Can Metformin Fight Aging? with Dr. Nir Barzilai

So I want to try to sell you on an idea.

I'm always looking to buy ideas. Sell it.

I don't know if you have to buy this, but. Okay, so listen, think of this. So Medkin is all about people who are looking for the optimal way to extend their health span and lifespan to ensure that they optimize the number of years that they are able to live long, healthy and active lives. And what if the idea is that you could actually fight aging itself, that aging is a disease that you could potentially cure?

I've never thought of it that way. I mean, doesn't that mean you could technically live forever?

I don't know about forever, but hear me out here. So essentially, we have all this money in research and time being invested in therapies for individual diseases. So cardiovascular disease or cancer or diabetes or Alzheimer's disease, you are more likely

to get those diseases the older you get.

Totally, yeah. Your risk factor goes up, like, by orders of magnitude at the age of 75 relative to your risk at 25 or even 15. What if aging, the effect of time on our cells, is a condition that we could treat the same way we treat, you know, numerous other diseases?

And so is there research being done on this concept, or are you the first person selling it?

Well, there's actually a pill that some people believe could be a treatment for aging. That's what our host, Sean Francis, CEO of medcan, is going to explore in, in this episode. Hey, I'm Christopher Shuligan, executive producer.

I'm Jasmine Ratch. I'm managing producer.

And in this episode, Our host, Medcan CEO Shawn Francis, talks to Dr. Nir Barzilai. He's a gero scientist and the founding director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York City.

And he's also the world expert in the diabetes drug metformin, which some scientific

research suggests could be a pill that fights aging itself.

Amazing. Let's do it.

Here's our host, Shawn Francis, in conversation with Dr. Nir Barzilai.

Dr. Barzilai, I'm delighted to have you on the Eat Move Think podcast, and keen interest of both Medcan and myself is longevity. And I know that you're a prolific writer and scientist in the field, and, you know, maybe if you could just for our listeners, give us a bit of your background and how did you become more interested, this idea of health span and longevity?

Well, you know, it was kind of interesting. Our kids, they don't see themselves becoming like their grandparents, right? They're like how did they get there? You know, who are they? We're not going to be like that. This process of aging when you were born, and just seeing the generation is not something that occupies you. And it did for me. When I was young. I was walking with my grandfather. The year eventually died, and he would told me about his stories and his wars and everything else. And I was like, something is wrong here. This guy was kind of fat and slow and bold. He couldn't have done all those things. And even as I went, I went and I was a medic in the Israeli army. I was in medical school. I went to Third World to treat people who were hurt by wounds or by. By diseases. And it was always a question that was bigger than anything else. You know, even when I became a doctor, I couldn't say who has a high glucose or high cholesterol or hypertension, but I could see who's old and who's not. And I knew that the old people have all those diseases. So it was natural for me to say, this is the biggest issue. Except that people didn't think that aging is something that can be targeted, which is something that, thanks God, we discovered, we proved, and we're ready for more action.

So is aging itself a disease? Like, how do you describe it clinically?

For me, aging is the mother of all diseases. In other words, if you're born and you have an APOE 4 genotype, which is a genotype, that means that you most probably will be Alzheimer. You don't get it when you're born or when you're one year or 10 year. It takes decades to come out. You need the biology of aging for things to come out. So aging is the major risk factor and the major mechanism of why we started getting diseases with aging. So it is the mother of disease, which is different than saying that I want to call aging a disease. This is very problematic. And it's even more problematic after Covid, because what did we do with the elderly? We isolated them, right? We put them in islands. The elderly don't want to be called sick. The American Federation of Aging Research or the Gerontological Society of America don't want to call aging a disease. The FDA doesn't want to call aging a disease. So we shouldn't go to a war where we're trying to help the people who are now against us, right? So while I think that aging accelerates all those diseases, I would shy away by calling age a disease. And in fact, practically we can avoid it. Because when I'm discussing With the fda, a study to show them that we can prevent aging, then the outcomes. I don't need to call it aging. I can call it by. I'm just moving several diseases away. You know, you will. You will not get it or you'll delay that. And I think it's good enough.

