah, I think 0.2%, maybe will be better if we want to optimize that. There's a paper that gets a lot of attention. I think it's 2013, the Raphael de Cabo paper, which gets touted as, oh, look at Metformin. I gotta be honest with you. If you look at that paper, I don't know how the editors let the title of that paper slide with the actual data. Let's call a spade a spade. You had two groups of mice, one of them getting 0.1%, one of them getting 1%, the group getting 1% were assassinated to your point. I mean, these animals were killed by the toxicity of

Metformin. The group getting 0.1% lived a staggering 4% longer. I mean, it was basically a null trial that was touted as the definitive animal study for why Metformin works. It's like an onion article when you dissociate the title from the actual data. Look, the average when I took and make a table with all the longevity data, the effect of Metformin across studies were between 7 and 10 percent. Not a huge effect. Well, that's pretty good.

7% to 10% in animal studies, if it's consistent, would be pretty good. But the nice thing with mitforen, the effects on health span is much bigger. But what are the health span effects besides the metabolic effects? Prevention of cancers. Isn't that effectively already captured in lifespan? Rich Miller will give you a better thing. I mean, the problem for us with animals, by the way, it's the problem with centenarians also.

They die with cancers. We don't know if they die from cancers. Right, it's like the prostate cancer issue. Right. As much as we say in humans, it's cardiovascular disease, cancer is probably the leading disease for that for animals. And it's true The other point which I think I'm trying to get to the bottom of that

But when you gave me forming two animals in the ITP in two centers They had 10 percent, you know, one was 11 and one was 9 percent increase in longevity But rich millers point was minus 2%. And I just wonder if they're all actually delivering the same dose and what's going on. And so it wasn't significant, but it actually was in two centers, there was a 10% effect. Yeah, there's always an issue that could be methodologic. Do you think that the animal studies in Metformin are largely irrelevant once we have tame underway?

One of the reasons that we rely so heavily on all of the animal data for rapamycin and why the ITP, which has studied rapamycin five ways to Sunday, starting at late-end life, starting at early-end life, high-dose, low-dose, pulsing it, not pulsing it, continuous, I mean, every way you study it, rapamycin works. And we have to look at that and really pay attention to it because I don't think we're going to get the human trial of rapamycin. I don't know that we're going to get the tame equivalent

of rapamycin. And if we are, it's not going to be for some time. But now that we're moving to a human clinical trial of metformin should we even care about this question and mice? Does it matter if it's 0.1% or 0.2%? No, what I'm saying is that the preliminary data from humans overall, as you said, there are problems everywhere, but it's the same story. It's a 20-30% effect on each study no matter how you look at it. It's a really very impressive studies and there's no better studies that came with different results. So, I think one stain is there. I don't know that we need to go into animal studies and discover

more about metformin at this time. Will tame allow you on its current budget, which I think is 50 million? Is the bare bones budget? Sounds crazy, right? On the 50 million dollar budget, how much will you be able to look at mitochondrial function and omics that are associated with other deeper markers that go beyond the hard outcomes that feed into your primary outcome. Well, the NIA has given us a grant that is now delayed to do basically the biomarker part of Tain. So even with this 50 million and with the NIH money with a FAR, we're going to store lots of

plasma, DNA, and other resources like sales and other things that will then be open for omics studies. And we wrote a beautiful grant about that. In part, it was preliminary data from our centenarian studies on proteomics. By the way, I just realized I used the word omix. Do you want to tell people what the full suite of omix means so that people listening to this know what we're talking about? Yeah, and it's really back to something that I said before when I talk about,

if I said my study, I mean our study. And when I talk about teams, I'm talking about teams that have computational capacity. I talked about Zeng Dong Dang that did a lot of my study about ushing so that he's doing functional genetics. I'm talking about Sophia Milman who are doing other studies. We're really big team.

And the reason to have a big team is very simple. All I knew when I started my training was insulin. I knew insulin, I know insulin, insulin, signaling. Now I'm losing billions of data set that are under my team. If you think of genetics only, all like some sequencing for 3,000 people or my proteomics which is 5,000 protein for 1 thousand people. It's all big data. And in order to do something with the big data, you have to ask the right questions

because what we noticed, the first paper that came out of the UK Biobank for Aging said that longevity is all about assortative mating. Now, yes, if you're a smoker, you may marry a smoker. If you're a visual-marie, if you're poor, you will marry poor. It all has consequence of health. But we knew that without the UK biobank. We knew that obesity is a risk for diabetes without the biobank, too. So you have to ask the right question. And it's really only asking the right question that you get the answer.

