Longevity Genes, Blood Biomarkers of Aging, & Targeting Aging with Metformin with Dr. Nir Barzilai

Both showed that our centenarians, compared to people who live now, get diseases 20, 30 years later. Okay, so it's not only the lifespan, it's the health span. And that's even not the most interesting thing we found. Those people have what's called a contraction of morbidity. They're sick, very little time at the end of their lives.

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Hello, I'm Ashley Reaver and I'm joined by Dr. Gil Blander. Welcome to Longevity by Design, how to live a Longer, Healthier life. We're produced by Inside Tracker, your science based guide to optimizing your body from the inside out. Our guest today is Dr. Nir Barzilai. Dr. Barzilai is the Director of the Institute for Aging Research at the Albert Einstein College of Medicine and and the Director of the Paul F. Glenn center for the Biology of Human Aging Research and of the National Institutes of Health Nathan Schoch Centers of Excellence and the Basic Biology of Aging. He is the Ingberg and Ira Leon Rennert Chair of Aging Research professor in the Departments of Medicine and Genetics and a member of the Diabetes Research center and the Divisions of Endocrinology and diabetes and geriatrics. Dr. Barzilai's research interests are in the biology and genetics of aging. He studies the genetics of longevity and his studies on families of centenarians have provided genetic and biological insights on genes and factors that delay aging and protect against age related diseases. Several drugs are developed based in part on these paradigm changing studies. Dr. Barzilai is also leading the team Targeting Aging with Metformin study to prove the concept that multimorbit morbidities of aging can be delayed by Metformin, working with the FDA to approve this approach which will serve as a template for future efforts to delay aging and its diseases in humans. He has authored over 300 peer reviewed papers and was a recipient of numerous prestigious awards including the 2010 Irving S. Wright Award for Distinction in Aging research and the 2018 recipient of the Ipsen Longevity Award. He is on the board of AFAR and its Scientific Director and a founding member of the Academy of healthspan and Lifespan, the Longevity Biotech association and the Healthy Longevity Medicine Society. He Also Co founded two biotech companies, Cobar and Life Biosciences. Dr. Barzilai has featured, has been featured in prominent papers, podcasts, TV programs, documentaries,

TED Talks, has consulted for this becoming very boring. You know, the only thing it tells me how old I am. That's all it is, guys. If you're listening, you'll get there if you live long enough.

Well, my last sentence, consulting for the Singapore government as well as several international banks, the Vatican Milken Institute and Davos Economic Forum. His book Age later was published in June 2020. And we've done it. I told you it was really long, but we had to get through all the accolades.

I fell asleep. Nothing was new.

Well, thank you for joining us again.

Yeah, Nir, we interviewed you a couple of years ago and it was a great episode. I really liked it and I think that our audience really like it and us, we liked it. And last year at the end of the ALD conference, we bumped into each other at the airport and we spent some time together and somehow I convinced you to come again. So thank you so much for that. And we, we really want to zoom in at the beginning on centenarian and try to understand what are they and how can someone normal like us can get to and have the benefit of people that live 100 and above. And so we would like to start with that and the, and maybe we'll start with some key insight from your research studying centenarian. What is, what is maybe the size of the cohort that you studied? And what about their ethnicity? Who are they? Who are your subjects?

Right, right. But I want just to tell you why, why we studied them. Look, we studied healthy centenarians that their life expectancy compared to the cohort that they were born was basically doubled. Right. Their friends died when they were 50. If they were born in 1900. And this is more than the model that I was using, more in the lab. And I, I also am a neurobiologist and you know, and a metabolic guy. But we use caloric restricted animals where we extended life by 30%. That is a lot, by the way. But centenarians seem even much more extreme to than that. And they were also humans.

Okay?

So that's why we started to do that. And when I got into this research from a human perspective, what people did. George Martin was a great leader to our field. He looked at progeria, which is a rapid accelerated aging disease. And I thought, but hey, why don't we look at the other extreme and see if we find something different? I mean, I already knew from genetic studies, I was doing a lot of diabetes initially and I knew you can, you can, you can interrupt with many pathways and get animals with diabetes. That doesn't mean that that's the diabetes in humans. So yeah, you, you have progeria. It's really tough. They're really aging fast, but maybe that's irrelevant and you age from something else. And so that was the background. So how do you do a significant aging study? Well, few things to consider. Centenarians are very rare. When I started, this was one of 10,000. Not only it was one to 10,000, we called them virgins in the sense that now centenarians are one of 5,000 or even less. But now they have hip replacement, pacemaker, they're more bionic. Okay, those were, when I started, they were like nothing. They just got there. The second thing, because they are rare. Well, how can we take a rare incidence and find substantial genetic discoveries? And the Icelanders showed us how to do it. So Iceland are half a million people and they're all children of five Vikings and four Irish women. Okay. They're like cousins, brothers. So if you have a population like that that has been isolated and some of them have diabetes and some of them not, then it's easier to find the genes for diabetes. Much easier. When you have a population that's diverse and you don't know their genetic background and you get so much noise that is absolutely incredible. And some of the noise is what depicts diseases for some, for some reason, and it's a total false positive thing. So with this in mind, we decided, because I'm in New York and in New York or in the northeast of the United States, there are lots of Ashkenazi Jews, which is, Tell me about it, tell me about it. Which are. You see, Gil and I look like cousins, right? We had this history of inbreeding, isolation, holocaust. And so we are much closer to each other. In fact, from our studies and, and others, we showed that in order to find the same changes in the DNA, we would need 50 times more people than if we do only Ashkenazi Jew, by the way. It's gene specific, so I'm kind of oversimplifying it, but, but this is a shortcut. And so, and so we have, we have two studies. One of them is the study where we recruited centenarians, almost 750 of them. And in that study we also recruited their children or one of their children. And A control. But we have a longitudinal study now that is really more important in many senses, where we take the offspring of centenarians and the control and we are watching how they age. And I can give you example of why it's so important to do that. And I would tell you the offspring of centenarians are kind of 10 years younger. They have less cardiovascular, less, Less mortality, less Alzheimer's than others. So we can get the effect of the genes on the next generation. And so this is our playground.

Yeah, and a couple of points, Neil. First, the point that you mentioned at the beginning that literally they live twice than their peers.

They.

