Dr. Nir Barzilai—Genetics and Lifestyle Factors of Centenarians

If you prevent aging, you prevent not one disease, but three, four, five diseases and other conditions. This is really where healthcare has to be.

Welcome to Longevity by Design, a podcast designed to give individuals access to the leading scientific information in the field of longevity. The ability to add years to your life and life to your years needs no opinion. Join us as we ask science to take the wheel. In each episode, Dr. Gil Blander joins a co host and an industry expert in the field of longevity. Shining a light and getting the answers to the key question, how can we live a longer, healthier life?

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 InsideTracker, 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, 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 in the basic Biology of Aging. He's a professor in the Departments of Medicine and Genetics and a member of the Diabetes Research center and of the divisions of Endocrinology and Diabetes as well as Geriatrics. Dr. Barzilai's research interests are in the biology and genetics of aging. He focuses on genes of exceptional longevity and has demonstrated that centenarians have protective genes delaying aging and offering protection against age related diseases. Thank you so much for joining us today.

Oh, thank you for having me and thank you for this introduction. It just reminds me how old I am.

So welcome Nir. And for a bit of a background, the two of us met in 2015 when I came to New York to launch our Inner Age product and David Sinclair introduced the two of us and we set a time for me to come to your lab and I came and apparently I got confused and I came a day later and somehow I found you and you've been kind enough for me to come and say, okay, I am busy but I will find time for you. So I think that that's a reflection of you, Nir. You are a very kind, very nice person and a great scientist. So thank you for joining us. And let me start by asking you about your background and whether you knew from a the get go that you would like to be scientist or when did it happen that you decided to become a scientist.

You know, before becoming a scientist, I really, I really Saw aging as a fascinating, as a fascinating thing. You know, I was walking with my grandfather, who was 68 years old, Every Saturday when he was telling me the story of his life. And it was quite dramatic. And I'm looking at this old guy that is obese and, and slow and white hair, or more of no hair and a little bit of white hair. And I said, just a minute. No, he, he couldn't have done that because although young people have imagination, they don't really see themselves as being their grandparents. Okay. They think, I don't know. I don't know what happened to them, but. But I'm different. And so throughout my career, throughout becoming a scientist, I thought that the greatest question is, what is this aging pro process? And even as a doctor in endocrinologies, you know, when I wanted to know glucose level or cholesterol level, well, I can look at the whole population and I'll never know who has high cholesterol or hypertension or glucose, but I know who's old and who's young. That was really a much more incredible question for me than anything else. So it started as a kid, and I always really wanted to be whatever I. Look, when I came to the field, we don't. We didn't have a field of biology, of aging. There are several hypotheses. Okay. So it wasn't that I was going to train. I went to train as an endocrinologist and metabolism because I thought, well, there's a lot of changes. If we just fix them, we're going to be fine. Which happened to be wrong. But that was where I wanted to be training. And since then, we have a field of geoscience and we know really a lot about aging. And not only that, we discovered that aging can be modulated, aging can be targeted, aging can be delayed, aging can be reversed in several examples. So it's really great to be in the field and it's really great to be where we went from hope to promise.

That's amazing. And I'm excited for us to dig into all of those. But I do want to back up and ask you to explain or walk us through your kind of career path, how you ultimately ended up finding the field of aging or finding your spot in the field of aging and where you are now.

So there were loops and long roads sometimes in my career. At one point I was doing more of a third world medicine. I went during the war when. When Vietnam conquered Cambodia to actually relieve it from Pol Pot. The killing field story. I was there for a Few months on a refugee camp. And it was amazing because I've saved so many lives a day that it was a really a great job. I went to South Africa during the apartheid. I actually went to the homeland of the Zulus, to KwaZulu and I built a nutritional village there. And maybe I should back up and said I was a medic in the Israeli army. And so before being a doctor, I had this profession that could be flexible. I could go to third world country and do things, or I could go and start doing research. And I did both. And eventually I ended up in the research and not in the third world.

Amazing, Amazing. Okay, well, can you walk us through one of the big projects that you've been part of is your work on the Longevity genes project? Just for a little background. This is a genetic study of over 600 families of centenarians and their children. So can you give us a little background on that project as well as what you're hoping to learn from it?