So the question that is very important for us, there are two questions. What are the biomarkers for aging? How can we do a test at 50 years old and know if we're 40 or we're 60? If we're 40, we skip colonoscopy, okay? If we're 60, we have to do something about it already. And the second part, it's more important for me is biomarkers that change

with treatment. We want to make sure that when we try all those treatments that we have in two, three months, an answer, are they likely to work? And then maybe we can get to face to and face retrial but we need something more immediate and that's what tame will try to provide. Now in my study we did this proteomic and it was really incredible for many reason and I'll give you a tidbit but we have those thousand people and five thousand proteins and we asked what changed between the ages 65 and 95. This didn't include our centenarians. And the answer is a lot of proteins are changing, but this is, I think, the most important part.

And a lot of the proteins that we're capturing, by the way, number one is IGF related proteins. Number one that comes up even in the proteomic, not only in the genomics. But then a lot of what you see is breakdown. You see breakdown of collagen, you see the granulation of thrombocytes, you see breakdown of extra cellulermatrix, lots of things like that. At first I said, okay, that doesn't tell me anything until I thought, no matter what we do, we have to stop the breakdown. This is probably going to be the best marker for any treatment, you just stop the breakdown. It's funny, that seems so obvious, doesn't it?

This gets back to what we talked about earlier. You wanna really know what health span is? It's not some nonsense definition that the NIA gives us about freedom from disability and disease. Who cares? Who cares if you have cancer, but you're living in remission with it, and you can climb

three flights of stairs with a bag of groceries in your hands. That's living. It's, yeah, when your college is breaking down, your knees aren't working. I mean, this is the essence of what we're talking about. I think the proteomic story is very interesting, and I hope it gets its appropriate funding. By the way, the other part of proteomic, there are a few other aspects that are important. The proteins that are 10 to the minus 80 significance. The two top ones, when you express them in animal, they live long.

In other words, they are protective protein. When you get those proteins, you don't know which are protective and which are causing problems. And that's a challenge because we are saying, let's bring it to normal. No, you don't want to lower the protective mechanism. The third thing that is really cool is the prottel of females is much more stable. In other words, it's only half of the proteins are significantly changing in women than in men between those ages. So you'd need to look at actually different biomarkers for women and men.

And by the way, this was Eureka moment for all of us. From ITP and on, female and males have different biology as far as aging. Some of the gerotherapeutics work for both like mitforming and rapamycin, maybe not equally, but work for both and some are not. They're totally sex-specific. Yeah, look at the 17 beta estradiol.

I mean, that's a remarkable story. And then the last thing that is interesting, those thousand people that I had, 500 are what we called opus. They are offspring of parents with usual survival, no longevity in the family. And one are opal, offspring of parents with exceptional longevity. The offspring of parents with exceptional longevity. The offspring of parents with exceptional longevity have half of the biomarkers of the control group

because they're younger, they'll get those biomarkers later. So look, I don't know that medilation is going to be the best biomarker for treatment. I think medillations are complicated, they're kind of stable, they are going up, they're going down, but they're kind of stable. I think proteomic is going to be a better biomarker, I think metabolomic is very complicated because it so depends on how you establish the sample. If somebody was fasting less or more, if their insulin level was less or more, you're done. Yeah, that's sort of my problem with these biomarkers. And you know, I mean, you've probably heard me rail on these biological clocks. I've never seen a worse biomarker than a biological clock.

These are so easy to manipulate and game. In fact, I need to do this just to demonstrate it, but I'm too lazy. Is get five copies of a biologic clock and do five different self experiments, and I promise you I can change my biologic age by 20 years. When fasting glucose and vitamin D level factor into a biologic clock, I'm sorry, that's useless. It might be valuable at the population level, it is as useful as a warm bucket of hamster vomit at the individual level. So we have to have things that can't just change on a day-to-day basis. Your fasting glucose, the difference between 95 and 105 has everything to do with the meal

you had last night. How much cortisol was coursing through your veins if your water heater broke that night, if you got startled in the morning before you got your blood draw. I mean, I'm just amazed near at the attention. I'm sorry I'm going off on this tangent, but I'm amazed at the attention that is being given to these clocks. And the entire cottage industry of businesses that are spinning out this type of, I think this is complete buffoonery. So Peter, I have more positive outlook of life, maybe because I'm so much older than you.