That's something that I haven't thought about it. But if you think about the date that they were born, the lifespan at that time was really 50. So you cannot compare them to today lifespan that is around 80. So that's an amazing point that I never thought about it. And everyone should appreciate those guys live much, much longer than their peers. That's really amazing. And the second point, actually earlier this week I was listening to a presentation at Tufts University and a professor there did a similar study to what you are doing. He looked at, I think like 10,000 people randomly. 10,000 people and divide them to people who live at least 70, 80, 90, 100.

That's the Centurion.

And then he basically looked at the appearance of a specific disease. And what he found is very similar to what you are saying. It's literally there is a delay if you live to 80 versus 70 or a specific disease, start a bit later. Like you have a shift to the right and the same from 80 to 90 and 90 to 100. And what I wanted to ask you is it overall shift or there are some diseases that starting earlier with centenaria and then the majority of the diseases.

So we have a study that's quite highly quoted because this is really the question, the question for us, are centenarians actually getting sick when we all get sick and they're sick for longer. Okay, what's the fun in that? Or is their lifestyle lifespan or health span goes together. So we did a study with the. With a Boston group to Tom Pearls, who has also a large number of centenarians. And we harmonized the data and we both showed that our centenarians compared to people who live now. Okay, so not their friends. Okay. Could compare now get diseases 20, 30 years later. Okay. So it's not only the lifespan, it's the health span. And that's even not the most interesting thing. We found those people have what's called a contraction of morbidity. They're sick very little time at the end of their lives. It's kind of what, what I wish we would do. We just leave, live, live and die. And it's not going to be too early. The CDC have actually looked. The CDC is doing lots of measurements. They were busy with COVID recently, but they're doing lots of measurements. And one, one of their assessment is the medical cost in the last two years of life. And when they look by age you can see that centenarian. The medical cost in the last two years of centenarians is third of those who die at 70. Okay. So we have a really a larger approval for this fact that they live healthier and have contraction of morbidity. And that has a huge consequence from the point of view of longevity dividend and what it means for the economy if we can make people healthier and not seeker.

Yeah, definitely. My dad is, his parents are still alive and they go to the doctors like four times a week. It is a full time job taking them to their doctor's appointments. So you have these ongoing studies going on. Do we know if being a centenarian does have a strong genetic component to it?

Yeah, absolutely. So I'll tell you another really interesting thing. So we had our first. We had the whole genome sequencing of our first 44 centenarians. Okay, what can you do with it? We don't have control. It's not enough, enough numbers. But we could do something very simple. We could ask do they have less genotypes for diseases. We know that we can find genes that are associated with diabetes and Alzheimer's and cardiovascular disease and all that. Maybe they have the perfect genome, you know, maybe they just have not of the other thing. That's why they get there. So we went to this web that's called Cleanvar. I don't know if you're using Cleanvar at that time. We're talking 10 or 20 years ago, I don't remember when. But they had 15,000 genotypes that if you had them, you most probably had a disease. Okay, 15,000. And we said, okay, we don't have a control but maybe they don't have any of those. We were not ready to see that not only they have, but everyone has 5 to 6 genotype that would probably have caused them disease. And they're 100 years old and they don't have the disease. And some of those genotypes like we have, we have centenarians who have APOE4 homozygosity this, you know, huge risk for Alzheimer at 60, 70, death at 80, and they're 100 years old and they don't have Alzheimer's. So this is an example. We have much more. But I think that's a striking example to show that it's not because they don't have genotypes for diseases, but their aging has slowed so much.

Okay?

Because all those diseases, you know, when you're APOE4 genotype, you're not born demented and not when you're a year or 10 year or 50 years. You need the aging, okay? So if you take this aging away, you don't get this, okay? So, so, so this was our first proof. I mean, I'm telling you chronologically it wasn't. But this shows that, that it's not, it's not that they're, they have perfect genome, but they have genotypes that are slowing their aging.

And, and what are those genotypes? What, what, what is different between them and us?

So there are many answers for that. I, I would just say one thing. There's no one pathway to be centenarian, okay? It's, it's kind of like the hallmark stories, the hallmark of aging. You can target one and you can still get health span and lifespan and affect all the others. You have to think of it this way. But I will start by telling you the most common pathway that is affected is the growth hormone IGF signaling pathway. Okay? And, and this is really interesting and it has actually a clinical significant and drug development significant because for example, the first thing we noticed is centenarians are, they're already centenarians, okay? They're all already 100 years old. And when we looked at the level, the median of IGF1 level, right. IGF1 level is really the peripheral measurement of growth hormone. Cannot measure growth hormone because it's complicated, it's pulsatile, it's not decline. And IGF doesn't come only because of growth or anyhow, IGF1 level is really the big marker of growth. And the, the women with the lowest level of IGF1 live twice as long as those with the highest. They are already 100 years old. But you could see that not only that those women had better cognitive function and they didn't have any trade offs, they weren't weaker or muscle or something like that.

But.

Okay, but let's try to understand this. And it has to do with this hypothesis that we are all talking about. It's the antagonistic pleiotrophy hypothesis of Aging, and that is the things that are good for you when you're young might turn against you when you're old. You know, you need a lot of cholesterol metabolism to build the brain, the ovaries, the testes, you know, whatever. But you know, if you have high cholesterol metabolism when you're old, you get coronaries, right? So not everything is good. We. So when, when I started research and I, I would tell you just an interesting anecdote for scientists, I got, you know, grants for like $40 million. I, I don't count anymore. And for a grants, you have hypotheses. And most of my grants, their hypothesis I disproved. That's okay. I found the truth, you know, that the hypothesis was good. The only hypothesis that I thought that's totally bullshit was when I said growth hormone is involved in humans aging. Although in nature the dwarf lives longer, right? The small dogs, the ponies, you know, all those live longer. But I thought not because actually the clinical studies didn't show that. We had a lot of correlation. It didn't show it, but I thought it's, it's a good hypothesis and it's the only hypothesis that I proved from every side almost. So we went, okay, so, so the concept is this, when, until the age of 50, it's nice to have a lot of growth hormone. You need it for reproduction, you need it for strength, you know, okay, it's good now you, you're over the tip and you're starting to breaking down, to break down. Does it make sense to invest your energy in growth? Okay. You need to now have the energy for breakdown, you need to, you know, do inflammation, things like that. So in order to show that, we went to the UK Biobank, okay, where there's a lot of data and they're like 250,000 people who had IGF1 level in all their clinical studies. And we showed something really interesting, that when we look at people before the age of 40, when, when they have high IGF1 level, high growth hormone activity, they're protected from everything. They're better, they're. They don't have diseases. Not of the kidney and not of the brain, and not, not mortality. And then it totally switched. After the age of 50, the higher levels of IGF kill them. So that, that was actually a really good proof of this hypothesis of antagonistic pleiotrophy. And it's really important because this affects a lot of people and a lot of people, you know, like Peter Attia, right. Who kind of does a Lot of the. If you don't understand this antagonistic pleiotrophy, then you think that everything that's good for young is good for old. And that's a problem. Okay, that's a problem.

