Nir Barzilai: The Secrets of Centenarians

What will happen is that maybe we start doing something when we're in the when you're 20 or when you're 30. And we'll have this treatment that will rejuvenate, you know, your systems and you will age, maybe, but age much, much slower.

Aging, none of us can escape. Like gravity, it pulls on each of us. Why do some of us age gracefully and others don't? How do our bodies and minds experience aging at a cellular and molecular level? Why do we even age to begin with? And maybe most importantly, can we do anything about it? My name is Gordon Lythgoe, and here at the Buck Institute in California, my colleagues and I are searching for and actually finding answers to these questions and many more. On this podcast, we discuss and discover

the future of aging with some of

the brightest scientific stars on the planet. We're not getting any younger yet. Hi, everyone.

Welcome to the show. I'm so delighted to have Nir Barzilai today on our show.

It's a tremendous pleasure to have a chance to talk to this trained physician who's really at the forefront of bringing interventions in the biology of aging into the human domain through clinical trials.

Nir, welcome to our podcast. It's a real privilege.

You're such a thoughtful and deep thinker of aging, especially human aging and exceptional longevity. And, you know, your leadership is really obvious to all of us in the field.

First of all, flattery will get you nowhere. I'm still happy to talk with you. I think you'll be forever in many minds be this pioneer who called the field geroscience and made us really geroscientists, which has lots of advantages. One of them is that we have to distinct ourselves from anti aging. And that's a good way to do it. So thank you for your contribution and your leadership and your thoughtfulness.

So, Nir, when we first met, we were reviewing grants together, and I was stunned at how detail oriented you were

and analytical as you dissected these grant applications.

But obviously you're also a big thinker, big picture person. So I guess my first question is the big picture question. What do you think the major challenges are in the field right now?

For me, there are three challenges. One is how can we delay our aging now? I call it the Dorian Gray effect. Dorian Gray stopped aging. When he looked at himself in the mirror, he knew that he's aging. And by the way, that's what happened to me in zoom time. Okay. I'm looking at myself and I'm saying, okay, I'm aging in Zoom. But I'm actually much younger. Okay, but how to do it? One challenge. The second challenge is what we call the wolverine or, or maybe the fountain of youth. Take an old person and put him in a pool and he goes up young. And I want to tell you this is the biggest challenge that we have. Although clearly in animals, we can take old animals and make them healthier. Even if we don't extend their life by much, we can make them earlier. But I think the biggest promise and I think what will happen, it's only 50 years away, but what will happen is that maybe we start doing something when we're in the. When you're 20 or when you're 30, and you'll come once a month or one a year and we'll have this treatment where it will rejuvenate, you know, your systems and you will age maybe, but age much, much slower. And I think in each level of those, we have a story and we have a promise. Okay. One of the things that excites me most from this perspective, not from the science perspective, because always science excites me more, but from this perspective is the promise of TAME study that will be launched soon. I hope it's been delayed, but the funding is. Looks like it's there. But the Thames study is going to demonstrate that we can do kind of a Dorian Gray. We can maybe delay aging and therefore delay age related diseases, a cluster of them significantly. But the major reason I'm doing that is to get an FDA indication that will allow aging to be a preventable situation.

I definitely want to talk a lot about the TAME study in some detail.

Yeah. I want to say for the other two, one of those wolverine, fountain of youth seems to be we can do good things, at least proven in animals for senescent cells. Okay. I think removing cells is of benefit and there are lots of studies. Now, I don't think we know that it works in human, but I'll be surprised if it's not working in humans. It's a question of how to do it. And of course, the third thing is something that we are thinking as a moonshot, but those moonshots, unlike sending somebody to the moon, I think have a different timescale to them. And this idea of taking Yamamoto factors or something and rejuvenating and erasing the epigenome and maybe doing some other things to secure the healthy work of the cells and organs and body is something that can, can go in parallel.

Yeah, super exciting. And you know, I think that I share your excitement about the field right now and all these possibilities. But I want to go back actually. I just want to know how you became a scientist. Maybe you could talk about the schoolboy near Barzillai and when you started to think about science and medicine.

