Longevity Secrets of Centenarians - Dr Nir Barzilai

One of the things we discovered in centenarians is that the genes of their longevity are exactly similar to what we learn from animals. Welcome to the Seamlund podcast. I'm your host Seamlund and our guest today is Dr. Nir Barzilai. Nir is a professor of medicine and genetics at the Albert Einstein College of Medicine. Nir has written the book Age Later, Secrets of the Healthiest, Sharpest Centenarians. The only way to truly know your health status and mortality risk is to measure your blood work. That's why I'm excited to have Insight Tracker as today's sponsor. Insight Tracker is an at-home biomarker service that you can use to test up to 43 different biomarkers like lipids, liver enzymes, inflammation, sex hormones and much more. The process is simple. You order the test kit to your home, use the little finger prick device to give your blood, send it back and you get your results to your online dashboard or app. You can get a 20% discount off all their tests if you head over to insighttracker.com forward slash Seamlund. That's insighttracker.com forward slash Seamlund and the code is Seamlund. Nir, welcome to the show. Nice being with you. Good morning. Yes, I'm also very glad to talk with you and you have a very interesting field of research because you know longevity sometimes, you know, a lot of the studies are done on like different animals like mice and fruit flies and there's, of course, you can learn a lot of things from those studies but it's always better to like research people who are actually, you know, living the longest, the centenarians and, you know, the humans itself. Like we are humans, we're not mice, we're not fruit flies. Although there are like some similarities, like different pathways that are similar, it's always better to like, you know, focus on the actual human outcomes and that's what you have done with your book of looking at centenarians and what is like, what are the reasons, their environmental reasons as well as genetic reasons of why they live so long. So yeah, I'm happy to talk with you. Two things in your opening that I want to just make a point on. You're using the term longevity. You know, when I started my research, I said I'm interested in aging, you know, meeting friends at the elevator, right? An elevator pitch and they were like, yeah, we're not interested in that. And then I said, oh, but by the way, I'm looking at centenarians, I'm actually, I'm interested in longevity. And it still didn't get an attention because people, most people, if you'll tell them, you know, what about living longer, they will assume that they're going to be sick for longer, not healthy for long. And that's where we clone the phrase healthspan, okay? Because I think what's, that's what people want. Lucky for us, it's the same mechanisms, right? If we're targeting the biology of aging, we're delaying age-related disease and deaths. And so it's kind of the same mechanism, but I think we have to be sensitive because sometimes buzzwords mean different things to different people. So that's about using the term longevity, which I like, as long as we understand what it is. The second thing about animals, and I started with animals, what, so let me put it this way. One of the things we discovered in centenarians is that the genes of their longevity are exactly similar to what we learned from animals, okay? And our hypothesis with animals that unlike for diseases, okay, which the animals didn't help us much for diseases, but when it came to aging, all animals kind of age the same way, you know, the skin, the hair, the skeletal, they get diseases when they get all different diseases, but the biology behind it happened to be really the same. So as long as we're looking at any disease of aging in the right template, which is in old animals, we can be more successful than what happened was studying cardiovascular disease on two months animal. It's not the same biology. So that was it. So I'm sorry, that was my comments on your introduction. But I think also covered the fact that animals and humans are the same and that we want not only longevity, but healthspan, right? Yeah, like that's a good clarification. So yeah, like the biology is kind of the same. And, you know, there are like, maybe some differences, like, or at least like a lot of the fasting literature or calorie restriction literature is like, yes, calorie restriction does extend lifespan in these animals, but maybe like the degree or, you know, with fasting, like the mice go into autophagy, for example, which is this process that increases during fasting relatively faster compared to humans. And the time span might or like the implications of whether or not you should fast for longevity are kind of different between kind of humans and mice, at least. I think the interpretation that we had from studying our animals was wrong. So we all did those experiments. And I did it on my lab lots of times when we take brothers and half of them get to eat what they want and the others get 60% of it, right? And they live exceptionally healthy and for much longer, 40% longer, you know, they live for a year long and mice live between two and three years. So this is really a substantial observation. And people say, oh, that means less for breakfast, less for lunch, less for dinner. But this is not what we've done. We would bring the food to the animals in the morning, they were hungry. So they ate the food and