So what you're saying, it's complex, it's IGF one is good for young people, but it might not be good for old people. So do you have, like, have you back up this hypothesis by looking at the offspring and see that the, the offspring of those long lived. What was the level of IGF1 in the younger age? Is it.

This is in work, actually, this is in the lab. But I'll tell you what we did do, okay? We, we. So this is discovery from humans, right? So we used to go from animals to humans. Now we go from humans to animals. So the pharmacy Pharma Pharmaceuticals have developed an antibody against the IGF1 receptor. Why? They developed it because cancer has a lot of expression of this IGF receptor. The growth of the tumor is dependent on this IGF 2. And they said, let's, let's shut it down. And actually they even shut it down. You get this injection once a week and you really decrease the ability of IGF receptor to phosphorylate by more than 50%. So now we moronize this antibody, we got it from the industry, we gave it to old mice, and, and guess what? They were much, much healthier and they live 10% longer. So the proof, the proof of concept was from humans to animal to animal, back to, you know, there's a drug, the drug wasn't successful to cancer. But, but, and, and it's hard to find an indication, you know, with. Aging is not an indication yet. But it's hard to find an indication. But, but this could be repurposed somehow for a different reason. Yeah. So.

So Neil, you're saying IGF1 is one pathway, but you said that you can become centenarian from diff for many other pathways. So what other direction make them immune or live longer?

So I think the most common, by the way, the IGF receptor, the IGF growth hormone. You need not only the whole exome sequencing or whole genome sequencing, but you need to do something that geneticists haven't done. You have to put it in a pathway. Okay. We used to do very simple thing. We used to have those millions of snips and ask, is this changing diabetes or not? Yes or no? We're not built from one SNP at a time. Right. We're built from many snips. So one of the Things was to put it into the growth hormone IGF and see what happens there and then look at some specific examples in the lab and show that they're function. All those are functional functioning mutations or biology to target that. So that was a very important part.

Okay, and what other pathway are important?

Oh, sorry, the other pathway. So the mo. So those are rare variant that were put. They're common variants that have functional consequence and they're both in the lipid metabolism pathway. Though both of them had same phenotype. What they do is they increase the good cholesterol and decrease triglycerides. One of them is enzyme called CTP, cholesterol ester transfer protein and one is APO C3. The interesting thing about that, that when we published our papers, pharmaceuticals started looking at that and Merck and Ionis, by the way, Ionis was ISIS at that time. So they had to change, to change their name. But Merck and Ionis have developed one CTP inhibitor phase three trial. Now they're going out to, with some combination therapy and Ionis also with an APO C3 inhibitor. And, but they developed it not for longevity. Okay. They developed it for cardiovascular reason for changing the HDL and triglycerides. And. But I'm, I'm thinking that if, if you have a, you know, if you have those, I'm thinking it's also should be considered as a longevity drug.

Basically.

By the way, I asked Merck, the people with a CTP mutate, it's not mutation, it's variant because it's common. The, the CTP variant, the people who had that had also the best cognitive function. Okay. Among centenarians. And so when Merck developed the drug, I said you should look at cognitive function. And they said we looked at cognitive function. It had no effect. Well, the test, you know, when, when you take middle aged people and give them a cognitive test there, there's no way, you know, they, they all get good scores. Right. It's like Trump saying he's a genius. Yeah, it's hard to fail if you're not demented. Okay, so they did, they didn't, they didn't. Unless you politics. But, but, but you, you know, the point is they didn't check it in the right population with the right tests. So I'm, I'm still thinking that once this CTP is out, people will test it and find because ctp, people with CTP genotype have less cancers, there's less Alzheimer's. So what, what, what's, what's going on and can we actually protect.

And it's interesting to bring up the HDL too, because you know, in relation to what you just said about. It's the pathway that's most important, not this one thing. You know, we know having higher HDL can be protective against cardiovascular disease, but no therapies to increase HDL have actually paid off.

Right. So those two are the next, next therapies.

Yeah.

Super interesting to play devil's advocate. I have a feeling that individuals that hear that if you know, know growth factor isn't there, your muscles are going to just disintegrate and your last 10 years, you're like spent in bed, so to speak. So your lifespan would increase, but not your health span. Is that something that, you know, you saw with those older people that had lower levels of IGF1?

No, they were health. They were healthy and good. So. And they did. I said they didn't feel for muscle. Okay. It's. It's complicated in the sense that the muscle is playing a funny thing compared to the rest of the body. And it kind of worries us. For example, rapamycin, right, which is a drug, we all talk about it elongate everybody's life. But rapamycin, which is an MTOR inhibitor, if you inhibit mtor, you cannot build muscle. Okay, it's good, it's good for longevity. But, but you pay with muscle. So how do you, how do you play around? There are trade offs and I would tell you just, I don't know, are we talking about metformin? I can, I can.

Yeah, we'll get, we'll get to that.

We'll give an example, I'll give an example of. But, but yeah, I'll give an example that has to do with IGF and mtor. And you're absolutely right, we have to worry about trade offs. But I'll tell you the overall thing. If something is good for your health, it's usually good for every organ in your body because it's kind of upstream of the aging of all cells. Not, not exactly the whole truth, what I just said. But the principle is.

Yeah, it makes sense. We are very complicated machine and it's not like the relationship are not always one to one. Makes a lot of sense. Neil, a few more general questions that I would like to ask about the centenarian. For example, is it a specific ethnicity that tend to live longer than other? For example, Ashkenazi Jew tend to live longer than other. Or, or it's the same for every different ethnicity.