So much older, yes. But at least it's good for the economy. Yeah, exactly. Hey, Theranos was good for the economy until it wasn't. Right. The other thing is even with methylation and I thought methylation was very interesting until the twin astronaut brother experiment. Then I stopped thinking it was very interesting. Remember you had the twins, right? The one astronaut went to the ISS for a year. His twin brothers stayed down here.

You then looked at methylation clocks of them after a year, and they were vastly different. And then three days later, after the twin brother was back on Earth for three days, they repeated the test, and it was right back to his twin brother. I mean, come on. How biologically relevant can this be when it changes like that? Right. Have you had Morgan Levin? You know about her. I do, of course, and I haven't had Steve Horvath on as well. I've communicated with him a little bit via email and I would certainly love the opportunity to speak with him about this. But there's probably something interesting there. I'm just having a hard time seeing that...

Because again, what's the purpose of doing this? We have to never lose sight of the purpose of biomarkers of aging. It's not so that you have bragging rights that, oh, I just took this test and it says I'm 37 when I'm 50. No, the only reason you do this test is if it can guide therapeutics. The only reason you do this test is if it helps you determine if I'm doing this thing, is it making me better or worse? And my fear is, I haven't seen a single test that is validated at a level that would give me even a modicum of confidence in that. Have you? No, no. I mean, again, I'm saying this in a very deliberately provocative way because I'm waiting for you to say, oh, no, no, Peter, you need to look at this test. No, so I'm telling you, I don't want to be a spokesperson. All I'm

saying is matilation because it's not mechanistic. I don't think it's going to help us when we come to Gerotherapeutics, even if they're examples. I don't know what the examples mean, just like the example you gave. I don't know what it means. Morgan Levine and Steve Horvett, by the way, they're really good and they're responsible and they understand exactly what they did and what they didn't do. And Morgan Levine has a mechanistic way of looking at epigenetics. In other words, remind me what the inputs are to the Levine clock. I'm not going to get the difference between the clock.

I want to talk about the way they're moving. Okay. So one thing that Morgan Levine is doing is she's saying, well, if matilation has a function, then I want to cause matilation and see that there's change in the expression of those genes. And that those genes are something that we know are relevant to aging, et cetera, et cetera. And then build a clock that is mechanistic because the only way this clock was built was to measure chronological age.

Will you guys be using any of the biologic clocks through tame as well? So what's going to happen with tame is there are two things. We are going to have a committee that we time and we didn't decide we're going to do the right epigenetic test. And by the way, we're going to do epigenetic, not the clock epigenetics, but enough epigenetic data on a genome wide in order to then discover which are the ones that have changed with treatment that way. But it would also be good near to have a clock running in parallel, wouldn't it? Because if you can do this longitudinally with multiple data points, you sample people every three to six months with multiple different versions of these clocks, and then you can look at how well those advantage of the fact that you have two things going for you that nobody has today, which is a very large longitudinal

data set with hard outcomes and an intervention that is relevant and interesting to study. Right. So let me explain again, if we're doing the matillation scan, we can obtain any clock from them. That's the idea. Yes, that's my point. I mean, you'll have the bio. I'm just saying, just make sure you're collecting all of the data that goes into multiple clocks in a concurrent manner, not just at a time A and time B. Right.

The second point is the NIA is going to have RFA for people who want to have sub-projects in relation to what we collected. Those RFA's can be in centers, for example, there's a center that wants to look at skin aging. If 250 people are enough for a project, then you have a center. If you need 500, you'll take two centers. In other words, there'll be a process by which application will be reviewed and people can come in and look at variety of things that they're interested in.

Can I, if it's not too late, make some crazy suggestions and I don't know if this changes your IRB, but are you going to be doing any bone marrow sampling even at time beginning an end? Because I'll tell you one of the other things I'd really, really love to see with a study of this magnitude is are you impacting immune function specifically memory T and B cell function. Obviously this is a topic that's very interesting in germane to COVID at the moment, but I think it goes well beyond COVID.