then they were fasting for like 23 more hours. So it's the combination of fasting and and caloric restriction that extended their life. And that's where intermittent fasting came from. When we give those animals the food throughout the day, they're leaner, but they don't live much longer. Okay, so that's where intermittent fasting came really to be. And you're right, the time course of autophagy, which is a really great example, I hope you're listening, know what top autophagy is our garbage disposal mechanism, you know, we have a lot of junk in our cells, lots of proteins that are not folded, right, or they're wrong or something. So you have to dispose them. And it's a mechanism, not only it's a garbage disposal, it takes it back to the LM elements. So you can have back all the components to make a new protein. Okay, so it's a terrific way. And this cleaning mechanism, the keeping our cells clean, in particular, when we age is really important, because we know that if we manipulate by genetic mechanism or drugs, if we manipulate autophagy, we get an extension lifespan and healthspan. Yeah. And but what is like, what's the time difference of how much do you like need to fast to see those effects in humans versus like mice? So that's, that's a great, that's a great question. And before COVID, we were set up to do that. In other words, to find a time course, not only the time course, there's because there's different biology between young and old people to do it in young and old people, and basically fast them for almost 24 hours and measure several components of the blood like that, like insulin or free fatty acid, because you're going to move from carbohydrate to fat metabolism and to measure autophagy and to really understand where is the switch and and this is needed to be done. And really haven't happened, though, the proof of concept that metabolically is better, I think is very well, well established, I can tell you, because I'm interested in my longevity, and I'm wearing all those watches and stuff. And I have actually a glucose sensor, sometimes I discover that although I'm exercising, although I'm doing eight, I'm fasting for at least 16 hours, and usually more, by the way, 16 hours is the minimum. If I exercise in the morning, my glucose actually goes up. And this happens more with elderly people, because you know, when you're exercise, your muscle needs glucose, who's producing this glucose, the liver, okay, but those mechanism might be a little bit out of sync for a variety of reasons. You know, if my glucose uptake decrease in the in in my muscle, and the liver has a little bit more glucose, I'll have high glucose. And but if I have high glucose, I also have high insulin. So I'm so I'm really stopping effectively, autophagy will not happen with high glucose on insulin. So what I'm saying, it's very individual, but still, there's a lot of advantage for fasting. Why? Why? Once you understand your body, and I don't exercise in the morning anymore. Gotcha. Yeah. So like 16 hour fast is still a good to do like every day to see some increase in autophagy or? Well, we have we have variability in how we're doing that, you know, some people are doing just 24 hours, once or twice a week, and some people are fasting for three days, every three months or something, there's a lot of variability, everybody has his stuff. And I think all of them have rationale. And I kind of think the major message is we were not meant to eat for 16 hours. That's not how our evolution worked for us. You know, we woke up in the morning, chase the deer, got it at night had high protein diet, high fat, high protein diet. And we really didn't snack throughout the day. And snacking throughout the day happens to be bad for most people. Yeah, that's true. And moving on with the like centenarians, or like, we can just also cover like the genetic aspects. So what is what is the genetic or what is what is similar in terms of the biology of aging between these animals and humans? Like what do we share? So so you know, there are two pathways that are really striking because we we could focus them to to a very, you know, really, really understand it on individual and and get it back to animals. So one thing is the insulin IGF one signaling pathway, this actually has been the first pathway to be implicated in aging, Gary Rufkin, Cynthia Canyon, Johnson, all have done experiment where they manipulated the insulin signaling pathway in nematodes and in our lower lower species later on, and each one of them have extended a lifespan significantly. It was taken then to mammalians and and it did the same and then we started finding in centenarians genes. Now the insulin IGF signaling pathway is a common pathway in lower animals, but in humans and by the way, I should say that when I said we are similar to animals, I said it generally, we're also different than animals. Okay, for example, one of our longevity gene is a cholesterol gene that's called CTP that does not exist in most animals, certainly not in mice and rats. So it's human specific. And it's actually interesting because it's it's also a connected to cognitive function, which is kind of different between animals, animals and humans. So I just want to underline that back to the to the insulin IGF. So we think that insulin pathway has to work well in humans, but it's the growth hormone IGF pathway that has developed and is very much associated to longevity. Now, there is an hypothesis in aging that's