We, we don't believe so. We don't believe so. Look, the Ashkenazi Jews are homogeneous in my population are homogeneous for another reason that is really important and that is the socioeconomy in the United States, your education and your salary determines your health. So you need to take it out. Okay. And so I would say that Ashkenazi Jews probably live as long as their education and an income. Okay. But we don't believe that they live longer. Okay. I would say just one thing. It's actually Israel, which has half of the Ashkenazi. And this is before the war. Okay. But life expectancy for men in Israel was basically the second highest in the world, maybe third. It depends how many countries you put in. But so, you know, maybe, but, but, but it's not, I don't know if it's Ashkenazi or not. And you cannot have the effect of the, the great food, the beach, the, you know, other, other, the social connectivity that, that is different. But we don't, we don't have evidence to suggest that they live long. That's not, in fact, we, we wouldn't have done it because we don't want them to live long. We just want those guys to live long. Yeah.

So what you are saying in a way that it's education and socioeconomic status is very important for longevity. So if you want to live longer, be educated and try to be rich in a way and then you have a better chance.

And I think the advice that you just gave will not have a view of the people who need to hear that. But, you know, that's another story.

Yeah, no, but that's the reality. I'm not saying that it's good, but that's the reality. A few more questions related to that. Interesting for us. Have you seen an effect of their lifestyle, their nutrition, their exercise that there is some support of a better nutrition, better exercise, better lifestyle and longevity for a centenarian or not at all?

Yeah, well, it's the opposite, okay. Which is very, actually very important to note. So for example, 50% of our centenarians are overweight or obese. So it's not because they are caloric restricted, at least not as a group. 60% of the men, 30% of the women are smoking. Less than 50% have even moderate exercise. I'm talking about housework, walking, biking. 2% are vegetarian. Now I want just to put it immediately in context because comedian when we published that comedians it was on the Tonight Show, Jay Leno, they all said the secret to for longevity is you have to be obese to smoke. And you know the point is, which is, in addition to what I said, they have genotypes, the terrible genotypes. They didn't, they didn't interact with the, with the environment. I always talk about one of my, I have those, my poster children. It's four siblings that were born between 1910 and 1920 in New York City. The youngest, the youngest sister died when she was 102. The rest 110. 109, 107. Okay. But the woman who was 110, I saw her first in New York apartment and I hope she opened the door for me and she was smoking and I said, helen, nobody told you to stop smoking. And she said, all four doctors that told me to stop smoking, they died. Or in other words, if you smoke for 95 years, you probably live long life, right?

Yeah.

I'm not, I'm not suggesting to try that, but it's for them. By the way, my discussion with Helen was always, I don't know how much you're going to live, but maybe if you don't smoke, you live even longer. So 110 is not the world record, you know, so I'm, I'm not saying it's not important, but it's very important for my study to say. It's not that they have less diseases, genotype, it's not that their environment and, and, and this is where you ask about their children. So we have this longitudinal study, right, of children of centenarians and basically their spouse. A lot of them are their spouse because they share the environment. It's the other gender, but they share the environment. And, and we have a lot of data and one of our papers showed that when we compare everything, their nutrition, their macronutrients, their micronutrients, their bmi, their glucose, their everything, it's all the same. But they had 40% less cardiovascular disease. Okay. So it's kind of downstream to their environment.

Yeah, interesting. What about women? Maybe it's not

directly corrected.

Correlated, Sorry. But women live longer and I assume that also in centenarian, they live longer.

Do you much longer? 80% of the centenarians in the world are women. Yeah. In my study it's different because I need, I need, I'm recruiting only people who had offspring. Half of the women, centenarians don't have children. There is an exchange in nature between reproduction and longevity. And even in our study, our centenarians had less children than women that were their friends. Okay, so there is an exchange in longevity, but there is certainly a women, a woman's thing. And look, we. We did a grave mistake. It's all life in retrospective. But in my lab, we all always studied male mice, male rats. Why? You know, we didn't want to deal with menstruation of animal. You know, we had excuses that were not actually not true even. But. But that's what we did. And now we know that even in those drugs that we test that they have different results in male and female and many other things. And of course in humans it's like in the United States it's four years different.

Yeah. Yeah. So. So what I'm hearing from you is a being a woman will most likely will allow you to live longer, but if you don't, if you want to really live longer, maybe don't have kids. That's. That's the.

I. This is. This. We. We didn't do this test. Right. I mean it might be different. You know, what about nuns? They have a protected environment. They support you. Maybe it's social connectivity. So all of them are healthier and some of them are getting to be centenarians. It's not, it wasn't. We don't have data on the longevity of women that had children or not. There is a data actually interesting data from the Amish where, where they have big kinder ships. Right. And. And so if you look at. At fertility or number of children, the more children they have, the more is their lifespan from like 76 to 83 or something like that. The more kids the. Until it's 13. 13 really kills them. That's too much it Ro. But of course. So this is the opposite of what I told you, right? Yeah, but this is really. First of all, it's not an exceptional longevity. It's longevity in the middle. But it has to do with if you're more kids, there are more people who care for you. And that has an advantage certainly in the Amish, you know, back culture. So.

But.

But otherwise in nature, any humans, there is an exchange between longevity and reproduction.

Yeah.

So. So the, the first point nir that you raised, and I think that's a very good point, and Ashley and myself discuss it several times, is somehow the scientific community like to research male mice or male human and so on, and that's wrong. And we see it even with drug, that a lot of the side effect of drugs are actually coming from women because they decided let's make it easy and don't test it on women. And then the women suffer for all the side effects, which is horrible. So that's one thing that we really need to change. We need to test or do experiment on males and females. The second point that I wanted to discuss, we know that women live longer and you said like four years right now between males and females. Why is it, why women live longer than their males.

Let me start with a joke that is relevant to our culture. Why husbands die before their wives because they want to. Okay. Otherwise I don't have, I don't have a better, a better answer. So let me tell you this. We have, we have, we're interested in biomarkers in our population and we did 5,000 proteins by Somare, by somalogic in thousand people, right? And it's interesting and there's a lot of proteins. It's, it's fascinating, fascinating story. But women have third of the proteins that are increasing between aging, between age 65 to 95 than men. Okay. Third, we call it their more stable protein. Now it could be in part the explanation to you, right, of well, they don't manifest the biology of aging the same way. Or it can also say that their aging is delayed. So wait, wait five years and they, they'll have the rest of them. Okay? But no matter how we touch the biology, also in humans there is a gender differences. By the way, the gender differences are also in the growth hormone IGF1. They're not as dramatic with male as they are with women. Okay. We don't have enough power because we have less men, but they're not as dramatic. So sex differences is a lot, there's a lot of explanation. And you always have to think what it means for drug development as, as you said. And by the way, drugs that, that are commonly used in their gerotherapeutics like, like metformin and like SGLT2 inhibitors and acarbos and you know, other things when you look at this study, they adjust for sex. Okay? Adjusting for sex is not the same as, let's see what happened with sex and is it different? We actually don't have, we're trying to get this information. We don't have this information. And I'm sure that there's going to be gender differences in drugs that are for age related disease. There's no way that it's not like that.