Yeah. 750 centenarians and their families. And I should say that we've learned so much about this project, but from a genetic perspective, we're going to validate it. A far American Federation of Aging Research is going to launch, and we have the money from a single donor, an effort to recruit 10,000 centenarians. So we can really find all the longevity genes and confirm them. But basically we had three hypotheses with centenarians. One is that they're doing everything that we should do with the environment. Right, Ashley, what you would recommend to people to do, they exercise, they ate. Well, they ate the right things. You know, they had lifestyle of the blue zone kind of lifestyle. And maybe that's why they get to 100. Because when they were in the community, when they were growing up, when they were middle age, that wasn't the recommendation. Maybe they just happened to do it.

Right.

The second hypothesis is, you know what? We know that there's a lot of genetic risk. Genetic SNPs. Okay? We call it ovarians that are associated with diseases with Alzheimer's and cardiovascular disease and cancer. Maybe those guys just don't have any, any of that. They have like the perfect genome. Okay. And if that's not true, well, maybe they have genes that slows their aging. Okay, so let me go one by one as far as interaction with the environment. 60% of the men, 30% of the women were heavy smokers. I have a woman who lived to be 110 and more, almost 95 years. She was smoking. Okay? So wow. If you smoke for 95 years, you can live long life. But, but it's more probable to say that, that, that, that she was resilient to the effect of cigarette. In fact, when I asked her, I met her when she was 100 years old and I asked her, nobody told you, you know, your physicians didn't tell you to stop smoking. And she said, all four physicians that told me, they died. Okay, so there was no, there's no less. Similarly, 50% of them were overweight or obese. Some are obese as centenarians as well, doing even moderate kind of work of exercise, walking or biking or housework. Less than 50% of the people, vegetarians, 2% of the people. And we could actually compare our cohort to NHANES 1. You know, that's the National Health Survey. NHANES 1 was the cohort that they were part of. And when we compare them, they're kind of the same or sometimes worse. So we are pretty sure that we can say that, that there's nothing in that, in the environment, I should say we have another papers because it's not only centenarians. We're looking at the children of centenarians who are healthy. And we had this paper where we showed that children of centenarians had half of the cardiovascular disease of our control. Those are people who don't have family history of longevity. But we accumulated lots of nutritional surveys. Not only nutritional, you know, we have BMIs and exercise and socioeconomy status and a lot on macronutrient and nutrients. And they were all the same between those two groups, they were all the same. The only difference was children of centenarians, okay. And they had 50% less of cardiovascular disease. Okay. The second hypothesis is they have the perfect genome. So our first 44 centenarians, which were sequenced for whole genome sequencing, okay, so we had only centenarians, not control, not anyone, only centenarians. But there's a website that's called Cleanvar that at that time accumulated 15,000 genotypes that if you have them, you're most probably to get a disease. And we said, let's look, if they have zero, then, you know, then they have the perfect genome. Not only they didn't have zero, they had on average five variants that should have made them sick and they didn't. They had 44 centenarians. There's 250 variants that should have made them sick. And by the way, those variants are impressive. For example, ApoE4 homozygosity for ApoE4 is a major risk for Alzheimer. You're demented by 60, 70, you're dead when you're 80, according to the textbook. And we have two centenarians who are 100 years old and not demented. Okay, so not. So if they don't do exercise and if they don't have perfect genome, something else slows their aging. Okay, and so what is it that slows their aging? And we make lots of progress there. And I'll just say for this podcast that the most impressive genotypes, or the genomic features of those centenarians, that 60% of them have functional mutations in the growth hormone pathway. Okay? In other words, their growth hormones are not active. And this is really interesting because it really tells you that when you start aging and there's a breakdown, you have to shift the energy from growth, which you need for evolution, reproduction, to, okay, let's deal with a breakdown now. And in fact, we validated those findings. There's an hypothesis in aging that's called antagonistic pleiotrophy. Something that's good for you when you're young is bad for you when you're old. Okay? Cholesterol. We need cholesterol for the brain, for the ovaries, for the testes. But if we have a lot of cholesterol metabolism when we're old, we're going to clog our coronaries, right? So it's antagonistic pleiotropy. IGF is the same. We took data from the UK Biobank. Anyhow, it's a big data where they had measures of one of the growth hormone, the important growth hormone, IGF1. And we basically showed that when you're young, it protects you against variety of disease and mortality. And when you're old, it's the opposite picture. It accelerates you when you have IGF protective when you're young, kills you when you're old. So there's a major genotype for that as just one example, because there's a lot in this pathway that we discover in centenarians, it's just not working well. And we certainly think that it's related to that. By the way, even when you're centenarian, okay, when you're centenarian and we measure this IGF one, this growth hormone, the women with the lowest growth hormone when they're old, when they're centenarian, live twice as long as the women with the highest growth hormone level, and they have better cognitive function and, you know, lots of other things. So this is an example of something that we realized is very important. By the way, dwarf animals live longer. Okay? I mean the small dogs live longer and the ponies live longer. And when you do in the lab where you mutate or you get dwarf animals, they always live longer. Even, even there's a dwarf, Lauren. A special kind of dwarfism because they don't have a receptor for the growth hormone. And we're not sure that they live longer, but they have less cancer and less diabetes and other diseases.