called antagonistic pleiotropy hypothesis of aging, the things that are good for you when you're young are bad for you when you're old. For example, you need high cholesterol metabolism for your brain, for your gonads, for other things. But if you have high cholesterol, when you're old, you'll block your corona, right? So not everything that's good when you're young, good for your old. The growth hormone IGF signaling pathway is good for you when you're young. It's good for you. It helps bring your muscle and strength and it protects you from variety of diseases and mortality. But after the age of 50, it flips. It totally flips. And we prove that using UK Biobank. We prove that that all of a sudden, when you're over the age of 50, the things that were protected for you are now becoming a problem, a problem for you. And before proving this hypothesis like that, we just started finding all those longevity genotype. And so let me define what's longevity genes. OK, we all have we don't have special longevity genes like another one that appeared. It's changes in the genes that we have, right? Which either under activate them, which is the usual case, or over activate them. That's what we mean by longevity genotypes or longevity SNPs, or when we just call it loosely longevity genes. So we started finding those mutation in centenarians. In fact, 60% of our centenarians have some defect in their growth hormone IGF signaling pathway. It's really a very major pathway. By the way, there's an experiment in humans. There's people who are dwarf, who are called Laron dwarf. They're in Ecuador and some of them are in Israel. And the unique thing about them is that they don't have cancer, diabetes, some of the major diseases. We don't know. They're not enough to really understand longevity in the context of their society, but at least they live healthier compared to other people. So I think from centenarians, from Laron dwarf and from what we know in animals, this must be true. And by the way, in nature, all the animal, you know, all the dwarf and or the small dogs live longer and the ponies live longer. And when you manipulate growth hormone in the lab, you get if you don't have no growth hormone, you live longer. If you have more of that, you live shorter. So it's all the evidence for that is really quite overwhelming. So the IGF-1 is like the growth pathway that if it's too high, like you can measure your IGF-1 levels and if it's too high, then it's might increase like the risk of cancer and premature death. Right. Actually of all diseases, all diseases. Yeah. But there's also like the association that too low IGF-1 is also linked to higher death. So what do you think? What's the reason? I think what and that's how we, that's why we did the paper that we did because the death in IGF-1, when you look at the literature, so some paper says it's good to have low and some it's bad to have low. Some associated with cancers and some with other things. But the thing that they didn't account for is the age of the participant. And look, think about it. It makes sense because when we start to break down, which is kind of how aging define, we have to move our energy from growth to protecting against the break. I think it makes total sense for that. Why would we start growing the cells and stuff when we're kind of breaking down? So this is kind of a major pathway for longevity. We also took a drug that was developed to human, to cancer. It failed cancer, but it's an antibody against this IGF that you mentioned, is the peripheral growth hormone IGF-1 against its receptor. And when we give it to animals, they leave much, much healthier and about 10% longer. We give it to old animals and we still have such a great effect. So we, you know, from animals to humans, back to animals, we have a full story and a proof of concept for this. Gotcha. Yeah. And could it be that if you're like too, let's say your IGF-1 is too low, then you're like more high risk for like frailty and hip fractures and those things, which could explain like the association of lower IGF-1 with increased mortality so that you're like too kind of frail, if that makes sense. Yeah. Look, there's no doubt that there's trade-offs. Okay. So let me give you an example. We have our centenarians, okay? We have our centenarians and we measure IGF-1 in our centenarians. They're already a hundred years old, you know? I mean, they're there, but then we looked at those with the lowest IGF-1 level and those with the highest IGF-1 level and asked, did it change? Did those levels change their mortality? It did. Those with the lower half of IGF-1 level lived twice as long as those with the highest IGF-1 level. And when we look at their cognition, those with the lowest IGF-1 level have doubled the cognitive score. And when we looked at the muscle function, they were the same. So there is an exchange. There are two things. And look, first of all, even with caloric restriction, okay? You know one thing, if you don't give the animals any food, they'll die within a few days, right? I mean, it's not an all or nothing. It's really finding things within a border, right? And I think it's for everyone. Are you asking me, can you live without IGF-1? No, but there are trade-offs. And when it comes to growth hormone and IGF-1, we always worry about the muscle. And what's good for the muscle is usually not good for the rest of the body. But if you can find something that targets aging, okay? Like metformin. Okay, or