Yeah, you know, it was weird for me because When I was 13, I walked with my grandfather every Saturday. We had this walk and he would tell me what he did when he was young, which was quite incredible. But I'm looking at a 68 year old man who by the way died when he was 68, who was fat and slow and bold and not energetic and, And I know that most of us do not think that we're going to look like our grandparents. They think that the grandparents got, you know, who knows where they're from? We have no idea. But that's not us. And for me it's something that I couldn't leave. Not only that, I was in Israel then I went to the army, I became a medic. I wanted to be in the medical profession. I, I went to a really great medical school. My mentors were Nobel Prize lorries. I went to the best internship and resident. But all the time it was kind of interesting. Everybody was, let's see the cholesterol level, let's see the blood pressure. And I'm looking and I'm saying, just a minute, there's something you can get right now that has nothing to do with these measurements. You can see it, who's old and who's young. You know that it's the old that are getting to problems. So why are they old and do they have to be old?

So you really came into medicine because of this observation about aging?

I came to medicine because I wanted to be a doctor, because my father and grandfather were a doctor. But the thing of aging was the most curious thing for me. So I thought that endocrinology maybe can explain a lot of aging. Maybe if you just replace all those hormones, you'll be young again. And so my formal training was in endocrinology and metabolism.

Let's get into your science now. You're very well known for your incredible productivity around exceptional longevity and this, this very rare group of humans that seem to be doing something right that maybe the rest of us are not doing. But, but, but genetics is at the

heart of your studies. And I want to start by asking,

this is my profound ignorance, Nir, but we read recently from a Calico study that the variation in human lifespan, short lived, long lived, the variation in human

lifespan, only like 7% of that variation

is accounted for by genetics. First of all, do you believe that?

And then secondly, I want to connect

that to your work on exceptional longevity. And is there a contrast between those two things?

Yeah, exactly, exactly. Look, I think the efforts mainly of demographers to figure out how much is genetic and how much environment is a little bit funny even in their minds. Because in their minds, okay, 80% goes to this side of the room and 20% to this side of the room. When we know that it's the interaction between the environment and genetics are important. Let me say it in a different way. Let's say 7% is genetic. If we find what are those 7%, couldn't we design a drug that will protect us against the other percentage? The second thing is some of those studies, I'll give two examples. Some of the studies look at the correlation between lifespan of parents and their kids. Okay, so my grand, my grandfather I mentioned he died from heart attack at the age of 68. My father also got a heart attack at age of 68 and he got a stent and triple bypass and he died at 84. So the lifespan don't seem to match. But obviously they got the same disease at the same age. Okay, so the genetic was actually part of it. And the genetic was of hyperlipidemia, which I have and I'm, I've been treating it for all my life, so I hope, I hope to prevent it. And another example is from identical twins. Okay, yes, identical twins have 25% genetic contribution to their longevity. It's a bit more than 7% but it's still, it's still not that convincing. But this is the problem. I've studied this phenomenon with intrauterine ligation where we get pups to be small for, for their gestational age and they get.

This is. This is mice near or rats.

This is, this is rats actually. This is rats. And they get age related diseases. I mean amazingly, animals don't get diabetes usually. You really have to try hard. And they get diabetes when they're three and a half months. It's, there is a hypothesis, a Barker hypothesis. It came from an unfortunate experiment in World War II where yeah, people had famine and, and they were born small and they got into lots of trouble. Young, younger, on diabetes, hypertension. So identical twins, a lot of them are born not symmetrical, but one of them is small for gestational age. And if they're less than five pound and a lot of identical twins are less than five pounds, they get an aging mechanism that we think is epigenetic. And that doesn't reflect the rest of us. So I don't think this is a real good model. But I would say it now from the opposite side, in our centenarians, it looks like that it's more 80% genetics and 20% environment. In fact, from an environmental perspective, where 60% of the men were smokers, 30% of the women were smoker, overweight or obesity, more than 50% of them exercising, even modestly, you know, just walking.

Yeah, yeah.

Less than 50% vegetarian, 2%. So. So for our centenarians, it's clearly more genetics. And. And lastly, our offspring of centenarians, which are part of longitudinal study, we had the paper that kind of really nails it because we have all the data on the offspring in our control environment, we knew what food and what proportion of food they are eating and how much alcohol and how much cigarette they are smoking, and the micro. And the micronutrients and their BMI and everything else. And between the two groups, they were totally identical. Totally identical. However, their cardiovascular disease prevalence was almost half as low. Yeah, so you almost match the environment at a very. At an age where it counts, not in centenarians, but when they're 65 to 75, and still you see that the genetics plays a protective role because they get half of their heart attacks. And by the way, it's true for Alzheimer's, for other things that we are monitoring.

This is one really important contribution you've made is to be studying the children of the supercentenarians and centenarians.

Just before we get into that, how

many people make it to 100? What proportion of the population?

