#204 - Centenarians, metformin, and longevity | Nir Barzilai, M.D.

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all 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 peterattiamd.com subscribe Now without further delay, here's today's episode. My guest this week is Nir Barzlai. Nir is making his third appearance on the podcast, the previous one being in August 2020, which with Joan Manic and then originally back in January of 2019. In this episode, Nir 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, CTEP5, Foxo, TSHR, and Apoe. We talk about whether or not environment matters at all in these individuals, or whether it's all genetic. 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 healthspan. From there we get into a deep dive on 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 Nir'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, Nir 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. Nir Barzilai. Hey, Nir, 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. Perls, 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 100 or more. But there's so much nuance about what it is about these special people. And 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, all 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, genes 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 offsprings. 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 impact in 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 a comparison. Do we have twin data? Because it seems to me that 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 Barger 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.

Nir, 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 healthspan or is it just lifespan?

Well, it's mainly health span in humans that we know. First thing that's obvious when you have a small for gestational age twin, there's a catch up growth of the small baby. And those twins born in the same day in 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 changes in imprinting 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 100? What is it that the centenarians have in a polygenic sense that the rest of us schmucks 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 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, nir part of that hypothesis is the absence of bad genes, not necessarily the presence of good genesis.

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 there 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 whole genome sequencing at the time. Huge expense. But we only had those centenarians. We don't have header control, but we had a great instrument. We thought it's called Clinvar. It's an accumulation of all the genes that have shown to be causing diseases. If you had a clean variant, you are 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 were 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 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 had 15,000 variants and we asked, do our 44 centenarians have variants? And the answer was each centenarian had between five and six bed 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 had 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 centenarians who have the ApoE4 homozygosity that puts them at major risk. One of the best genetic risks for Alzheimer's that the textbook says they would be demented at 70 and dead at 80 and they are at 100 and not demented genes 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, our protectives, 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, Nir, 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 100 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, 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 were 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 was more obvious in the offspring of our centenarians even than our centenarians. So we have offsprings 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 phenotypes. 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 CETP genotype and one was an APO C3 genotypes. And those genotypes increased from about 8 to 9% of the homozygosity in control to almost 20% 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 of. 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, if the drug is really good, it targets exactly that without side 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 CTEP inhibitors?

Yes, and I don't totally understand it. I listened to one of your podcasts. I forgot the name.

Yeah. Tom Dayspring 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. I mean, that would be putting it mildly. And I think the challenge with the CTEP 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 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. A 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 this pathway 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 ApoE4 genotypes. They both had very high HDL cholesterol and they were homozygous 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 got to the study were between 50 and 70 years old. So there's no results for that.

I Know this off the top of your head, but even offline, I'd love to hear what you learned about the variants of Clotho that those people had, especially the ones who were homozygous for APOE 4. You're probably aware, but there are variants of Clotho that seem to completely abrogate the effect of E4. Meaning you take people with APOE4 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 cloto and cloto was the example of what we call a V shape or a U shaped genotype. Cloto basically seemed to kill 50% of our subjects by age 85. The genotype has disappeared by age 85 and all of a sudden after that, at age hundred, it was the same. And our interpretation was that those centenarians were born with cloto, but they were also born with longevity genes, which made the cloto not significant. But another hypothesis is that the actual cloto that they had is a cloto 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?

What?

Or did you arrive at VOXO 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, nir. 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 the AI people and the doctors and the physiology. So it's we. 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 live 10 times longer. By the way, the gene was bugging me because it's the insulin receptor or the IGF insulin receptor gene. And the nematodes were insulin resistant and they 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 signaling 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, that impairs growth hormone IGF signaling pathway, including the Foxo 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 deletions 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 nir, 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 height. But the growth hormone is the growth hormone pathway or the growth hormone signaling 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, which is 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 Larond 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 and in exchange for others.

Correct, Right. I'm always describing it that they're 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 Gillet Simon, who was a fellow and then a faculty with us. He's still involved, he's now in Israel. But he. We looked at all the pathway and we discovered that our centenarians have deletion of Exome 3 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, Gilbert, 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 homozygous were taller than the controls?

Yes, significantly taller.