let me say differently. There is another pathway, I think you mentioned that already, mTOR signaling, which is another pathway that we see in humans. The mTOR pathway is involved in longevity, like it is in animals. And there's a drug out there, right? Rapamycin, that people are trying, experimenting. There are experiments in dogs. There were clinical experiments in humans that is quite exceptional in animals. We still don't know if it works well in humans, but it's exceptional in animals. So what rapamycin is doing is inhibiting mTOR. But if you want to build a muscle, what you have to do is activate mTOR. Okay, so there's an antagonism here. So when you give, for example, metformin that also inhibits mTOR to people who are exercising, to elderly who are exercising, they would not build as much muscle as those that are without metformin because it affects all the mTOR-related genes. However, if you look at the quality of the muscle or the function of the muscle, the people who take metformin and have less muscle have exactly the same function as the people who don't. So that means that they have small muscle, but every gram of muscle is better. And when we look at what the muscle has, it's really better. It has less inflammation, it has more autophagy genes, it has lots of other things that are happening. So there are trade-offs, and some of the trade-offs are not going to be good for an individual something. Okay, so that's one point. The second point that is also interesting, I can see, although I think that low IGF-1 is really good, in fact probably necessary for exceptional longevity, there are conditions where growth hormone can be good for a while. There are papers, for example, of giving growth hormone after strokes. So after stroke, you have destruction of cells, and maybe if you give growth hormone, you help to build those cells. Maybe it's not good for the whole body, but it's good for a period of time when you start to recover from something. Okay, so it's not all or nothing, even on that way. You know, I'm not going to say, no, growth hormone is terrible in any case. It's probably not. It's just that it's usually not good. Let's start with that, and then we can build a case. Yeah, you know, it's probably like the amount and the frequency of how much you stimulate these pathways, and yeah, like how much are you increasing your IGF-1 with, you know, primarily with protein and carbohydrate intake and just calorie intake, all those things are the ones that increase IGF-1 the most, kind of, versus how much time are you spending in like the other side of the coin, which is more like this anti-aging pathways, like with calorie restriction and fasting and lower calorie diets. But what is it, like you mentioned the centenarians, what are they doing then? You have the book about their secrets, so like what is the reason why centenarians live so long? So half of our centenarians are overweight or obese. 60% of the men were heavily smoking or are heavily smoking, and 30% of the women, physical activity, even housework and walking or biking, less than 50%, vegetarian, less than 3%. So, and that's not different from what we know from the people who lived at the same time with them. You know, we have some national health surveys, so we know they're just as bad or even worse than other people. And you can say that we don't know, we don't need to do anything for longevity, and we stop doing any effort because, and people have done that, Jay Leno, who's a comedian in Late Night Show, has made a joke about, you see, if centenarians, what is it to be a centenarian? You smoke, you party, you know, you drink, all that. But the point is that for them it didn't matter, okay? I have a woman who I met when she was 100 years old in a New York apartment and she was smoking. And I said, nobody told you to stop smoking. And she said, you know, the four doctors that told me to stop smoking, they all died. Our conversation was, she lived to be 110, okay? And our conversation turned into, well, you know, if you stop smoking, you live even longer. You know, maybe she could have been 122. But I think the point is that because they have longevity genes, they're protected from the environment and they survive disease. In fact, we have clear evidence for that from their genetics. We have, for example, centenarians who have apo E4 homozygosity. This is a genetic condition that will probably, if you have it, you'll probably have Alzheimer's when you're 60 or 70 and you'll be dead when you're 80. And they're 100 years old and they're not demented and they're not dead because their genes have slowed aging so much that it didn't become relevant to them. You know, with this gene, you're not going to be born with a dementia or when you're a year or 10 year or 50 years, okay? You need the biology of aging for that. And this biology of aging hasn't happened to those guys. So yeah, it's like they live so long generally, not because they followed some sort of this optimized healthy lifestyle and supplementation or whatever. It's mostly because they have these genes that kind of protect them against some of these diseases. Like if you have good genes against cancer, then you probably don't get lung cancer. But you know, for every, I like to say that, you know, some people say that, yeah, like I have this uncle who lived a hundred, he smoked all the time, but you know, how many people smoke and didn't make it to a hundred? So like for every one person