So, so, so first, thank you so much for the great introduction for the project that you are doing with the long lived human. And also it's very exciting to hear that you're going to 10,000 for 750. That's mean that the power of the statistic will be much better to find maybe more genes like that. Looking at the literature that you published, one of the findings that you had is that HDL cholesterol was a bit different between the long lived human and the controls. Can you discuss it and try to explain why is it?

Yeah, that was a very early phenotype. So you know, when we were poor and started this study and to do any sequencing was tons of. So what we did is actually we tried to look at the phenotype and look at the genotype that's related to the phenotype. And one of the things that came up almost immediately on the 10 first centenarians and then again in the next 20 centenarians is that those families have very high HDL cholesterol. Now HDL cholesterol levels in men are average 45 and in women are average 55. And I'm talking about people who had above 100 up to 150 HDL cholesterol. So it was a really important markers. And we started to look for genotypes associated with HDL cholesterol. And we found two genotypes that were very interesting. One is a CTP genotype and one is an APO C3 genotype. And I don't know if you want me to go through biology, but the more important thing is that a genotype and that's why genetic research is so important. Now pharmaceuticals want to have a proof of concept in humans because they, before they develop any drug, they want to find the humans who have mutation that makes a disease or mutation that prevents a disease. And CTP targeting CTP was very important for companies. Pfizer started it, but then Merck Pfizer developed a terrible drug. Okay. It wasn't the pathway, it's the drug that wasn't good. But Merck developed a drug that was much better and they came and wanted to see the data because if their CTP inhibitor is doing what our genetic is doing, then it's a great safety signal because those centenarians had hundred years of inhibition of ctp. Okay. And so you can cross that of your worries. And the same happened with the APO C3 genotype with two papers, one from Amish population and one from US. The first was from US to say that people with this mutation had high HDL, low triglycerides and, and their highest high percentage of them in centenarians. Not, not all centenarians had CTP, but it went from like 4 to 8% to 15 to 20%. So when you have a genotype that kind of survives in centenarian, you kind of assume that it's a longevity genotype. So that's what happens. So they develop drugs and had phase three trials and those drugs have been really effective. So it just shows you there's a way, a direct way to go from genetics where you find the mechanism to developing drug. And it's also, you know, when people are saying centenarians, but I'm not a centenarian. Well, that's exactly the point. The centenarians don't need that. But we can develop drugs. So you can have a drug. And they said, you mean not a genetic fix? We don't need to have genetic intervention. No. Most of our genetic finding can be targeted by drugs.

Yeah. It's also for me, showing how important is it to do a basic science and to allow to a brilliant scientist like you to do whatever they like to do, because that's the way that we will progress as a society. And I think that what happened in the last couple of years with COVID also showed that without the scientists, we will still be stuck with a lot of COVID I think that the scientists actually help us to get out of this Covid situation. So I'm 100% with you.

Right. So first of all, flattery will get you nowhere with me. I'm doing this podcast anyhow. But you're right about science, although. So I'll tell you a story. I'm sure you were not going to ask me about it, but really picking up on the science and how people perceive us and, and you're right, I think Sign Science won. You know, the science won the impact. The impact wasn't as good as we wanted, but the science won. And I'm in a group that starts to thinking about lobbying to Congress of changing our perspective our funding and starting targeting aging itself. And it's interesting because our two major supporters that help us in the lobbying are Newt Gingrich, who's a Republican, a very conservative Republican, and Stephen Israel, who is a New York Democrat. Both of them are not in the House anymore, but both of them are influential. Both of them believe in the science and the fact that we have to lobby. And both of them believe that it's a, it's a, it's a bipartisan thing.