And so in your research, I mean, what causes aging? Is it the natural sort of genetic process?

Yeah, aging happens to all species, and it ends in death, no matter who you are. But, you know, when, when we try to understand diseases, we think of the evolutionary forces that got us to where we are and what went wrong with them. But aging is all post reproduction, right? When we had our kids, if we die the next day or we live 40 or 100 years more, is not part of evolution because we gave our genes away anyhow. So aging is post reproduction, which means it's kind of accidental. And the major thing that happens in physiology is when you go into reproduction, you have to have a lot of growth. You have to have everything grow and be strong. But now you go into aging and you're starting to have a breakdown. And you have to shift the energy between growth to repair the breakdown. And this is kind of where we are at understanding aging and trying to eventually stop this breakdown.

And so you're saying you go through this reproductive and then growth stage, and at some point it works against you because your cells start to break down.

You know, you said it absolutely right. And it actually has a term, it says antagonistic pleiotrophy. Antagonistic pleiotrophy means that there are some things that are good for you when you're young and they turn against you when you're old. For example, we need cholesterol to build the cells for the brain, for the ovaries, for the testes. Right. We need a lot of cholesterol. But when we age, we get into trouble. So there, there is an antagonistic pleiotrophy. It's the same with growth. You need to shift from growth to protecting of breakdown, which is kind of what happens when you get over reproduction. Decades over reproduction and age.

Can you prevent aging or how do you, if you are, ensure a higher quality of life?

Right. So first of all, the second part, high quality of life. We are really talking about healthspan. The mechanism to increase healthspan are linked to the mechanism that increase lifespan. Okay, so we can choose what we want to talk about, but it's the same thing. We're talking about healthspan and longevity, really. And this is really what we're trying to do. We showed that in many experiments all over the world that we can do it. We can extend the health span and lifespan of many, many animals by targeting several of the hallmarks of aging and getting really great results. Some of those tools that we used are actually in human use. So we can start thinking about it and implementing it pretty rapidly.

You know, there's the lifestyle part of it. I know. And then there's the medical intervention side of it, too, which I want to discuss. But, you know, what do we know? Like, if you were to prioritize those things that you think might have the most benefit, where would you start?

Right. Right. And it's right to start with that, because the lifestyle has a lot to do with aging. And in fact, we can change a lot, our prospect of aging by doing several simple things. Well, it's not simple for individuals, but we can recommend to do several things that will most likely get you a longer health span. And I would say the first is exercise. And it depends the age of the person, but it's moving. If you can move, if you can exercise, it has unbelievable effects on every organ in your body, your health span and your longevity. This is a major thing. The second is diet. So during COVID if you were 80 years old, your chances of dying from COVID was 200 times than if you were 20 years old. Okay. Aging was a major risk factor. At the same studies, obesity was a risk factor of eight. Okay. A huge risk factor, but nothing like aging. But obesity really accelerates aging. So not being obese is very important. But for me, it's only part of the answer. In fact, there are several part of the answer of what to do with nutrition. But the main lessons for me from the lab is the following. Early on and through my career, we used to take animals, whether it was mice and rats and caloric, restrict them, give them 30, 40% less food, and what will happen is they would live healthier and longer by 40%. Okay. It's really a huge intervention that influences maximum lifespan in animals. And this was taken as saying, have less for breakfast, less for lunch, and less for dinner. But that's not what we've done. We brought all the food to those animals in the morning, they were hungry, and they would eat all the food within 20 minutes. And then they would be fasting for more than 23 hours. So it was fasting that we did. It's not only caloric restriction. In fact, when we gave them the food throughout the day, they were thinner, but they didn't live much longer. So fasting is a major way to improve our ability to age better. There are several ways to do it every day. Basically it's 99% of the days fasting after dinner for 16 hours at least. If I have to pick the one thing about the nutritionist to do that. There's also advantage. I think I've never dieted in my life but, but my feeling was if you'd give me a diet for three months, I could break any day. But if I have an hour or two hours to go and then I can eat whatever I want, I'm not going to break. So I think it's diet that most people can find very helpful and easy to do and will feel much better with that.