who smokes and makes it to a hundred, there's like a hundred thousand who doesn't make it to a hundred and they die to like 60 or 70. So. Right. And that's why I really, I really don't like this question of what's their secret, because a lot, when you, when we ask them, and this is also published, we ask them, what do you think? Why do you live longer? But by the way, the first, the, the most common answer is, you know, genetics. You know, my sister is a hundred years old. My father was a hundred and two. My grandfather was a hundred and eight. You know, it's in the, in the family, you get a lot of that. But after that, it makes no sense. You know, I smoked, I ate chicken fat all my time. Some of the things they have could be healthy. Some of them don't sound healthy, but the truth is they're not the people who are going to tell us what's good because they got there by other mechanisms. Yeah. So what, what kind of genes do they have then? Like what are the good genes or bad genes? Well, so I gave you an example of, of the growth hormone IGF. I think that there are other genetics, common genetics on, we have two genes that are mutated in centenarians and they cause them to have low triglycerides level and high HDL cholesterol, which is the good cholesterol. And, and that that's been a finding. The interesting thing is for those and for several other of the genes that we found, there's also drug develop. And the drug is not developed for longevity. It's developed for diseases, for preventing heart disease and things like that. But I think those drugs will, will have the benefit of not only changing cholesterol, but also extending healthspan and longevity. So we're waiting to see. Gotcha. So like having these better genes for heart disease or cancer is kind of the main thing. So are there like any lifestyle interventions or like supplements or drugs that can help to mimic those, you know, you can't, you know, obviously mimic the genes, but you can mimic some of the effects that the genes work on. So, so, so let me tell you, and it's kind of a chapter in my book that I kind of reluctantly wrote. And I started by saying supplements are good for the economy. Okay. So buy them. And, and my thought was in most cases, they don't have what they claim they have. Okay. And even if they have what they claim they have, it's usually not dangerous, but I've changed my mind a lot about that. So this is, you won't find in my book, because I realized two things. First of all, some of those supplements that didn't have the claim they had, have got better and they're very potent. So now, now I have to worry. And second, and in combination is that if you take a hundred supplements, okay. And you assume that each one of them makes sense. And so they'll add to each other or even synergize each other. You're mistaken. Okay. You're mistaken. Those supplements can be antagonistic to each other and their cases and their people out there that I know for sure have aged rapidly, at least on, on their, on their biomarkers have changed rapidly by taking those. And some of them, we even understand and study their antagonism. So this idea that people will hear one day, you should take that and they take it. And then they accumulate all those things. In my mind, it's dangerous. And, and, and you have to know that, you know, you have to know that when you do something. Yeah. I mean, too much of anything is bad. And especially with a lot of the supplements, you know, even if you take, let's say a hundred supplements, you don't know which one actually works. And like you said, some of them are actually, might have some antagonistic effects. So, you know, at worst, you know, at worst case scenario, you are damaging your health. In the best case scenario, you might be just wasting a lot of the money and helping the economy. No, no, not wasting money, supporting the economy. That's okay. Yeah. But yeah, I guess my question was more like, you know, you know, exercise is probably good and not overeating is probably good. And you mentioned metformin. So like, are there any like things that you know, generally will have some like these similar mechanisms as these protective genes have or that they kind of slow down aging in some ways? Yeah, look, I think from an environmental perspective, there are four things, okay, that we definitely know that has a biology that really interferes with aging or if or the opposite or can delay your aging, or you can maximize your aging. And first of all, is exercise by far the most important thing. The second thing is diet. We talked about intermittent fasting or Mediterranean diet or something like that, low carbohydrate, you know, there's a variety of things we can consider. The third, so exercise, diet, sleep, sleep, you know, we have to maximize our sleep, we cannot binge movies and sleep short time when we're young. And when we're old, we have to be in a dark room for eight hours, hopefully we'll sleep six, seven hours of that, but you have to do that and social interaction. And that's also a big subject. All of them have biological effects on pathways of aging. And this is something that each of us can maximize. And when I say maximize, you measure steps and you did 10,000 steps, why don't you do 12,000 steps? You know, it's better. Your cholesterol, your LDL cholesterol is 100. Yeah, but you know, 70 is better. There's a lot of things that we can maximize and have to maximize in order to prevent the biology of aging that