Oh, it's actually hard to know. It depends what method you do. But when I started, it was considered that 1 out of 10,000 is 100 years old and that there are more of those because they are a little bit bionic. There's more people with, you know, pacemakers and artificial beams and stuff like that. But, you know, we tried to look at that through the voter registry in the Bronx, where Einstein is, and we found that the ratio of centenarians is 1:2000. Until we realize that we have like hundred people over the age of 150 and thousand over the age of 130. In other words. In other words, you know, we have to know that there are voters out there that are using some other instruments. But it's really hard to know and to even validate the real age. But I would say one out of. I would say it's rare. It's from genetic perspective. It's rare enough.

Yeah. And then supercentenarians over 110 again, that must drop off to a remarkably small number.

A huge drop off. I mean, look, even in centenarian you lose 30% each year. Okay. So you know, your, your chances of being that, that is really not so, not so high.

So.

So for the non geneticists out there,

just describe how you, how you, how

do you find genes that are associated with longevity or exceptional longevity using this structure that you've used, this control group of younger individuals or children? Just unpack that a little bit for us.

Right. Let me just say, let me before that just say another thing because I want to eliminate some other possibilities for their longevity. I kind of told you from the environment perspective, they haven't really reacted like that's not the reason. In fact, in our paper we have control of their cohort, okay. That's called NHANES1. And we see that they're a little worse than their cohort even. So that's not it. The second question for us is, you know, we know that there are genes for Alzheimer and cardiovascular disease and cancer. Maybe our centenarians just have the perfect genome, I call it. You know, they just don't have any of that nonsense. So the first experiment we did, which is just cool and easy to explain, we had 44 centenarians that we had the whole genome sequence. No control, no young control, no just them. But there is a resource that's called Clinvar. Clinvar accumulate all the mutations that are associated with diseases. And we wanted to have those that are most probably causing disease. And we said, you know, at least we'll see if they don't have any of those mutations. They have pretty good genome. We were not ready to the fact that 44 centenarians had over 130 mutations that should have made them sick. And among them as an example are two people who have two men who had APOE4 mutation. And the textbook will tell you they are demented at 70 and dead at 80 and they're 100 years old and not demented.

Incredible.

Which kind of shows that if they, if they have slow aging, they can escape some of those diseases. And of course Alzheimer's, you can born with Apoe 4. You're not demented when you're born where you're a 10 year old or 40 year old. It takes you, it takes the biology of aging to bring this disease. So if you can escape it long enough, you even don't get this disease. So I just wanted to take off the environment and the perfect genome out of the equation. Now to tell you, and I think we've done this gene, the fact that the genome was sequenced was such a breakthrough and it's very important. But then we did something really silly. What we did is we took one mutation at a time and one disease at a time and we said, are they correlated? Let's look at one wrong sequence for diabetes, okay. And let's see in the old people, all people in the world, let's take 100,000 people and see if there is a connection. When in fact we're not built of one change at a time. We're built from many changes at a time. Some of them are upstream and some of them are downstream. And the biology is complex. And, and although we use this to find significant findings, what we are doing now is actually finding all the differences between long live individual and those without longevity. Okay, so they're younger.

Yep, yep, yep.

And unrelated. Okay, that's not. The offspring are unrelated. But what we're doing with computational, with AI is putting them into pathways. Then we're asking what are the difference in the pathways between those with longevity and those without. The interesting thing is we're getting what we got from animals all along. IGF insulin signaling pathway, MTOR pathway, you know, MAP kindness pathway. In other words, we, when we do it this way, we get confirmation that the models you're studying, Gordon, are as we claim, that aging is conserved, that even the longevity part is really conserved. And I think that's one very important contribution to remember that we're relevant in all our models.

Isn't this amazing? Like I can't believe really we're having this conversation. And when I started working on C. Elegans, the tiny little microscopic nematode, I never thought we'd have anything significant to say about human aging. And I actually, when your longevity gene project, Isn't it like 24 years ago it started?

Yeah, in 98. Exactly.

So in 98, what was your thought processes?

So I guess you're reading some of these papers from worm people and fly people. Maybe you're going to conferences at, at that time, talking to them. I mean, did you really foresee that the stuff that they were doing would be relevant to your thinking about human aging?

So let me tell you a funny story. Gary Rufkin, Cynthia Canyon Wright had their papers and it was fabulous. The concept that one gene changed lifespan was just the most fabulous thing. But for me, it was the wrong gene. It was the insulin signaling pathway. And I am, I'm an endocrinologist. I'm actually a diabetologist. I'm seeing patients couple of times a month. Okay. And the problem with type 2 diabetes, they're insulin resistant. Which. What, what, what? The nematodes were pretty much.