Okay?

That it shouldn't be. Not that. And I questioned them on that and I think a podcast will come on that and you, you could see it. But I said, well, the science became bipartisan. You know, why are you so sure that this is not going to be bipartisan? And they said what? What I realized was true. They said what. What annoyed people is that the government tells them to take something, okay? That's the politics here. Now with drugs for aging. You're, you know, if you don't want to take it, don't take it. Right? It's not going to be a government thing. So it's going to be bipartisan. And they also said, you know, even the Democrat and Republicans that will not agree on anything, okay, Each, each congressman needs to show that he worked on something with a Democrat, okay? So they're looking for things that can actually bring people together because they have political benefits from that. So I'm sorry, I expanded on the science and the winning. But made it an aging point now.

No, no, it's a good point, Neil. And one follow up is how can our audience help you with this endeavor? Is there a website that they can click and say we support it or how can we help you with this important cause?

Well, I'll send you guys a link to that and to this organization and you can. It's just in. It's being formed now. It's being formed now, but it exists. I don't know. I don't have a recollection of seeing the website, but there is something, some link, and so I'll be happy to help to point to it.

Aging is for sure a bipartisan issue. Democrats and Republicans will both get old. Maybe we've solved it. Could you describe for us a little bit about how those genes, I think the ones related to HDL would be really interesting for our audience. Going into the biology of those a little bit. How those genes, Is there a known mechanism for how they protect those people?

Now, that's a good question. And like everything in biology, it's, it's Very complicated. So I'll take. I'll take just an example and that. A complicated example and explain why it's complicated and how I look at it. So CTP is a cholesterol ester transfer protein. Okay. So it basically takes the cholesterol and move it. Okay, eventually moves it out of the body into the bile out of the body. And as I said, the CTP is inhibiting this process. And what happens, this cholesterol is stuck on HDL that's becoming bigger and bigger. Okay, so on one hand, we're doing something not so good or balancing something not so good. We're stopping the cholesterol from going out. On the other hand, we're building this HDL that might have an importance as a molecule to protect, you know, coronaries, endothelial things, maybe other cells. But I don't know. You know, I. I was careful to say that we were looking for biomarkers or. I said phenotype. Maybe I meant. I meant biomarkers. An example. And I don't know if the hd, it's the hdl, or the fact that all the lipoprotein are large. Okay, so the LDL is large also. And small LDL is one that we certainly know induces coronary disease. So maybe it's not about hdl. Maybe it's only about large LDL cholesterol. Okay, So I. But by looking at this study, we see associations. And I cannot tell you mechanism. In fact, the mechanism is very, very confusing because I have somehow to balance two things. I cannot stop totally ctp. But having a large HDL and the other size are. Are. Okay, so that's just an example. I. I will tell you another thing.

Now,

you know, high HDL is associated with less coronary disease. But what was more important in our study, it was much more strongly associated with cognitive function. People with the highest hdl, people with F CTP mutation, had the best cognitive function. So we might be missing other actions of. Of this hdl. And when Merck did this study, I suggested that they use the opportunity to do cognitive tests. And they did cognitive tests, but they did cognitive tests on people over the age of 50. You don't see those things. You know, between 50 and 70, you have to have an older population in order to see effect on cognition. So I think, in a way, it was a missed opportunity. And. And maybe it could have been different.

Do you see there someday being a way to estimate lifespan or age using some of these phenotypes? Is that something that could be possible?

Yes, but but, well, okay, so the hdl, this is how I'm using the hdl. If somebody comes to me and says my, a grandmother or mother, you know, father is a centenarian, I would ask them, what's your hdl? And if their HDL is high, I would say, I think you're very likely the bad news for you. You're very likely to be very old. Why bad news? Because I don't know if you can afford. Okay, so, so that's how I use that. But, but we are doing, we are doing other biomarkers in our study. So for example, and my favorite is, we did by Aptamer technology. It's a new technology. 5,000 proteins in thousand of our subjects. Half of them were children of centenarians and half of them were control. And the nice thing with proteins, so, so we have very good clocks for methylation to, to, to do our, our biological age, but methylation is kind of stable. And what, what we want is not only a biomarker that tells you your biological age. We want a biomarker that will change when you're giving a gerotherapeutics. Okay. That's what's important for us. And I think the proteins are much more likely to change. For example, some of our proteins are proteins that are reflecting a breakdown. It's plasma proteins, but they're reflecting breakdown, extra matrix collagen, degranulation of white cells or thrombocytes. And I think however you target aging, you have to stop this breakdown. So I think those proteins are going to be maybe better biomarkers than others. By the way, in everything in the genetics as well as in the proteomic, things that are related to the growth hormone IGF pathway are also changing a lot in our subject between 65 and 95. So there's, there's a lot to that. So, so the biomarkers, we're doing omics now and we're measuring biomarkers, different points of view, from methylation, from histone deacetylation, from protein, from metabolomics, in order to find what are the sets that are going to predict not only your age, but will change when you are intervening.