drives all those diseases. Yeah, for sure. And tracking them is, yeah, like very good to keep track of what are the changes and what you need to focus on because some people might have blood sugar issues, other people have sleep issues, third people have cholesterol issues. So yeah, it's tracking is kind of important. But metformin, so this is obviously pretty much the world's most famous diabetic drug, but it also is used, some people use it for longevity purposes. So like, why does metformin have these longevity effects? And like, is it something that should be considered for people? So by the way, it was the opposite. You know, metformin is an extract of the French lilac. And in the 1900s, people have realized that metformin is doing really great things. People who had arthritis took it, it was taken to prevent flu and malaria. In other words, people were using metformin, and they've noticed that people who had diabetes and use metformin, their glucose levels were lower. And so it was kind of hijacked to diabetes. And it was a good drug in diabetes. And thanks God to the diabetes community, there are lots of studies with metformin. And all those studies of metformin that are clinical studies, which are very important association studies, all show that people of metformin had less diabetes, less cardiovascular disease, less cancer, less cognitive decline, and Alzheimer's, and less mortality. Okay? Why is it doing it? So, you know, when we're talking about mechanism of action, we usually start with what we call hallmarks of aging. And the hallmarks of aging are really pretty much things that go wrong with aging. And when we fix them, we get our animals to live healthier and longer. But the most interesting thing about these hallmarks is that they're interactive. In other words, you can target one, you know, we talked about autophagy, you can target autophagy, you improve also mitochondrial function, metabolism, telomere length, you know, other things are affected as well. And this is, for me, to be a gerotherapeutics, so by the way, so you don't have to target all the hallmarks to get an effect, right? Which is terrific. We can start right now. But this is the interesting thing. The true gerotherapeutics, right? What we call anti-aging therapies are really affecting those hallmarks of aging. Metformin affects all those hallmarks of aging. Rapamycin affects all those hallmarks of aging. SGLT2 inhibitor, which is another drug, affects most of the hallmarks of aging. For me, if you're targeting just one hallmark and you don't affect the other, you're not a gerotherapeutic. You can lower cholesterol with statin. It's very important, okay? It prevents heart disease. But if you give statin to animals, they don't live longer, okay? It's not a gerotherapeutics. It's a specific prevention for a specific disease. Metformin hits all the hallmarks of aging. Now, you're asking, really? I mean, one drug with such a biology? And the answer for all those drugs is that whatever they do, they take an old cell or an old organ or an old body and make it younger. And when you make it younger, you fix really a lot of those hallmarks of aging. That's why they're interconnected to each other. So we can talk about what metformin does first and what happened after that. But it doesn't matter. The point is that it affects all the hallmarks of aging. And that's why it's a very potent drug for longevity. Yeah, so it works on like lowering your blood sugar levels, and it also suppresses... Well, it doesn't lower glucose level for people who are not diabetic, okay? And remember, it wasn't taken for diabetes initially. And it's not lowering blood glucose for diabetics, for non-diabetics. What it does, it lowers insulin level. And lower insulin level might be good on its own, but it's not lowering glucose level. That's not the mechanism. Not metformin, not SGLT2 are working through glucose. In fact, with rapamycin, you can get higher glucose and still get benefit of longevity. So it's not through glucose. Okay, so it's like the mTOR complex or... Well, there are a few things. Yeah, metformin and rapamycin interact through mTOR. SGLT2, I think all of them have some mTOR activity, but that's not the only thing they're doing. And they're distinct. And when you give rapamycin and metformin to animals, if you're giving the combination together, they live longer. So they're kind of additive. So like the combo of metformin plus rapamycin does better than one alone or... In animals. Okay, right. But do you think, you know, what's in the next few years or a few decades or something, do you think that the metformin is going to have like more of this research that does show that it is actually slowing down aging in humans and is going to be used more like recreationally or more easily? So look, I have a dilemma, right? When I started this idea of metformin, I was like, don't take metformin because we haven't shown, you know, the way we show that it targets aging, we cluster, we do a study where the outcomes are prevention of a cluster of diseases. Okay. But remember, metformin has shown to do it individually for all of those diseases. We use metformin as a tool to basically say, hey, we target aging and we prevent not one disease, two disease, we prevent a cluster of diseases. That's why we're doing the metformin study that's known as STAIN. Okay. So now people have started using metformin, right? And my dilemma now is I can, as a doctor, repurpose any drug. In