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Yeah, and Neil, I think that that's a good segue to the second segment of this interview. And that's the experiment that you mentioned that you looked at the SOMO logic. And by the way, we interviewed Tony Weiss, Corey, a few weeks ago and we released this episode. So I know that this work was done in a partnership with him. But can you discuss a bit what, what have you done in this study and what was the goal of the study?

You mean our latest, the Nature, the latest Nature paper? Yeah. So we, we were collaborating with Tony Weiskori before in Nature Medicine several years ago, we demonstrated really the proteomic biomarkers of aging. And I think what was interesting there, but for me, but wasn't very obvious in the paper, it's not linear. Okay, yes, you, you start aging from, from zero. Okay. But the rate of aging is not similar at any period. You know, it depends how, how you want to do the statistics there. We certainly see a huge, you know, aging is accelerated. Once you get to 60, 65, aging is accelerated and you can have more biomarkers. And we wrote about that specifically otherwise. But when we did this study, there was another thing that we didn't publish. We published it in, in another time. So if you put, if you take all those proteomic biomarkers and you put them in a group and try to see how do you what are the pathway right for those, by the way, the first one that comes, whether it's genetics or proteomic or metabolomic, is the growth of an IGF signaling pathway. It, it always comes. But there are a lot of breakdowns of tissues. There was a breakdown proteins that are breakdowns of collagens, extracellular metrics, even platelets that are breaking down and neutrophil that are breaking down. And at first I was like, okay, okay, there's breakdown. But I I want mechanism, you know. And then I realized, you know, those breakdowns are really maybe the most important because no matter how we're going to target aging, we have to stop the breakdown. And the breakdown has, because of my study, I, I, when they ask me what's aging, a lot of people say it's when you start to breaking down. And I, I, I don't think I use this until all of a sudden, yeah, you're breaking down. I see now clearly. So certainly there's breakdown. So Tony guys did something interesting. I, I want to say based on this observation and they said, you know, you, you have those breakdowns of neutrophil and car. Maybe we can focus better and see what the. We have those 5,000 proteins. Some of them are coming from breakdown of specific organs. Let's see if we can identify which are very unique to this organs because a lot of, of breakdown will be kind of the same, you know, as I said, collagen metrics, you know, whatever. But what, what is be specific to those organs. So we use the same data, but in order to find what comes from organs. And then how do we correlate the age of our body to the age of the organs? And I think the interesting news is that 80% is correlated. I don't need, I could take proteins that tells you the age of your body and it probably will tell you the age of your brain, kidney. However, 20% are not. So for example, we are working now on, we have subjects who are slow aging. Okay, they're younger than their age in our proteomic, but not their brain, their brain is older than their age. So we're trying to really see the relationship between those proteins to organs because maybe some of your organs are leading your aging. Maybe some of your organs are sick and you don't know that. So look for something, you know, if your liver is old so you know, stop drinking or something or see what's going on. Do you have impaired liver function? So I think this is really another, it's not only about the, the biomarkers of aging. It's also could we know from the biomarkers of aging what happens. We are now writing a paper actually on, on the kidney function, right? We, so we have the biology of the, of the kidney and people are saying, you know, if your kidney are sick, all your body is sick. Is that true? And it's not totally true. Okay. It's partly true. Okay. But not totally true. So I think there's a lot, a lot to find out. Not from only Your biomarkers of aging. But do can we identify something weak that, that we can work on? Yeah.

Super interesting. That was a really awesome episode. Dr. Weiss Coria, if you haven't listened to it, and I do want to make sure that we get to metformin because you've mentioned that we want to get there for a little while in, in this episode. So maybe. Yeah, starting with explaining. We've touched on it a little bit. That TAME trial, what it is. I think that's the right one.

I don't know. I don't want to bore myself. And, and you know, I'll tell you, I'll tell you what I find people, people don't know, okay. About tame. So the TAME trial is to, so the TAME trial is to show the FDA that aging can be targeted. Okay. Because we need that. Otherwise people are saying, ah, FDA didn't approve. Right. So that's really the purpose. Metformin, that's what people don't know is an extract of the French lilac, but it's modulated. So it's a drug. Okay, it's nutraceutical, but it's a drug. But between the 1920s to the 1950s, it was used to treat arthritis, to prevent flu. They gave it to malaria. There some, somehow the old women, the nurses, somebody knew that there's something special about it. But what happened then is they also noticed that in diabetic patient it lowers glucose. So it was kind of hijacked to D to diabetes. And, and so people are saying it's a diabetic drug. And I say, well, how does it work? And they usually send me a paper that I wrote when I was a fellow at Yale in 1987 because metformin was already in England a long time. But the FDA needed to show that metformin works on Americans too, and not only on Europeans. So, but I was looking at the mechanism of action of metformin and I, I basically demonstrated that it improves the sensitivity of the liver to insulin. Okay. So people are saying, you know, that's what it does. I said, I know, I wrote this paper, but, but, but since then I realized that metformin is much more important because since then we discovered that first of all, metformin prevents diabetes by the DPP trial. We, we, we knew from the UK PDS that people on metformin have less cardiovascular disease and less mortality. Clinical trials, we, we knew that people on metformin have much less cancers and all kind of cancers. We knew that in clinical studies that people who are with Mild cognitive impairment. It, it improves them. A correlation to less Alzheimer, to mortality. So all this became apparent. And so the question, does it really touch the hallmarks of aging? And we had this paper in cell metabolism where we demonstrated that metformin, like rapamycin, like other gerotherapeutic, change the whole hallmarks of aging. Okay. For me, a gerotherapeutic should me that it, it does more than one thing and, and I'll know it's true. It's really, if you take, if you do, if you take an old cell or an old organ, an old body and make it young, you're going to change all those hallmarks. Those hallmarks are totally interrelated to each other. So, so it was, it was the obvious choice to go to the fda because we had the preliminary data, we had the statistical power, right? We had a drug that was already safe. We couldn't have done it with rapamycin. You know, rapamycin, it's not the dose. We didn't have preliminary data. We couldn't say in animals it works. It's, it's not how it goes. Metformin, we have, we have everything. So we basically went to the FDA and what we asked the FDA people saying the FDA didn't give you approval? No, we went to the FDA and it's documented in Ron Howard film to tell the fda, look, that's what we're planning to do. We don't want to finish the study and you'll tell us you should have done something else. So, so what, what are you going to do? And we got basically all the head of department of the FDA with the deputy director and we had this meeting there and they came and said fine. I mean they, they actually didn't say fine. They gave us, they gave us some suggestions and we incorporated it and changed the statistics and stuff. But basically we know that if the study is successful, the FDA said bring it on.