Yeah.

And not only that they're insulin resistant, where the inpatients, their main problem, they have abdominal obesity, they have lots of intra visceral fat and the nematodes that fed in their intestines too. And I remember organizing this symposium in the American Diabetes association meeting and bringing Cynthia Kenyon and it could have been great except she's done a re faux pa. She basically said in the diabetes that if everybody will be type 1 diabetes, they would live longer at the time that it was hard to maintain them alive. So. Okay, but, but you know, it's not only the insulin signaling, it's the IGF signaling pathway. And. Yes, and it was. And I'll tell you, I'll jump ahead and tell you. 60% of our centenarians have some functional alteration in, in the IGF1 signaling pathway. 60%. It's the most common genotype. I think it's almost a genotype. It's, it's, it might not be the only one, but it's really relevant and it's consistent with the fact that, you know, that the small dogs live longer and the ponies live longer and those nematodes live longer and the Barki mice live longer. And it was very consistent with that. But this is just for the story sake. The human data. We just figured out the human data recently where they had an aging cell paper not long ago where we resolved this issue. But the data that was existing for IGF was very confusing. Some showed that IGF is good and some show that IGF is bad. IGF is the insulin growth factor. Insulin growth factor one is really one of the major a factor of the growth hormone system. Okay, just.

Yes, yes. And that explicitly makes the connection to the small dogs, large dogs thing.

Right, Exactly. So, so when I wrote my first grant on the IGF system, it's one of the grants that I said, I'm writing it, I can write it, I can justify it. I really don't believe this shit. But this is actually maybe the only draft. You know, we all write grants and we discover important things no matter what, but our hypothesis is usually not right. This was a hypothesis that I didn't believe turned out to be right.

Yeah, no, it's an amazing story. A little bit more about the sort of methods around studying humans and studying human Genetics. I know most of your work has been in animals and endocrinology, but you're very well known now for these discoveries and exceptional longevity.

Tell me the story of the Ashkenazi

Jews and why they are so important to your studies.

Yeah, look, it's not only that there are few centenarians, it's also hard to recruit them. And we try to find basically a shortcut. And the shortcut in genetic research is if you have more homogeneous population. So rather than go in New York City where it's one of the most diverse, or the diverse, I think I just read the most diverse in the world where there are so many genes and so there's so much noise that you have to account go to a single population. And that time the single population was the Icelandic population. And they really were having major discoveries like up to 10 years ago, they were the population where you had discovered it's only 500,000 people, but they were all brothers, cousins. Right. The other population that was example are the Amish. Okay. The Amish population have hundred founders, so they're also pretty much relative inbred. And so for me, the next population, a population that I'm one of them and I had connection, was the Jewish population and the majority of Americans, American Jews are like more than 90% are Ashkenazi Jews, which means they come from Eastern Europe. And because of an unfortunate history, there's lots of inbreeding and also death bottlenecks that made this population European, but very homogeneous genetically. We know that because when you have such a population, some of the rare heterozygosities can become homozygous just because you're the same population. So diseases like Taizox and some hemophilia are more prevalent in Ashkenazi Jews, just to exemplify how unique they are now. So genetically it's homogeneous. And we actually retrospectively went and showed that we would need it's, it's, it's mutation, it's genetic, it's genotype specific. But yeah, sometimes you need 20 times more people, sometimes 50 times more people to get the same effect. So I had to recruit, you know, in a exponential magnitude, more people to get the same effect. So this, this thing has helped a lot.

Is there a social component to this in terms of recruitment, for example, and then retention, why people would stay in your program? Is that part of this population as well that's strong?

Yeah, absolutely. But the reason is even different. In the United States, most of the western world, the poor people live 15 to 20 years less than the rich people. Okay. Or I would say differently. I think it's the level of education. And the level of education of the Ashkenazi Jews in our study is very homogeneous. Okay. Their income vary, but the education is the same. They all have access to health care. So we didn't have to adjust for one of the major factors that are associated with impaired longevity.

Yeah. Okay, got it. So in studying this population, you find genes.

Tell me something.

I mean, you've hinted at this already. Obviously, the IGF signaling pathway is a strong component. What other individual genes have come out as being major players?