And it would be very interesting to know if metformin is having any impact on immune function, specifically memory function, because it doesn't just play an important role in infections, it plays a very important role in cancer. So look, the answer is mundane. We're taking elderly people into a study, we're not going to torture them, we're not going to have any excuse for them to leave us. It's the same with our centenarians. By the way,

what we're offering the offspring, we're offering MRI of their brain, we're offering them coronary CT, we're offering things, but we're not doing biopsies. That's in another study. Are you doing brain MRI and tame? No. Just because of cost. Yeah, look we are powered enough to do things Eventually because it's not going to happen before and after we're not going to have everything from before and after This is only the things that we have to measure for the outcomes What about exercise function? One of the things I want to talk about before we leave metformin is The impact metformin may have as a negative

impact on cardio respiratory fitness. Right. So no, the answer is no. We're not going to have anything like that. Because of cost? No, because of how much time can you get an elderly to spend time with you every three months when really what you want to make sure is that they're taking their drugs. That's why. How many centers you said 3,500 subjects? Yeah, well we have currently before we get okay to expand the beat we have 14 centers and about 250 people in each centers. All in the U.S. All in the in the US. I don't know I think that would be potentially a lost opportunity not that you have to do

CPET testing every three months, but would doing it every two years be an issue at a minimum I would look at fasting lactate levels or resting lactate levels Everybody has suggestion Vittag. I know everybody has their pet idea for you. Yeah, of course. Right. And by no way, I'm saying it's not important. I'm just saying, what are we practically ready? Because at the end, we want the FDA.

Let me state it again. I'm doing take, not because I don't believe in metforming because we need to have a target that's similar to aging. That's the reason. So, let's talk a little bit about this other issue, which is, I've talked to you about my experience, right? So, I took metformin for eight years or something like that. But three years ago, when I really began checking and constantly monitoring my lactate levels,

both in and out of exercise, it became clear to me that my lactate levels both in and out of exercise. It became clear to me that my lactate levels were too high. So my fasting lactate level was typically above one millimole, it was between one and two millimole, and as a result of that my perceived mitochondrial efficiency was lower, and there's ample data to suggest that fasting lactate level. Now, of course, this is not necessarily in people taking metformin, but if you take lactate levels in people at rest, there's a high association between what that tells you about their general health. So the less healthy an individual is, the higher

their lactate level is. So for me, I just said, well, boy, there's sure looks like a lot of compelling reasons why metformin could be beneficial. But if I really stop to look at it, none of the cohorts of people in whom we would infer that look anything like me. These are not people who are exercising constantly doing all of these other things. So that was the decision for me three years ago. I'm not going to take metformin anymore until I have better data. So now we have a couple of studies that have looked at the impact of metformin on cardiovascular fitness. And we see that it is indeed impaired. And then we have studies that look at the impact on metformin of strength training. And we see a mixed response. We see

that it does not appear to impact strength gains, it only appears to impact hypertrophy. The good news is we know that strength matters more than hypertrophy in longevity. I had a whole AMA on that which you probably heard, so I think it was pretty clear that we can say strength matters more. So what do you make about these potential limitations with respect to metformin on cardio- fitness. And what do you think it says about people who exercise a lot? First of all, I think one point that is very important is when we go from a drug that has certain capabilities to personalize medicine and all of a sudden it becomes about the person.

And there's nothing I can say about what you're observing except that lactate is one of the biomarkers of giving metformin in every patient. In 1987, when I did the metformin study, lactate went from below one to above one in everyone who took metformin. I hope in tame you are measuring lactate if for no other reason than determined compliance.

Yeah, absolutely, absolutely. By the way, there is a better test. It's called GDF 15. It's one of those peptides that goes up with aging. It's a protective peptide. It goes by three and a half fold in people who take mid-forming. So there are other ways to look at it.

But this is the point with exercise and let me make the most important point. We can talk about muscle, but remember just like with exercise itself, exercise is not only about muscle, it improves brain function, it decreases cancer. Medforming has many other effects, so let's remember that medforming has other effects than its effects on the muscle. As far as the muscle is concerned, what we've done with Charlotte Peterson, which you reviewed two papers of her during the time, we took the biopsies and look at the transcript

of the people who were on exercise and met forming versus exercise only, right? That's the only thing we had. And the reason we did that was because in supplement four of her first paper, she showed that the strength of the muscle didn't change, which means that per gram muscle, you did better. And we try to understand what is the biology and it became very clear. Look, in order for muscle to grow, it needs to activate amtore. So, amtore is good for muscle and for muscle growth. It's not good for aging, but it's good for muscle growth. A huge transcripts of amtore has

been decreased by metformin, which was not news for us. On the other hand, there are other transcripts that had to do with inflammation and autophagy and oxidative markers that were in people with metformin and not with exercise. So there are trade-offs. You get less muscle, but the muscle is healthier. Is healthier, can we really say that? Or can we just say is as strong? It's biologically younger or as strong? Yeah, whatever, they're trade-offs.