Cool. Neil, I would like to switch gears and maybe move to your favorite subject, at least in my opinion. Maybe I'm wrong. Let me know if I'm wrong. And that's metformin. And can you start by describing the history of metformin, how we found, found it, what was his initial indication of metformin? And maybe then what is the effect on longevity and how metformin impacts something the world is currently experiencing with COVID 19.

So first of all, I want to come clean with your declaration, my most favorite subject. It's the most important subject because metformin for me is only a tool to have an indication for the FDA for targeting aging. Okay. That's my interest in metformin. I don't believe that I'm going to find anything new about this study that I'm proposing because those studies have been done in other contexts. Okay. So I don't think that I'm going to find something so new except having this ability for the FDA to say, okay, maybe we should prevent aging rather than treat diseases. Okay, so why metformin is such a good tool? Well, metformin is a good tool because it's an extract of the French lilac. If you want to call it nutraceutical, you can. Although it's modified and it's a drug, of course, but it's really coming out of nature. And people more than 100 years ago or about 100 years ago, started to using some extracts of the French lilac or metformin or analogs of metformin to treat flu, malaria, some other inflammatory diseases. And it was noted in parallel that it lowers glucose in diabetic patients. So all of a sudden metformin became this diabetes interest and has been diabetes interest until now. The good news that it's been used for so long as an anti diabetic drug for about 80 years and diabetes is a chronic disease. People were taking it. I mean, there's tens of billions of years of use of metformin. So it's the most known drug, the side effects are all known. Everything that needs to happen with metformin has happened already. You know, the idea is we don't want to kill anyone on the way to success, right? We don't want to because there might be better drugs. We don't know, by the way, you know, the fact that something is better in mice has nothing to do if it's going to be better in humans. But, but anyhow, we don't want to want do anything. So we had a drug that is safe. Another thing, it's a drug that's generic. It's the cheapest drug on the formulary. It, you know, you get 500 pills for $40 or something like that. If you get it from Mexico and Canada, it's even cheaper. And so there's no pharmaceutical involved. It's very important that for the FDA we went scientists without a Company. Okay? We're just going to repurpose the drug. We are not putting a new drug. And by the way, with the fda, we never discuss anything about metformin, okay? Because metformin is. You can read in the FDA site everything you want to do about metformin, we just ask. We want to do this study. Is it okay? Do you have comments? Okay. That's the only thing we wanted to do. In animals, Metformin extends lifespan and health span even more impressively in humans. In clinical and association studies, it's shown to have major effect on preventing of diabetes, on preventing of cancer, on preventing of cardiovascular disease and preventing of cognitive decline, Alzheimer's and mortality. Okay? Which is all the outcomes that we're going to measure. So those are independent studies, okay? Independent study against the disease. And there are still people who said when our grant was reviewed at the NIH and rejected the reviewers who didn't read the grant, but they had an opinion, said, okay, so first of all, you think that all those diseases can be prevented. And second, you think that one drug can do.

Do it.

You're crazy. Okay? But the truth is. So now explain to me how this drug has so many actions that is specific for all those diseases. Okay? That makes less sense. So. So that's kind of. That's kind of what we know about metformia, and that's why we're using it as a tool to do a study and to show that whatever, whatever disease you're going to get, you're going to get it later or not at all during this study.