So the major players that come. That came out, and I call them major players because they were already translated into therapy. One of them is a functional SNP in a gene that's called ctp, cholesterol ester transfer protein. By the way, this gene does not exist in mice and rats and in many other animals. But when this gene is inhibited and it has to do with cholesterol ester transfer. I don't want to bore anyone, although I'm very excited about telling you this, but when you inhibit cholesterol ester transfer, what happens that you can measure is that HDL cholesterol, the good cholesterol, goes up and triglycerides are going down. Okay. Has nothing to do really with ldl.

Yeah.

And it was interesting for us. And the reason we looked at this gene is because our families of centenarians had very high HDL level and very low triglycerides. And we found that this functional change in the CTP gene went from like 8% in our population to 20% in our population. And it was kind of going on. It has a linear increase with age. In other words, with age.

Yes.

More people survived, the more of them had this snp. Now, Merck was interested. The CTP target has also a long history, but Merck was interested in that and developed a drug that went through phase three trial. It's not a drug that they are selling right now. They're looking for some opportunities. But the results of their study showed that people who took this drug had much lower cholesterol and much less cardiovascular diseases. A phase three trial. Similarly, we found almost really the same story in another gene that's called APO3. APO C3. Sorry. And APO C3 is also kind of a cholesterol gene also associated with low triggers. And high HDL also goes from like 8 to 10% to 18 to 20%. Some overlap, but that really means that almost 35% of our centenarians have one of those. And there's a company that at the time was called isis. They needed to change their name. They're Ionis now, but they also had a drug, and I think they're going to sell it. It's a. It's an antisense for the APO C3. And the effects were pretty tremendous. So I'm just. I think the moral of the story, thinking as I told it, is that people say, oh, you're doing genetics. Well, good for you. We don't have these genes. We need gene therapy to do it. No, the genetics is to find mechanism. When you find mechanism, you usually can find a drug. You don't need to do crispr. People are saying you have to do crispr. No, you don't have to do crispr.

Well, okay, let's talk about drugs. When do you think we're going to treat people? At what portion of their life would some sort of aging intervention most likely to work?

Can I ask you, are you taking anything?

No, I'm just taking exercise. Well,

we have geropherapeutics and geroprotectors. So you're doing a geroprotector because. I'm taking metformin. Okay. But frankly, my doctor put me on metformin because it's some stage of my life. I was pre diabetic, and I'm not anymore. But I didn't stop Metformin and he didn't stop it for me. And I'm, you know, I'm kind of. I'm saying it now. I wasn't proud initially because we're very few doctors. You know, Eric. Eric is one of the doctors, Jim Kirkland and Tom Randall and. And, you know, when you're a doctor, you realize that the first day in medical school, they teach you do no harm. Okay.

Yeah.

So you're very conservative. You really don't want to do anything. Okay.

Yeah.

The second day, they'll tell you there's no always and there's no never. Okay. So you can give a good drug and it'll be bad, too. Okay. So you're confused. You're conservative and confused. And I'm always saying people at the FDA went only to those two days in medical school because they don't let us move at all. But I think we have to understand that we really, in our evolution of doctors, we always were just doing a little bit more good than bad, and we got forward with that. But we also killed a lot of people and probably were still killing people. So I think we have to be Conservative. And that's why I'm saying you have to have clinical trial in order to make a judgment. Look, metformin is a drug that's been around so much, billions years of use, very safe drug. Any doctor can repurpose metformin. It's the right of every doctor. But if people ask me, is there a proof? I said, no, there is no proof for the study that I'm doing, although there is a proof to each component of this study, but not the study the way I'm doing it. I'm very reluctant as carrying this obligation to say, well, I'm taking metformin. But on the other hand, we're getting at the age where we see that it's slow and we know that there's a promise. And what should we do? Sacrifice our aging, our healthspan?

Yeah. Well, actually, we did a study in nematode worms with Patrick Phillips and Monica Driscoll quite recently with metformin. And you probably remember that Monica published many, many years ago Metformin extending lifespan in Worms. In this most recent study, we're looking at different strains of wild worms and different species of wild serumditis. We saw really diverse effects. It simply didn't work in some strains and species, and maybe it was even detrimental in some. That points obviously to genetic background being really important in the response to drugs. This is probably no surprise to anyone, but it does get to this question about how do you, ahead of a clinical trial, how do you actually structure it? Is there a way to find a subgroup of people who will respond to the drug in aging and those that would not? I mean, that would be fantastic to know. Right? Because if we just take a random population, we may not see the effect size that we'd like to see.