And 2 to 3 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 Gil, what do you do with genetics? First of all, you need to do validation. So paper is not accepted without validation. I said, do 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, a false difference in their growth hormone in this deletion, which was very compelling on its own. But still, why do they have lower IGF one?

Sorry, just to be clear, they had lower growth hormone, they should have lower IGF one. You're saying? But they were taller.

Why they were taller. Sorry, I meant why they were Taller?

Yes. Yeah.

So Hassi Cohen, who's the dean of the gerontology school at USC and one of my collaborators, is a growth hormone expert and he took the cells. And by the way, that's another thing that we have. We have the lymphoblast of our centenarians. So if you have a genotype, you can actually look at its action with lymphoblasts. And he took this lymphoblast and he incubated them with and without growth hormone. And something really interesting happened when they were not incubated with growth hormone. The florylation of this receptor, the activity of this receptor was lower as we thought it would be because they have deletion of an exon. 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.

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'm going 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 ctep. 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 the growth hormone and 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 IGF1 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, I was just about to say it's a very complex relationship. IGF seems to protect from everything but cancer.

Right, right. Except that, 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 increasing 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 pleotrophy 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 pleiotrophic relationship is that the cutoff is quite, quite old. So if you really think about this just through kind of a Dawkins lens, you would think that that cutoff would be done by 25 or 30. At 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 things 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 hormesis, they'll come back and you'll be more resilient. It's okay. But I actually wrote a paper saying people in the Old Testament are quoting methuselah to be969 and Moses to be120. Maybe they were right. Maybe we had this capacity because we're losing longevity genes because of reproduction.

That'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 merely 2000 years ago.

You know why it's a 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 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 longevity 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 is 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 prolongevity tool but as an agent that clearly helps health span but might be not as destructive to lifespan as I believe it could be?

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 pleiotrophy and it's relevant to tame and metformin. 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 asking me on any of those geroprotectors, geropherapeutics, vitamins, when do we start them? The answer is I really don't know. I think you shouldn't get senolytics before you are 70 or 80 years old. I think probably metformin. Although we start this study at 65, most of the studies so far that showed really large effect of metformin are people who 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. Well, what do I tell them? I don't really know based on literature, based on clinical trials.

So last question on this nir. 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?

We don't know that. 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 metformin 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 hormone 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 Millman who's running the longevity studies now. And she measured IGF1 in all our patients and she looked at our centenarian. So they're 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 are 85 females for every 15 men. We have better results because a lot of the female centenarians have never got married. Nuns and other things going back to your problem with your kids. But we need people with offspring. Our study is 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 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. Which again gets to a question that we are going to talk about today, which is healthspan 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 APOE2 than noncentenarians? 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 Apo E2 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 ascertainment bias that to our study we don't get people with APOE 4 because they are demented 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 APO E2 and APO E3 and it's not. It's really an APO 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 APO E2 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 cloto.

Yes. 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 biologists, we interacted every one of those bad genotypes with a longevity genotype and actually the centenarians with high L.P. they are 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. There may be something that LPA, because you have to think LP is common. It's about 10% of the population. So 10% of the population overexpresses this thing. 10% of the population has an elevated phenotype for LP. And it's true that evolution wasn't selecting against atherosclerosis, but there are arguments to be made that LP 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. 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 easier, irrelevant. What is LP 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 CTEP as an example, they happen to have a CTEP mutation or a CTEP 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 lp. And then eventually, at some point when everybody else has died because of their lp, they're still standing and they might even be getting some benefit from LP that everybody gets, but it's in other people's cases, it's so dwarfed by the damage of lp. Again, total hypothesis or speculation, but it's plausible.

It is.

Okay, tell me about tshr. 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, NIR maybe give people the two minute Story on what TSH is and how it functions.

Sure. My sisters are listening to you. And I promise 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 out of your glands. Okay, so that's tsh.

So when we see a high TSH in a normal person, we ask the first question. Is their 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 lived 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 endocrinologists or the thyroidologies are looking for business. So once TSH was above 10, and then they said it might be subclinical at 7 and we went to 5. And now if you're 3 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 five to eight.

Wow.

So normal is like until five.