So, Neil, first is what is the mechanism of metformin, in your opinion? Or what do you know about the

mechanism of this drug without doing it too complicated? Metformin targets all the hallmarks of aging. Right? We agree on eight, nine hallmarks of aging. Metformin targets all those hallmarks of aging. Now you must listen to that and said, I'm crazy. How can this drug targets all those hallmarks of aging? And the truth is that it's similar to almost any other drug. You know, resveratrol had multiple effect and rapamycin had all those gerotherapeutics. People started arguing it's doing this and that and not this. And really what happens is really quite simple. If you take an old cell or an old organ or old body and make it younger, then a lot of things are being fixed. Okay? That doesn't mean that it's doing it primarily or independently. It's just fixing it as part of being a gerotherapeutics. And it's true for the hallmarks themselves. You can fix one hallmark and affects all the other. It's exactly the same thing because those hallmarks are not the causes of aging. There's something that goes wrong with aging, and if you fix it, you extend healthspan or lifespan. Okay, so this is the same with the drugs. Now it does mainly two things, I think. On one hand, it targets the mitochondria complex one of the mitochondria and shifts energetic in a way that has a lot of metabolic. Metabolic outcomes on insulin action, but also mtor, then autophagy, you know, a lot of other things on one end. On the, on the other hand, it. Because it's kind of a little. It's. It's an inhibitor for the mitochondria. It prevents some of the oxidative damage, inflammation, and other things. It also has actions that are not through the mitochondria, not through AMP kinase, not. Not other ways. But we don't know which of those effects are important for aging. Okay. So we rather use metformin with everything that it seems to be doing, rather than select and say, you know, let's just hit complex one of the mitochondria. It might not be enough. So, so that's simply, by the way, I have. And I can provide. I have 2020 paper in cell metabolism really showing all those effects of insulin with a big, you know, with a big pathway where all the hallmarks are in the bottom and metformin and its action on top. So it's very, it's very complex to. To look at that.

But yeah, we would love to add it to the show note. So I think that that will be great to do. So I know that you are trying to run a clinical trial in human with metformin. I just heard from you that it's. The FDA maybe is not excited about that. So can you give us some update about where do you stay and what is the size of the study and when are you planning to start it and so on?

No, I think it's the opposite. The FDA is very excited about that. But we don't need the FDA to do this study. Okay, what we asked the fda, we said, look, this is what we want to do. We don't want to come to the end of the study. And you said, oh, you should have done something else. Okay. Second, what do we call it? Okay. And it was part of a bigger effort. We went also to the Senate and to the Congress, and we, we try to see if, for the fda, it's important to call aging a disease and apparently it's not important. Okay? It's not important. And it's not wise to call aging a disease. And we don't need it. For the fda, we all agreed that our outcomes is the prevention of a cluster of age related diseases. We know it's aging. They, they can still think that metformin is doing it. I, I don't know how, okay? They don't need to accept the concept of aging, but it's not necessary. You know, it, it's like pornography. When it happens, we'll know what it is, okay? If they don't want to admit it, it's still aging. So, so, you know, so I think that's what we are, that's what we're planning to do. It's interesting actually, Ashley, for maybe from your perspective, one of the things we wanted to show that we prevent diabetes and they didn't want it. Okay. And in fact, we had to change the numbers a little bit because the FDA says, you know, diabetes is a chemical diagnosis, okay? If your hemoglobin A1C is above six and a half, you're diabetic. And they said that's not a hard outcome because, you know, after 10 years, only 40 of the people have complications. So it's not, it's not like you have a heart disease, you have Alzheimer's, you have cancer. Okay. Or you have mortality. It was kind of interesting. And I'm a diabetologist, so I was, I was initially really insulted and somebody said, never mind, never mind. Of course there is a study that showed that metformin prevents diabetes, but, but it's not part of our outcomes.

So again, what is the size? Just to give us some understanding, is it going to be hundreds of people, thousands of people?

We're actually trying to rethink some things. Apropos the COVID we try to rethink, but it's going to be between 3,000 to 3,500 people in 14 to 16 centers around the United States where we're really, really ready to go. But it's going to be a post Covid call and we are trying to get funded for six years, but we might. A lot of the metformin studies were funded for five years and stopped after four years. So, you know, I think it depends how it's going to do. Maybe depends. If we have 3,500 people, we're trying to push it as fast as we can.

Okay.

And it's placebo control, obviously. Right. It's A placebo control.

Yeah.

And there's another part of this study, and that is to do a really good biomarker. In other words, we're going to do every biomarker possible to see what change in the people with metformin versus without metformin.

Very exciting. Looking forward to see the results.