fact, metformin itself was repurposed for a polycystic ovary syndrome. Okay. Doctors are doing that. It's not an FDA indication, but if you look at the textbook, people say, you know, you can use metformin. So drugs can be repurposed. And in my mind, since metformin has been doing all those things, I don't see any ethical problem to tell people, you know, you could consider that because it's a cheap drug. It's a safe drug. Time passes. What are we waiting for? Really? I thought we'll do the studies in a few years, we'll be done and everybody will know. But now that it takes longer, I'm thinking, you know, I don't need to be so careful anymore. Look, I'll give you an example that I think really made very much difference for me. When COVID started, there were almost nine papers around the world that said that people on metformin had basically half the mortality in hospitalization. Okay. Remember, metformin targets all the hallmarks of aging, including immunity and inflammation. Okay. Then there are clinical studies that were giving non-diabetic people metformin within three days of COVID, and they prevented almost half the hospitalization, the mortality and long COVID. Okay. So metformin is a very effective drug. My problem is, why am I, and by the way, it needs a prescription. So I'm ready to talk with doctors, you know, and for a salient patient and tell them why I think it's good. But this is how I look now at what we're doing. Metformin has shown to do everything that it's been doing. I don't think anybody doubts that. Okay. It's a safe drug. It's generic drug. It's cheap. It doesn't, you know, every poor people can take it. Why not? Doesn't have any like side effects. Obviously, if the outcome is a little bit longer. Okay. So, so what we said, everything has trade-offs, right? I think that the thing that people misunderstood, remember this antagonistic plethorapy, things that are good for you when you're young or bad for you when you're old. Metformin is not a good drug if you're young, you know why? Because it lowers IGF-1 for example. Okay. And also it lowers some testosterone in men. So if you're, if you're a young man, you know, if you're diabetic, maybe it's a different consideration, but you have your young man and you're building your body and stuff. No, metformin is not the drug for you. Okay. Wait until you're 50. Okay. So that's a trade-off. The second, the side effects of metformin are appearing within the first week and they're usually gastrointestinal. Okay. Diarrhea is a common side effect and it usually resolves within a week. If it doesn't resolve within a week, which is between three and 6% of the people, you cannot take metformin or you shouldn't take metformin because it really means that your transporter, the OCT-1 that is the transporter for metformin is in low concentration or may, maybe genetically mutated and you don't absorb metformin from the gut. That's why you have diarrhea. But even if you would absorb from the gut, it wouldn't enter the cell. So there's no reason to take. Gotcha. Yeah. Everything has a trade-off. And, uh, you know, of course, if you have diabetes, then it's going to be pretty lifesaving in a lot of ways of taking metformin, even if you have the side effects, then, you know, living longer is still kind of better than, yeah. And, and look, it's a public, it has a public effect. In other words, in those studies, the effects of metformin are between 20 and 30%. And that's with intention to treat. Now think of what it means for intention to treat. If you had diarrhea that lasts over a week and you're, you know, let's say 5%, then those 5% are not taking metformin, but they're considered as if they're taking metformin. Okay. Then there's the issue that some people don't take metformin, although they say they are, or they're not taking the full dose. So the, we don't have an answer. If you take metformin, if you take metformin, what is the effect? And that drives me crazy in clinical studies. I understand why you want to do intention to treat, but I won't be able to tell my patient, listen, if you take this drug, okay, you're, you're going to have a decrease in cardiovascular effect by 50% and not 30%. Okay. Because we need them to adhere to therapy and we want to impress them. Now, if he has diarrhea, well, he's not going to get the effects of metformin, but if he can tolerate metformin and take it, we have to tell him how effective it's going to be. And I think that metformin is a very public drug that will be good for most people, not all, but most people. Right. Gotcha. Well, that's, I think it's a good point to wrap it up and people can definitely check out your book for more details about the longevity genes and the mechanisms and metformin as well. So yeah, people can check it out, but where can people find the book? In Amazon, it's called Age Later and really thank you. Look, I think, I think we're making huge progress. We really are eager to realize the promise. Okay. And, and you're part of this team, you're a soldier in this army and thanks for you taking the time or coming to me to do that. I think it's really important. So thank you very much. And thanks for the good questions. Well, thank you too. And I'll see you around. But do you want to slow down aging and live longer? If yes, then I'm looking for more people who want to reverse their biological clock. If you're interested, then email me the word health to info at seamland.com and I'll send you the details.