Right. But look, our preliminary data, that is very substantial. Okay, so I'll give you two examples. The study that's known as the DPP Diabetes Prevention Program took people who are normal glycemic but had risk for diabetes, obesity. Family members took risk, but they were important to know they were not diabetic and gave them either metformin or lifestyle changes that include exercise and diet. And it was a five year study, but it was stopped after four years because both lifestyle and metformin significantly prevented diabetes. So delayed diabetes and the effect was 30%. Okay, so you're asking, well, why it's not 100%. But most of the drugs, like the cholesterol lowering agents that are really considered good, have 20% effect in a population. By the way, it's 20% over the observed years. Okay, yes. Okay. So. Okay. But basically when you have an effect that is over 10%, it's not a private event. It's a very common event. Okay. You can say that at this period that most of the people are going to benefit from metformin. And the effect, the number of people that we chose for this study was based on the dpp. Even the amount of drugs we're taking is based on the dpp. Similarly, there was a UK study, it was called UK pds, where metformin was in diabetes, was compared to other three classes. One class of drug by three drugs that are called sulfonylurea and insulin and only metformin significantly decrease cardiovascular disease. And I can go on more and more studies. It was also a 30% effect. If you look not at clinical study, but if you look at 250 studies about cancer and metformin use, it's a 30% effect for all cancer except prostate cancer, when you have a 30% effect over an observed years. This is a public player. Okay. And you know, and then there's the side effect because 180,000 people in UK that were studied with, you know, those without diabetes, those with diabetes on sulfonylurea and metformin, people who took metformin who were diabetic, more obese, and had more disease to start with, had lower mortality over five years than people without diabetes.

Yes.

Yeah, it's amazing, by the way. It's, you know, when Rich Miller says, hey, you know, I don't get itp, metformin or the effect of metformin are low and it has to do also with your nematodes. Yeah, that's in mice and that's with the dose that you give them. That was. There's a dose response. Okay, yes, but we already know in humans that the effect is greater even compared to normal. Look, metformin versus sulfonylurea in human is 50% less mortality and from non diabetic it's 17%. So it's more than Rich Miller's already in a statistical. So some of those drugs. And I think, look, we can expect that maybe rapamycin, maybe metformin is better in humans and rapamycin is less than what we thought from animals. It could be, you know, but that's.

Yeah, no, makes perfect sense. Makes perfect sense. Do you think that.

How do you see biomarkers playing out here?

Because maybe we can improve even these numbers by appropriate dosing and maybe that's a response to the drug that we can track with biomarkers whether it be epigenetic or protein or others. Do you think that's likely?

So remember, the biomarkers are not interesting only to distinct between biological and chronological age. We want them to change with therapy. Okay. We don't want to do phase three trial for 100 drugs and spend trillions of dollars on them. Right. We want in two months on a phase two study to see are the biomarkers changing. Okay. That's our challenge.

Yes, yes.

And I picked actually proteins as the most likely biomarkers. Also listening to Harvard who said, look, you're not going to change methylation in nine months or even more than a year of treatment. And we measured 5,000 proteins by haftamer on thousand of our people in the longevity study, half offspring and half control. And we ask what's changing between ages 65 and 95? And there are many proteins, but the ones that are really incredible to me are proteins that show breakdown, for example collagen, extracellular metrics, even degranulation of platelets or breakdown of some cells. Because I think that it's the breakdown that we want to stop. We can stop it by many treatments, but it's that what we want to stop. So we now had actually a conference in the NIH supported by Mayo and Afar and other people. I brought in some ideas that we're going to accelerate because there are some. The dpp, for example, that I told you about, they have samples where we can actually look at the effect of both lifestyle intervention and metformin by omics, do omics of everything, proteomics, metabolomics, methylation, whatever, and really try and see what happens in those study. Also there's another drug, SGLT2 that I think is really a very important gerotherapeutic in humans. You give it to diabetes, but you prevent heart disease, you prevent kidney disease, you prevent all cause of mortality. Itps show that it elongates lifespan of of Rich Miller's mice. So I think that's the way to go fast.

Very promising, very promising. I mean, we've seen recently in mice with Brian Kennedy's lab that we actually can see a compression of morbidity in this case with a metabolite. That's what's going on with these human results. Right? You're really reducing the period of sickness and that has an enormous social and economic effect down the line. Nir, this has been fascinating. Thank you so much for your time. I've learned a lot and thank you for your public outreach and your advocacy at the FDA and other places for this field and I hope to see you soon.

Thank you. Me too.

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