Yeah. And it's interesting to also hear about your work with the government as a dietitian for Medicare. We can only get paid for seeing someone with diabetes or with chronic kidney disease. And I'm wondering if you see prevention as an issue for them to give support or anything like that in the things that you're doing. Because, you know, obesity used to be something that you could get nutrition counseling for through Medicare and now it's not. We can't help with prevention whatsoever. And seems like something to delay or prolong aging. It kind of also falls into that preventative category.

Right, right. It's a preventive study. And in fact, the FDA has set up us for failure because sarcopenia is an indication that the FDA would look at and frail. Some forms of frailty. But the thing is, this is really too late. You know, I don't think that biologically it makes sense to take a muscle that's so old and revive. Really has to be. Why are we getting to sarcopenia? Let's prevent it. You know, you just do it years, few years before and you prevent that. It makes no sense. You know, it's like. It's like giving statin after you have a heart attack. You know, what is the point of that? You have to prevent this heart attack.

Yeah.

So this concept that aging is a preventable age, if you prevent aging, you prevent not one disease, but three, four, five diseases and other conditions. This is really where, where healthcare has to be.

So, Neil, you may be the one person in the world that's seen the most 100 plus human. And you have seen them. I haven't seen any. My father is 90. I hope that you will get to that age, but you have seen so many. So I think that it's a great question to ask you about what do you think can be the maximum lifespan and what should be the average lifespan? And also about healthspan, because healthspan is not less important than lifespan. What do you think can happen, let's say, in our lifetime? Where can we expect?

Yeah, well, first of all, you're absolutely right. And we have to speak about healthspan. You know, when I went into research, I said, I'm doing aging research. Nobody wanted to Listen to aging. You know, in New York, people are busy, they're young, they're. They don't want to learn about aging. So I said, but oh, actually I'm doing longevity. I said, let's talk about longevity. Well, longevity, people assume that. What I'm saying is they're getting sick and now they live sick for 30 more years. You don't want that. Okay. And it's really, it's to realize that healthspan is important. Like I said before, for me, healthspan is the goal. And the side effect is longevity because maybe you cannot afford it. Right. So healthspan is definitely what we're talking about. We're talking about quality of life, about cognition, about ability to move and all that. That's really the goal. Now biologically, they're linked together. If you improve, if you target aging, you're going to delay mortality too. So you're going to have extend longevity. They're kind of linked. I don't know how you do one without the others so much. So human. Maximal human lifespan is considered to be 115. I'm just quoting a Nature paper by Jan Vig's group. And I believe it. It's a statistical modeling. Now you can say somebody lived up over the age of 122, but you know, but statistically 115 is the top. We are dying before the age of 80 on average. So we have 35 years to realize without thinking that we need to be so dramatic. Okay. To do an interventions. That sounds really science fiction now. Okay, now saying that. I'm not saying that it's not possible to extend the lifespan below 115. I think that the most reasonable way to do it is to start a treatment at age of 20. You know, do a treatment where you have, I don't know, you use Yamamoto factor and you erase the epigenetic and, and do it every month or every year. And people will just be Peter Pan. They'll be young, right? Young forever. I mean, it's not going to be young forever. And methylation is not everything, but it probably slow aging. And just by that we could probably pass this 115. I think it's possible. Can we be 150 or 200? Yes, but that's in 150 or 200 years simply because if we start to intervening and as I said, intervention is soon, it will take that much to know if we can do it right.

Yes.

I'm just using it as an excuse. I'm not saying that it's not Possible. I think that it's not possible now. Even senolytics, senolytics in animals have increased health. Spanish this is the example of reversing aging. Really. Okay, you really take animals that are doing very poorly and you're improving their biochemistry and their function with senolytics. But they don't live longer, okay? They just have a rectangulation of their longevity curve. They live healthier, healthier, healthier. They are dying at the same age. So, so pick your age. Do you want to be, you know, if I tell you you're going to be for you, 90Gil is not an issue because your father, you know, is above. But you know, if I tell you 95, you can live till 95 healthy and then you die the next day. Is this a deal that you accept, most people will accept?

Yeah, I think so. And I call it like the food fly enigma. So they live, live, live and then all of them die at the same time. And they don't need to lie on the bed and be connected to a lot of tubes for 30 years. Nobody want to be like that. So I'm 100% with you, Neil. And I think that all of us,

that's the way you mentioned earlier of the. One of your subjects, for lack of better word, that you know, smoked for so long, my great grandma, she died at 98 and smoked till she was 96. Put mayonnaise on everything, soy sauce on everything and always took a shot of whiskey when she felt sick. So she probably is one of those outliers. But she did have a lot of the other factors that we also find in those blue zones, like a really strong sense of community. I'm curious if in your research with centenarians you found that, you know, long lived humans do have some of those other specific commonalities, lifestyle factors or you know, community aspects that maybe you could also share as tips with our listeners of, you know, things to do or try and seek out.