And what do you expect to see as a result? Like what will be the life lifespan effect of treating with metformin? And you are treating people above 65, correct?

Right, it's above 65. So I think what's very hard for people who are in diseases, they don't get it really, because they, people with diseases don't know that aging is what caused their disease.

Okay.

They still, this message is not so clear. We said, hey, we are agnostic. We, we don't know what disease you're going to get next. Aging will decide, you know, if your mother is diabetic and you're obese, you're going to get diabetes. Right. But we don't know. So we just cluster those diseases. And for every disease you get, you get one point. And we'll show that over time those on metformin versus placebo, they don't get this disease or get it later. Okay. That, that's, that's kind of the concept. It's kind of hard to understand because people don't get aging and don't get that aging drives diseases. And so it's kind of. But this is what we're going to show. And they said, you know, and by the way, at the end, they said, okay, so you prevent. By the way, it's cardiovascular diseases, several cardiovascular disease, cancer, cognitive decline and mortality. You know, it's not lifespan, it's mortality. We're going to decrease mortality. In a five year study, you don't do lifespan, you just do mortality. And, but it's all a cluster. Okay. And you get points for each one of those for the, for the study to be significant.

So you, you are more looking at health, spend and lifespan and you come say people on metformin will have a better health span in a way.

Both. Okay, both because we have the diseases, hard outcomes and mortality. So it's kind of a combination of healthspan, lifespan. Look, we are talking. I'd like to expand healthspan. Right. But the mechanism is the same. So if I extend healthspan, I extend lifespan. Right? I mean, you know, that's the truth.

And we see it from going back to our first section about centenarian. You already told us that centenarians start being sick a decade or two or three later. So it's very similar to what we discussed. I know. Around an hour ago, which is exciting

and unmet memory deal. You're, you're really, your aging is really under control.

I'm not taking metformin yet.

Not yet.

Do you. So it improves insulin sensitivity in the liver. Do you think all of these other things are impacted through that same process or pathway? Or is it doing other stuff too?

Okay, so let me. That's a great. I hope somebody is going to give me this opening during, during COVID There are nine papers around the world that showed that people on metformin, so they were diabetic, okay. Had almost half the hospitalization and death. Okay. Around Italy, the Far East. Okay. So in the United States, you have to show it by clinical study. There was a clinical study that was published in New England Journal of Medicine that gave metformin within three Days of a COVID positive, it decreased. In the New England Journal they showed it decreased hospitalization and death by over 40%. And in Lancet they showed that it prevented long Covid by almost 50%. Now you're asking me now how does that work with the liver? Insulin sensitivity? I'm telling you, metformin is a gerotherapeutic. Okay. One of the things that it's doing is that, but people were asking me, should I take Plavix and stuff. I said no, you take Metformin.

Okay?

Because it's, it's much easier to take. It has much better result and that's what you should do. But this also makes the point that some of the hallmarks are right? Immune decline, inflammation. Well, metformin does that. Okay, does he do it through something else? I don't know, but he does it also. The advantage of gerotherapeutics is like in the case of metformin, it's not only that it improves metabolism or immunity, it improves the whole body ability to sustain a very severe disease. Right. I mean we're doing a holistic aging thing here, right? Through those hallmarks or through the things. So I, I think that's very important. Everybody who says, you know, it's metabolomic, you know, you just lower the glucose. No, no. And by the way, those were in people without diabetes. The studies I told you is not diabetes. It's not related to diabetes.

Yeah.

Metformin is also an anti diabetic drug. It also does that. But, but we're talking about gero, about, about hallmarks of aging and geroscience.

So, so Neil, going again back to your example of IGF1 and gross hormone, is it the same for metformin? In a way it's good for the old but not good for the young. Do you believe that that's the case?

Yes, I, I absolutely. So metformin decrease IGF1. Okay. Metformin in some people decrease testosterone. Why would you take it before the age of 50 unless you have diabetes or women with PCSO or some or something like that? I, I actually a lot of the antagonistic, their antagonism about metformin came with young people who should never have done that.

Okay, so, so basically what you are saying, if you are below 50 and you're taking a metformin right now, I assume off label, stop taking it. It's better to, to be above 50. And there is one side effect that I heard about Metformin and that's the combination with exercise that basically the building muscle. So that's. Some are related to the testosterone level. That's how.

No. So, so. And this is also, thank you for asking. Because this, the everybody knows the first part of this study and not the second part of this study. So the study that's called the Masters, Charlotte Peterson did this beautiful study. She took elderly people and exercised them with and without metforming her hypothesis. An example for hypothesis that didn't turn out right is that metformin through AMP kinase will incre. Will be synergizing the effects of metformin. And she didn't expect that. Yes, everybody who exercises had had bigger muscle, but it was significantly smaller in people who took metformin. Okay, Significantly smaller. Now I read the paper and I also read the supplements, and in supplement two they have all the four tests to, to. To. To see the change in muscle strength. Okay? All the four things, they were identical between the groups. Identical. Which means the people on metformin had had smaller muscle, but each gram of muscle was better. Right? How do you explain that otherwise? So I told Charlotte, can I have the. She took biopsies. I said, can I, can I do some tests? And I looked at the transcript of this muscle and what I discovered is two things. First of all, metformin is also affecting mtor. Okay? So all the MTOR related genes were lower in the metformin group. If you want to build muscle, you have to have mtor. Okay? MTOR is how you build muscle. So it was lower. On the other hand, there was other set of transcript that are related to inflammation, autophagy, other thing that were different. So the muscle maybe wasn't as strong but was better biologically.