But how do we say it's biologically younger? Because the change in transcript that we saw is from an all-transcript to young transcript. So in our studies, we have biopsies from people who are old and young. And with every treatment and we've done it for us, very trolling, we have biopsies from people who are old and young. And with every treatment, and we've done it for resveratrol, and we've done it for metformin, and we've done it for acarbose, and for exercise, and now we're doing it for fasting. We have young and old, and we see, if in old, with intervention, the transcript goes back to young. And it does. So the exercising people without metformin versus exercising with metformin, the with metformin group had a maintenance of the transcriptome or it actually declined

relative to the other group. No, it's transcript specific. It's which groups of transcript changed, and did they change other with decrease or increase, did they change to resemble more young than old? And this was done on the patients in the master's trial? Yes. And what was the duration of that trial? 16 weeks, I believe.

So what do we think we can learn in four months with respect to the transcript? How much does it apply from what you've learned over a much longer period of time in a non-intervention setting? First of all, the answer is what we learn in four months, we learn what it is in four months, but I think it's a long period of time. It's also a dynamic period of time in this experiment

because they were building muscle throughout time. So it is what it is in this experiment, but in this experiment, the transcripts were younger by metformin, and the amctor was increased by exercise. And this was the trade-offs. And what about in terms of the cardio respiratory fitness differences? I mean, I guess what I'm getting at is the most plausible explanation here for a blunting of cardio respiratory fitness would be what you said earlier, which is metformin

is a mitochondrial inhibitor. It's a weak one at the doses we take it, but it nevertheless is. So, it seems to me that that's the most obvious explanation. That's the place I'd be looking for the fire given where the smoke is. So do we think that the net benefits of that are probably positive in some people, but in others, for example, those who exercise a lot, it might not be beneficial because they're getting so many of those other benefits of exercise as you point out. Yeah, I look, I'm taking it for me in and exercise, but I have a different way I'm thinking about it for me, we're very personalized. And this is back to the issue of when do we start

metformin? Or what is the biological age of those people who exercise and take metformin? And I would say that if you're young or biologically young, I don't think you should take metformin when you exercise at this level. Maybe Peter, you've been doing it for years, you're young or biologically young, I don't think you should take metformin when you exercise at this level. Maybe Peter, you've been doing it for years, you're probably biologically much younger than most people. I don't know if metformin is for your age and for what you're doing for your health. I can tell you that with metformin and fasting, my exercise capacity has increased. Significantly I'm not measuring lactate. I'm not exercising the way you are.

So I think those are good discussion will find out eventually who can or who cannot. But we have to make sure that we don't generalize where we're being so specific. Yeah, no indeed. Again, I said at the outset, I get asked about metformin constantly and the only people who are asking me for whom it really matters are the patients. I don't particularly care what someone asks me on social media, but it has been a change in my practice over the past few years where I'm really reserving metformin only for people in whom I see an otherwise obvious indication, such as even a trace of insulin resistance, hyperinsulinemia, that is not otherwise treated with the right amount of exercise, nutritional changes, sleep

and things like that. So it will be interesting to see what tame does and how it can change that practice, but I also worry that it won't fully answer the question for our patient population, because the tame patient population is not a very healthy population by definition if they can't walk a certain speed, they're 65 to 80 years old. You're basically selecting people who we expect to have a bad outcome in five years. So it's a very important question for the world at large. I think it's important that people listening to this understand, we may not get the answer we want for them for the healthy 40-year-old person.

Absolutely. Remember, all I want with tail is an FDA indication for aging. That's all I want. What do you think that opens the floodgates for? How does that change things now? Assuming that we get there and that we now have an FDA indication for aging. What follows? First of all, pharmaceuticals will jump in and they wouldn't make many mistakes because I think

the biomarkers will be there from tame and others. There'll be more biomarkers, better biomarkers so that they could do testing two and three months and find out if their drug is working and then do a face retrial. Now face retrial, think of it. For any diabetes treatment, you need 12,000 people. For 10,000, you need 3,000 people. The study is going to be much, much cheaper. We think this is still a hypothesis that being tested, right? Is 3,000 the right number?