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 T4, normal free T3, but they walk around with a 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 genes 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 Euthyroid high TSH patients, Right? Right. What's the hypothesis for that? Is this simply a biomarker 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 endocrinologists that are looking at our data and analyzing it. I'll be happy to come again or, 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 advantages. 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 questions? 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. Do you want to explain a Mendelian 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, this 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 are 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 genotypes 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 are not built with one genotype at a 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 without longevity. And we're going to take all those rare genotypes less than 1%, because to be centenarians, 1 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 a specific genotype. And then we get really important information. And by the way, the important information that we got in the study, in the summary statement is that the genetics of longevity in humans is exactly what we learned from animals. It's the insulin signaling pathway, it's the mtor signaling pathway, it's the mepkinas pathway. It's exactly the same genotype. The 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's, they're not good for other things. But for aging, actually, our models are really good because it's so conserving evolution. All our animals, their skin, their hair, their skeletal, they 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. 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, Apoe 4. 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 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 a determination. And it's looking at E4 plus Tom40 plus mitochondrial haplotype, plus Clotho, 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. LP is part of the 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're 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 as kind of a general resilience gene that is less disease specific and more broadly protective?

Yeah, I actually count Foxo 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 pathway 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 are 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 at 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 leave 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 Yuxinsu, 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, $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 were not in our longevity lexicons.

Nir, that's interesting. Only $2.8 million is required to recruit 10,000 centenarians plus their offsprings, 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 Regeneron 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. So you said there's somebody out there maybe who's going to 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 at 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 complicated me again and I'm taking back. First of all, when I said 150, I think the maximum of human lifespan as a species for us is about 115 years. Even if we argue, even if there is 1, 2, 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 me 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 at. 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 APOE 4 was a 20 fold 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 APOE 4 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, in surgery, in 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, you know, it's not the things that I'm doing predictions on.

No, it's interesting to me because 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 it, 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, 82, 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 variety of age related disease 20, 30 years later. Our control group between 60 and 80 accumulate lots of diseases at 80, only 10% of them don't have a disease. In our centenarians 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 span. This is not really the important part. The important part that it's 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 boundaries. So first of all, there's 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.

I 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 centenarian 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 centenarians 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, 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. 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 a scientist and the advocates, which by the.

Way, our mutual friend David Allison, 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 are 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 are 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 healthspan 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 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 age dependent and it's outside of the purview of 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 mils per minute per kg and the other is 30 mils per minute per kg. 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 onto 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 healthspan 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 healthspan. 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 healthspan is well defined. Definitely. So there are two comments that I will make for the NIH back to tame for them, what is aging is if we can prevent diseases, that's their measurements, which is not satisfying. Not to geriatrician 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 CDC has data in centenarians, the last two years life are third the cost in 100 years old and in when you die in 70.

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 healthspan 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 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.

Yeah.

And I'm telling this, 80 years old what I'm telling you, you know, you're 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. Okay? 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 100 years old, 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 bad 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, remembered a lot from both bad 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 to 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, Nir. 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.

Oh, okay. So all of them at least had.

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, Nir. 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? Yeah, 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. 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 a 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 100 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 I'll like, I'm not gonna be an important part of their life. Meaning the only people who I matter to are very narrow and close to me now. 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 centenarian study. If you're going to be centenarian, 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 span. However, we want to define that, and that's really what I'm trying to 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 gleaned 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. Okay, 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 killed them in other ways. Right. So died in their homes versus thousand. 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 are 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 got 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 5 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 JIRO 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 Metformin study. Can I volunteer? Can you assure me I'm not on placebo?

Yeah, I was just about to say, are 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 Metformin 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 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 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 Metformin? 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 Metformin myself. Of course I'll give Metformin. Or the other is the doctor said, I'm busy. But, you know, metformin is a safe drug and stuff. Let me just give them Metformin. And that's the end of that. And that's 100% success. Everybody can get Metformin 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 Metformin is an extract of the French lilac. Some people say it's nutraceutical, it is modified, and it is a drug.

The three best drugs in the world are rapamycin, statins, Metformin. There you go.

Right? But you need prescriptions. But also, look, one of the modifications was phenformin. It's an early form of metformin that.

Kind of was a little too potent.