Okay?

So I'm saying you can kind of have to decide if you want to. If you want to show your muscle and build your muscle, then don't take metformin. Certainly if you're young, don't take metformin. But if you want a muscle that's healthier, you should do it. But there's another point here. You were talking about muscle and muscle muscle. People who deal with muscle, that's their world. They're muscle. But metformin has those other effects, right? What about protection from COVID Right. What about metabolism in the liver? Right? So it's like exercise. Exercise is not only about muscle. It improves cognitive function, right? It does other things. So I think it's the same if you want to be holistic and, and then, then you, you could be. I think metformin is something that you should consider. You don't have to. And there are trade offs and side effects for everything we'll do. Okay, there's no doubt. I'm not going to defend. It's not for everyone. And we'll find out who is it for. But by the way, you guys, right? Gil, you might, you might, you know, eventually what your company will do is maybe be able to say you're on metformin and you're on rapamycin.

Exactly. Exactly. And that, that's where, that's where I'm going in here. And it's, it's good what you're saying because people are always looking for the silver bullet and say, okay, everyone should take the metformin. And what you are saying, if you are below 50, don't take metformin. Now we discuss women versus male. I don't know, maybe women, maybe women should take it later because they are living longer. Maybe you should take it when you sick, you, you caught a cold, take metformin for a few weeks and stop it. I don't know. It's, it's might be much more complex than just saying everyone should take metformin. That's, that's my opinion.

Right. But I, I would say one thing is when a drug has on a period of time a 30% effect, it means that it's, it's good for the public. Okay, look, you, you never know if you give a drug that saves 100 people if it doesn't kill three. Okay, it's always, it's always going to be a problem. But I think from a health perspective, metformin is as good as what you show with statins and you know, the drugs that we've been using all along. So yeah, you're right, it's not for everyone. And we can find the groups, but it's still a public medicine. And as far as women, I told you that I don't know that it's better or less better in women, but, but there's no huge difference. Okay, Metformin is effective in women and men. Maybe not to the same extent, but it's still effective. And lastly, age 50, but again, if you're biologically 40, so even when you're 50, maybe don't take metformin. Right. Peter Attia taking Metformin because he said I took metformin, it is this and that and that. Why are you taking metformin? You're 40 years old and you're claiming you're 30. So that's not the drug for you. And then you ruin it for everyone.

Yes, Some people are trying to compensate for the future, but they may be compensating too much because you like a joke, Neil. So just.

I'm not sure that it's a joke,

but it's a story that we know that exercise is almost good for everyone. And I always meet people that telling me I'm not exercising. So I'm asking them why. They said, I know a person, he used to be a marathon runner and then he died from heart attacks. So if he died, why should I run? So it's the same like that. It's like there is one of a million person that is poor, he has a bad luck, and he died from heart attack during marathon. Doesn't mean that running is bad. So I think that's something.

My story is, I gave. Actually it happened in Israel and I was on a television interview and I left the interview. I went to this coffee place and somebody there said, were you. Were you on television right now? I said, yeah. He said, I was in the gym and I saw there, you changed my life. I said, what do you mean? He said, my grandmother is 102, I don't need to exercise anymore. I said, no, no, no, no, no. I didn't say that.

That's.

Well, continuing with our theme of humans to animals, animals to humans, we do have some lifespan research or lifespan studies that have been done in mice in the interventions testing program. And metformin didn't show that there was any increase in lifespan in mice. Is there a reason or an explanation that you think that that happened or didn't happen?

Yeah, there, there's a reason, explanation. But what's funny for me is this has been done in humans already. Why do I, why do have to. Why do I have to defend the mice? It's. It's really funny. And I'll tell you the. The problem with animals and their variety of things of studies with animals. Metformin extends lifespan of almost every animals, less so in mice. But I think the reason is there's no dose response in mice. Look, metformin has a mechanism that targets complex four in the mitochondria, okay? If you abolish complex four in the mitochondria, you'll die. Okay? So when you give a lot of metformin to animal, they die, okay? Particular mice are sensitive to that. I think the dose response has not been established. Okay. Extend lifespan in most animals, by the way, even in the, even in the itp, two things happen. First of all, when you look at male mice, there are three centers, right? In two of them, it extended lifespan by about 10% and in one it decreased by 2%. So it's not statistical, but I think the way you do metformin is very dose dependent and you cannot get it always right. You put it in water, if it's warm, they drink more, you know, So I think, I think that's a, that's a problem. The second thing in the itp, the longest living animals are the ones who were treated with rapamycin and metformin. Okay? Now it, in this study, it wasn't compared, not in the same animal, to rapamycin or metformin alone. So, so I don't want to make. But even in the itp, it's not really totally negative. But for me the problem is, guys, find the right dose. If you don't find the right dose, you can kill them. And, and I, I don't know, it's 0.1% in a solution. I don't know what it means at all, you know.

Yeah. Neil, the goal of your time study is basically to establish a way to test drugs that can ex. Increase the lifespan. And in the last few years we have a wonder drug for diabetes and weight loss called GLP1 agonist. Do you believe that that's the next game changer in the longevity?

Yeah. Yes, I do. I don't think it's game changer. I think it's another tool. Right, okay. So I have to tell you, I'm a diabetologist. I'm not a geriatrician, I'm a diabetologist. I'm once a week, not once a week. It really happened once a month. But when I'm here on Thursday morning, I'm attending a fellow clin. We've been using GLP1 for seven years. They've changed our practice. You know, it used to be diabetic, first of all, diabetic. Come your clinic, you say lose weight and exercise. Yeah. Nobody, you know, 3%. So, so, so then you used to give them drugs, you give them insulin. With insulin, they get fatter, so they get more diabetic. It, it was just a punishment. It totally changed it. We give them GLP1, they lose weight, they lose their diabetes. It's an incredible drug. And it's so nicer now to go to clinic. Once we couldn't get the hemoglobin. A1C is the biomarker for diabetes. We couldn't get it down. Now, patient after patient, they're now not diabetic, basically, you know, so it's really a good Drug. It's also immediately you, you can think of it as a, as a calorie mimetic. Right. Because our whole aging stuff started with observation that. Right. That, that thin animals lived 40% longer than, than, than animals that ate all the time or ate whatever they wanted. So that's certainly a drug that achieves that, but I think that it has even more properties. So I saw some studies, for example, where this drug is given to thin animals and is not changing their weight, but they live longer. Okay. In other words, there could be additional effects. So I think those drugs are important. Like everything else. They're trade offs. And if I would use them for longevity, it's only to tell people who are overweight or obese to lose weight and get to the right weight and then switch to metformin. Okay. Or something like that. Okay. I think it's an important tool. I have no doubt that it decreased mortality. Okay. It, it, it's shown to decrease mortality in diabetes. It's going to decrease mortality in obese people or people who would use it as part of a strategy to maximize their health.