So, so the, the best story with the moral here is. So, so we published a lot about the personality of our centenarians, right? And they are very outgoing, they're extrovert, they like people, they play with the community. Okay, so I'm going to see a centenarians, he's 104 years old and he's amazing, okay. He's like the nicest guy I've ever seen. He is thoughtful, he talks about his life, he thinks his son is great, his daughter in law cannot do wrong, you know, really wonderful. And I'm going outside the room. And I'm bumping into his son who's by the way, 80 years old, right? And I'm telling him what I told you. You know, your father is the best guy I've ever met. And he looks in my eyes and he said, you should have seen the son of a bitch when he was my age. He was a terrible, terrible person. And we started realizing that we think personality doesn't change with age. And if you look at those studies, it was until the age of 60 or 70. But there are two things that are happening. On one hand, the brain still ages, even in the 100 years or right? I mean, 100 years old by now there are 30% chances of their dying next year. So their brain is older, but more. But even as important, they, you know, they are retired, they lost their spouse, they moved from one house to the other. Maybe they are now in an independent living. So they rolled with the punches a lot. And we realized that personality has changed. Old people are very interested in being happy and it doesn't take a lot to make them happy. For every bad thing, you need five things for young people to make them happy. And you need only one or two in elderly. If you show them, if you show young and old people pictures of bad and good things, okay, cockroaches in pizza or islands in the Caribbean, okay, young people will remember everything. Old people will remember less. But the good things. I'm looking forward this, by the way, so I don't think that I have the answer of the blue zone. That's why we're looking at their offspring and trying to figure out what personality they brought up with and how many are jerks that are turning to be nice people. Okay, so.

So if you have a bad person at work or somewhere around, just wait 10 or 20 years and it will become better. That's what you're saying.

Or.

Or kill them right there. Or kill them.

That's cool.

That sounds like a great place to end it. Thank you so much for joining us. This was.

Can I talk about something else? Ashley, Can I talk about something else? I'm taking.

Absolutely.

One of the things that I've done, always done in my lab still doing is caloric restriction. Right. The idea that if you take brothers and some of them eat whatever they want and then you give only 60% of them to, to their other brothers, they would leave 40% longer. And people always took it to say that you should have less for breakfast, lunch and dinner. Okay, what we are doing is something very different. We are bringing the Food in the morning for the day. And those caloric restricted people, mice, rats, are hungry so they eat everything in 20 minutes. And it's not only that they are caloric restricted, they are fasting for 23 hours when we start feeding them throughout the day they are leaner because they have less calories, but they don't live longer. And this is where the idea of fast, intermittent fasting came in. It has many flavors and people are doing many things. I'm doing 16 hours, at least 16 hour fasting every day and it has improved. First of all it's easy to do because all you do is skip breakfast. Now it might be look a lot but all I have to do is wait an hour or two till I eat. It's not like in a three months diet I could break any time. Okay, but here I'm not going to break because I can, I, I don't eat for another hour. And not only that, then I eat whatever I want. Which initially was, yeah, let's eat something really good. Now it doesn't matter. I eat, I eat whatever and I probably eat loss. Most people lose weight, men more than women for some reason, but most people lose weight. But more important, some of the aging phenotype like my exercise capacity have increased since I'm doing this intermittent fasting. And I think it's really important to distinct between obesity, which by the way drives aging, but the treatment for obesity and the treatment for aging. Okay, because they're, they're subtle in they're not everything that you treat as obesity will affect aging the same way. That's my point.

Very interesting. I think most of, honestly most of our podcast hosts so far have talked about fasting in some way. So definitely a good take home recommendation for our listeners to figure out a way that makes sense if it's appropriate for them to try and implement that. Well. Thank you again for being here. Incredibly enjoyable.

Okay guys, thank you very much. Thanks for asking this question. It was fun for me too.

Thank you Neil.

Bye.

And we look forward to exploring the research in the field of longevity each month with you and the leading scientist. For more please go to www.insighttracker.com podcast.

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