Too potent on the mitochondria and caused the trouble. But we're over that for 80 years. But metformin 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 metformin. So the whole metformin moved to diabetes.

And that was about the 1950s or.

60S, right, right, 1950s and 60s. Interestingly, in the United States, it was approved only in 1993 or so. I came as a fellow to Ralph DeFronzo 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 that described that metformin decreased hepatic sluice production rather than increase insulin sensitivity in the periphery. It's serendipitous. I didn't think about it as aging. I came to Aldefront and I did aging in another way to insulin resistance and aging, but not metformin. But the point is there are billions, billions years of use. Remember, every patient takes it for years. And there are people on metformin who are 90 years old. I actually know them. So there are billions use of year. And I cannot think of a drug with better safety record. If there are any side effects to metformin, 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 general therapeutics. And that's exactly where Metformin 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 compliant with the 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 were 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 geoprotection 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 who are in Metformin 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 write about we had this discussion about the mortality data and you pointed out that maybe the control were 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 there 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. One for half a year and one for one year. And some of the outcomes have changed and there is no difference 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 were 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 was 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 is diabetes, you're going to get diabetic next. We have two things in geroscience that aging is going to drive your next disease and therefore it's the cluster that is going to count. 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. And the important thing of the cluster is that we cannot do time 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 this 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 trends. 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 this study for subsets of mortality. Yes.

Subsets 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 2 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 2 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 going to be taking statins, they're going to be taking medication for blood pressure. Some of 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. It's not going to be, 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 inclusion criteria. You have to have something that shows your 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 predimed 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 going to. I mean it's morbid to say this, but you're looking for people whose risk of death in the next five years is high enough that you're going to 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 20ft 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 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's 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 cancelled.

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.

So I'm sorry, I misunderstood. What is the primary outcome of tame?

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 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.

And 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. Let me explain. We would like to start longitudinal study where we capture a lot of the other healthspan 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 question 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 Hellspan.

Yeah. 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 ITP 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 mice studies have. It's also done independently at three separate laboratories concurrently. And then the final thing is they look at all cause mortality. 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 rapamycin 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 true in mice, it's not true.

Well, which 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 are using the dosage in animal where if you look back as 0.1% in a solution to 1%. 1% is deadly. Because listen, metformin, after all is a weak cyanide. It binds to a complex in the mitochondria. It probably affects complex one and also complex three. 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 metformin. 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 Rafael 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%. 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 metformin, the effects on healthspan 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 of death 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 metformin to animals in the ITP, in two centers, they had 10%, you know, one was 11 and one was 9% increase in longevity. But Rich Miller's 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 in five ways to Sunday, Starting it late in life, starting it early in 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 in 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 once TAME 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 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 tame. So even with this 50 million and with the NIH money, with afar we're going to store lots of plasma DNA and other resources like cells 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 omics. Do you want to tell people what the full suite of omics 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 Zheng Dong Deng that did a lot of my study about Yu Shin Su that is doing functional genetics. I'm talking about Sophia Millman who are doing other studies. We're a 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 signaling. Now I'm losing it. Billions of data set that are under my tip. If you think of genetics only whole exome sequencing for 3,000 people, or my proteomics, which is 5,000 protein for 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 obese, you will marry obese. 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? 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 and answer are they likely to work? And then maybe we can get to phase two and phase three trial. 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 reasons, and I'll give you a tidbit, but we have those thousand people and 5,000 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. 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 degranulation of thrombocytes, you see breakdown of extracellular matrix, lots of things like that. And 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 want to really know what healthspan 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 collagen 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're 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 proteome 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. For all of us from Itpnon. Female and males have different biology as far as aging. Some of the gerotherapeutics work for both, like metformin 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 opel 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 methylation is going to be the best biomarker for treatment. I think methylations 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 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 in 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. 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 brother 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 Levine? 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 methylation, 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 Horvat, 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 saying, well, if methylation has a function, then I want to cause methylation 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 with 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 nir 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 clocks predicted the actual outcomes you will see over five to seven years. That strikes me as a very valuable way to get at something that no one is doing today. Because in other words, take 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 methylation 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 RFAs can be in centers. For example, there is 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 and 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 and 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 in 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 cardiorespiratory fitness. 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.