Yeah. If this composite outcome works. Yeah, if it were, look, the 3000 is a question of when and not if for me. How many years will it take us? And I hope that we'll actually do the 3500 and not lose a lot. Also, the question is, who's stopping the study? That's another thing. So, in others, that's administrative questions. But the reason we do that is to get an indication that for the FDA is not making aging a disease, which is another big topic. But for us, it's, okay, you can call it whatever we want,

but if there's a drug, the target targets variety of age-related disease and mortality, that's for us a general therapeutics. And this is what we want to get. All the other question, when to use, whom to use, you're absolutely right. And the one thing we don't want is to kill anyone on the way to success. We're almost at a time, but one thing I want to just touch on before we go, we've talked a little bit about rap and ice and a lot about metform and we didn't talk about the other one you and I probably get asked about a lot, which is the NAD precursors. Where are you and you're thinking on the efficacy of these as neuroprotective agents? They're in a different class because they're not pharmaceutical, they're nutraceutical. How is your appraisal of

the data in that space? As a biologist, I have a problem understanding it. On one hand, you give it to animals, and the animals are doing better. Not in the ITP, but... You're right. Not in the single most important animal study. They didn't do better, yeah. But when you ask people, okay, follow the drug, tell me where it goes, where can you measure it? You cannot measure it anywhere and you cannot measure the rivetive of that. So I don't know where is the biology.

So Joe Barre, you know Joe Barre from UPM, he's a really good NAD biologist. He basically thought the NAD goes, we swallow that. It goes to our microbiome and our microbiome. Sorry, when he says NAD, you mean the NR or NMN? Right, the pre-course, right. Yep. It goes to the microbiome and the microbiome either transfer the NAD or does something, the microbiome itself does something,

you know, there's indirect health benefit from a Duffer system. And he actually did a really good study where he discovered that the NAD for the microbiome comes not from the food but from the gut walls. Everywhere you try to understand what's the biology, I don't get it. And when I don't get the biology, I'm a little bit more worried of what kind of a placebo is it. Actually, one of the studies I wanted to do, those short studies when I get elderly, do placebo control crossover and do biopsies and look at the biology I wanted to do an AD and then I said I just have so little belief here that I'm now doing

intermittent fasting one but uncomfortable with it. Now saying that I started taking an amen at one point and what I noticed is my REM sleep has improved a lot and I stopped it and my REM sleep wasn't so good. I restarted it and my REM didn't get better again. And then I tried, there's a Japanese company, I don't remember the name of the top of my head, that has really the best preparation. David Sinclair tells me about that. He has the best preparation of NMN, $900 a month supply for the low dose, $1,800 for the high dose. I got some of the supplement as a present.

More expensive than a PCSK9 inhibitor and rapamycin combined, okay. All right. And my ARIM sleep didn't return, so I'm currently not taking anyone. So what am I telling you? I'm telling you I'm just not convinced. It's not the whole truth, you never know the whole truth, but I don't know enough of the truth to make anything about it. Again, if people want to know it's good for the economy, I'm not sure that the preparations out there look, they are very sensitive preparations.

If they have a high time shelf, I think you lose a lot of it. I don't know which to recommend. Yeah, I think it's always problematic when your rationale for taking a supplement is that it's a mini stimulus program to the economy through this supplement company. I think it's a general rule if we're going to talk about principles for trying to optimize your health. I would put that very low on the list. Peter, I did many jokes. Do I have to go over and tell you which was a joke and which is not? I don't know. I know it's a joke. This is my joke right back at you. Yeah, yeah, exactly. No, no, this is my sarcasm coming right back to you.

It's, yeah, supplement company stimulus program, not a high on my list reason for it. Anyway, Nier, this has been great. Thank you again for the generosity of your time. And behind the scenes, people don't know how much I bug you and how much we interact on all matters that pertain to this stuff. You're one of the few people that I know listens to every single podcast reads every single

newsletter and at least a quarter of the time sends me a note with something remarkable in it that expands my thinking on a topic. So I want to thank you for that. You're part of the people who spread the gospels and I think it's so important. In fact, you're one of the messiahs really. That's an awful stuff. I don't want to be a messiah of anything. And I want to come clean. I'm usually not there for the last half an hour of the podcast. That's a shame because I always save the best thing for the last half an hour.

You really? Okay. Next time I'll listen to the last half an hour or see how it's a pleasure, Peter, and any time, and good luck, and I'm looking forward not to this one. I'm not going to listen to but to the next one. Very well. Thank you, Nier. Okay. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. After that end, membership benefits include a bunch of things.

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