That's.

Are they ever used together metformin and GLP1s like until.

Yeah, yeah, yeah. There's a lot of people in our studies that are on both in our clinic. I mean, not in our study, in our clinic.

Yeah, I agree with you. It's a wonder drug. And everyone, I think that it's also for a obese population, especially for them, they always believe that they have something wrong in their brain. Everyone said, hey, why can't you lose weight? And I can lose weight. And now they have the explanation. It's something in, in my body, in my biochemistry, in my genes. And now I have a drug that I can treat it. So it's also allow them to feel better. I'm not crazy. It's something that a biochemical problem that I have in my body.

Right, right. You know, so some of the trade offs that are worrying us from an aging perspective is when you lose weight, basically half of the weight, almost half of the weight is your muscle.

Yeah.

Okay. So now actually from aging, bio age, I don't know if you know Kristin Fortney. Right? Yeah, of course they have Apilene. That is, they thought of sarcopenia first, but now they have this deal with Lilly where they're developing a GLP one with apelin because, because it'll be terrific if you could do your lean body mass. Otherwise you have to tell the people you have to exercise, you have to do strength, otherwise you're you're going to lose that.

Yeah, no, that's, that's a good point. So Nir, if we're looking at the tame study, let's say in a decade, what in your opinion are the top five candidates for the next experiment?

So I wrote a paper and now I, I have a new one coming in in March to change a little bit the list. So we had in our, in our paper we had a 12 point. 12 point is maximal. 12 point that we are sure that this can already be repurposed. Actually at the top of the list is SGLT2 inhibitors. That's another fascinating study for, for many reasons but you give SGLT2 inhibitor to diabetic to non diabetic, they have less kidney disease, less cardiovascular disease and less mortality. You give it to animal in the itp, they live longer. Okay. So you know, it's, it's a general therapeutics. So this is, you know, this is a drug. But all, all the data is there except the combination of the other drug. So GLP1, we talked about the other. That is kind of interesting. The osteoporotic drugs, tidronate has a huge effect on longevity. We missed it a lot. I, I actually I read the paper and I thought that's, I, I don't know if to believe it but women with a tidronate in icu, they survive, the rest are dying, you know, so it has some effect. But then they started to do clinical studies and studies in animal, animals with a tidronate are living longer, humans are living, have less mortality. So I think it's a 10 on our, on our 10 points on our list. I think it's third or, or fourth. So this came basically out of nowhere and we even don't know exactly what happens. I mean the bone marrow has lots of stuff going on, right? Inflammatory, you know, there's a lot of stem cells. So we don't know what it's doing. But those are the four top candidate. And not to talk about rapamycin and acarbos that are also eight or something like that. The problem with rapamycin is that there's no clinical studies. Right. It's used as an immune modulator in kidney trans, you know, in organ transplant where the dose is about 7, 5 to 10 times the dose that you need in order to get the longevity benefit. So people are practicing it, but we really don't have a result, a result for that. So we have to have more clinical studies.

It is fascinating. And the osteoporosis drug, it was A surprise to me. But if you think about it, most of us will die from a fall and breaking our hip. So maybe it's helping us not to do that. Maybe that's the reason.

Well, that's also true. But, you know, when you fall, when you fall and break your heat, you should have taken care of your aging before. Right?

I agree. I agree. It's like, yeah, it's. You need to paint your house every 20 years in order to prevent, you know, the rain to go in. So if you don't do that. Yeah. You break your hip. Absolutely.

Okay, so to wrap up our second podcast with you, thank you so much for the conversation. A lot of laughs. I very much appreciate that. We always end with a top tip for healthspan that you could share. And other than being born to the right parents, is there anything that someone or yourself, maybe you do regularly that you would encourage someone?

I just want to say what I'm working. I wasn't born to the right parents. Okay. But I think that's the point. Our centenarians, when centenarian come and say, what's there for me? Right. I say, you're it. Right. It's actually for the people who were not born with the right parents. Okay? I myself, I'm. I'm doing. So first of all, exercise, intermittent fasting, sleep, social connectivity is nothing I can do. I'm. I've never met a stranger in my life. It's not my problem. You know, it's a deficiency. So I'm okay. So those things. Those things are. I'm doing it. I'm trying to maximize, okay? Which means if I can do better, I'll do it better. Okay? I'm also taking metformin. Now. I'm doing another thing since I started saying that, and that's what I'm ready to say, because I think that's. That's something the public should do. I feel safe of doing that. You know, I'm an MD On. On the first. The first day of medical school, you learn to do no harm, okay? That means on a distribution, half of us don't want to give you anything, okay. Not giving you any drug. A very conservative. Right. And on the second day of medical school, you learn that there's no always and no not never, okay? So you become unsure of yourself. Okay? So this is kind of what's behind who I am. Although I'm on the side of not conservative, but that's how I was trained. So that's what I'm ready to tell you. But I'LL tell you another thing. I have a longevity doctor and I go to my longevity doctor every three months and we're saying, what should I do? What should I try? Because I'm interested. For me, okay? Not for you, I don't. If I'm doing it for me and it's only me, I don't, I'm not going to tell you, okay? And, and we say, okay, what do I do? What do I test before, what do I test after? How do I consider a success? And so I'm trying other things, which I'm not going to tell you. But I think that longevity medicine is going to be about us taking our, you know, Fitbits and stuff, getting our data, having an app that will tell us how to maximize our health and when to take medicine and what medicine we should do. And I'm, I'm trying to kind of predict it as best as, as I can until you're doing the better job. And I wish you luck.

So, Neela, you just described insotrucker.

In a way it, Sorry, yes, this live in such. Exactly. And I would, I'm, I'm, I'm, I'm looking forward.

We are all hopeful to get that very long introduction from a well, well lived, long life that we read at the beginning of the podcast episode.

Thank you guys.

Yeah, it was an amazing interview. Thank you so much.

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