You. Yeah, well, we have currently, before we get. Okay, to expand a bit, we have 14 centers and about 250 people in.

Each center, all in the U.S. all.

In the U.S. 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, verte.

I know. Everybody has their pet idea for you. Yeah, of course. Yeah.

Right. And by no way I'm saying it's not important. I'm just saying what are we practically. Because at the end, we want the fda. Let me state it again. I'm doing tame, not because I don't believe in metformin, 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 with 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 were too high. So my fasting lactate level was typically above 1 millimole. It was between 1 and 2 millimoles. 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 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 cardiorespiratory 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 cardiorespiratory 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 personalized medicine and all of a sudden it becomes about the person. And there is 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 1 to above 1 in everyone who took metformin.

I hope in tame you are measuring lactate if for no other reason than determine compliance.

Yeah, absolutely, absolutely. By the way, there is a better Test. It's called GDF15. 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 metformin. 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. Metformin has many other effects. So let's remember that metformin has other effects than any 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 metformin versus exercise only. Right. That's the only thing we had. And the reason we did that was because in supplement four of our first paper, she showed that the strength of the muscle didn't change, which means that per gram muscle, you did better. And we tried to understand what is the biology and it became very clear. Look, in order for muscle to grow, it needs to activate mtor. So MTOR is good for muscle and for muscle growth. It's not good for aging, but it's good for muscle growth. A huge transcript of MTOR 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 were trade offs. You get less muscle, but the muscle Is healthier.

Is healthier. Can we really say that or, 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 old 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 resveratrol and we've done it for metformin and we've done it for acarboz 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 either with decrease or increase? Did they change to resemble more young than old?

And this was done on the patients in the masters trial?

Yes.

And what was the duration of that trial?

Sixteen 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 MTOR was increased by exercise and this was the trade offs.

And what about in terms of the cardiorespiratory fitness differences? I mean, I guess what I'm getting at is the most plausible explanation here for a blunting of cardiorespiratory fitness would be what you said earlier, which is Metformin is a mitochondrial inhibitor. It's a weak one at the dose as 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, look, I'm taking Metformin and exercise, but I have a different way. I'm thinking, 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 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. We'll find out eventually who can and 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'll 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. 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 phase three trial. Now, phase three trial, think of it. For any diabetes treatment, you need 12,000 people. For TAME, 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 3000 the right number? Yeah, if this composite outcome works.

Yeah, if it works. 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 other words, 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 that targets variety of age related diseases and mortality, that's for us at Gerotherapeutics. 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 out of time. But one thing I want to just touch on before we go. We've talked a little bit about rapamycin, a lot about metformin. 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 in your thinking on the efficacy of these as geoprotective 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 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 derivative of that. So I don't know, where is the biology? So Joe Bauer. Do you know Joe Bauer from UPenn? 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 precursor, Right, Yeah. It'll go 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. I 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 NAD 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 NMN at one point and what I noticed is my REM sleep has improved 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 is a Japanese company, I don't remember the name off the top of my head, that has really the best preparation, David Sinclair tells me about that has the best preparation of nmn. $900 a month supply for the low dose, 1800 for the high dose. I got some of the supplement as a present.

More expensive than a PCSK9 inhibitor and rapamycin combined. Okay.

Right. And my REM 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're 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 the supplement code company. I think as 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. Supplement company stimulus program. Not a high on my list. Reason for it Anyway, Nir, 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. 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?

Oh, okay. Next time I listen to the last half an hour, see how it's a pleasure, Peter, and anytime 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, Nir. 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. Now to that end, membership benefits include a bunch of things. One totally kickass, comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is Nobody's show notes rival these monthly AMA episodes or Ask Me Anything episodes. Hearing these episodes completely, access to our private podcast feed that allows you to hear everything without having to listen to spiels like this the Qualys, which are a super short podcast that we release every Tuesday through Friday, highlighting the best questions, topics and tactics discussed on previous episodes of the Drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to everyone, steep discounts on products that I believe in but for which I'm not getting paid to endorse, and a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member only benefits, you can head over to peterattiamd.com subscribe. You can find me on Twitter, Instagram and Facebook, all with the ID peteratti md. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiamD.com about where I keep an up to date and active list of such companies.