So clearly not being obese would be one major risk factor. But you're also saying that fasting, it's in effect a separate thing to being the obese side of it. So that age eat less and more healthy. So I'm not obese. But in addition, fasting can contribute. You know, I've read guys like Dr. Atti is fasting for days.

So there are several form of this fasting and the truth is we don't know. I'm doing a study in my institute where we're just doing this time course. We're taking young and old people and fasting them for 24 hours and we're checking their biology, we're taking biopsies and cells and we're trying to find where is the SW that is important for aging. And maybe it's in 12 hours. So you do 12 hours between meals and maybe it's 16 hours and maybe 16 hours is not enough. We'll say, you know, 18 hours is necessary. So we're kind of guessing it's probably kind of individual also. And you know, the truth will come up. There's lots of data that suggests that there are major benefits to doing it if in 16 hours.

And is that in effect having one, I guess major meal a day?

No, it's not the same. Look, I'm usually having lunch and then I'm having dinner, but within eight hours am I eating less? I'm probably eating less. I mean I was never. It's very helpful. I wasn't a breakfast person but I could have eaten a snack at 10 o' clock or something. So I'm skipping that anyhow, I'm drinking black coffee. But the eight hours, if I'm hungry, I'm eating.

Does it matter what you're eating?

So yeah, that's the Other thing, it probably matters what you're eating. And if I have to pick, one thing is carbohydrate. We should have less carbohydrates. It's interesting, the diet field, I feel bad for this field because it started by let's assume that we need three meals a day. It's already a long assumption. I mean, the cavemen didn't start with corn flakes. They probably woke up, started chasing a deer and getting it at night and having one barbecue meal, probably. So three times a day is already a lot. And then they decided 65% carbohydrates. Now, carbohydrates and their availability is relatively new. You know, it's a Marie Antoinette that popularized cakes. So this is a late advantage. And we were never supposed to have 65% carbohydrates. And then every year, the diet association have started changing because it all started by fat is the most dangerous thing. So it happens that fat is not so dangerous, in particular when we all have statins and it's easier to control the cholesterol than it is to deal with carbohydrates. So now it's much more fat and much less carbohydrate. And to tell you that that's the end. It's probably not the end, but if you could have less carbohydrate, you know, again, I think fasting for aging is the major thing. But less carbohydrates is also very important

because, you know, you read a lot of course on the Mediterranean diet or eat more green versus, you know, meat. So would you agree with that?

Yeah, I think the Mediterranean diet, there were several studies. There were a lot of discussion around the studies. And at the Mediterranean countries, it's already a different culture. But I think it's compelling evidence that if you have lots of olive oil and if you have fish and nuts, you're doing better than, you know, with steaks and potatoes.

Right. But do you think meat in itself? I mean, if you go back to your more caveman and deer example, do you think you need to really cut it out and become a vegetarian or. Or is there a healthy amount?

Look, no matter what you tell me, there will be trade offs. And not only trade offs, it's going to be personalized. Maybe the way I want to phrase it is there's a difference between science and advocacy. Okay? People were saying no meat or people were vegans. I think there are trade offs for that. And it's true that maybe it's better than having steaks every day. And Being obese, et cetera. But there are trade offs. You know, I'm trying to eat more fish if meat. I'm trying to have chicken, but I think beef has lots of B6 and B12 or, you know, whatever. And I think you have to somehow balance that. And I'm not sure that we'll get the true answer. You know, the truth answer means that you do a clinical trial, right? You take people, you supply them the meals basically for five years to look at outcomes. It's never going to happen. So you just have to try and understand what's the science behind it and what's the trade off. And I'm never in favor of taking something away totally, because I think lots of the things that we take in our mouth have some dangers and some values and we have to balance.

Talk to me about the molecule side of it, because a lot of people are hoping for the silver bullet, the anti aging medication. I know that there's a lot of discussion about various ones, but no accepted molecule yet. Can you just talk about that? What is the field right now?

So, first of all, I'm a gero scientist and what I like to do is have gerotherapeutics and geroprotectors. We talked about exercise and diet, but gerotherapeutics is something that we'll eventually need. And I can tell you why we need gerotherapeutics, even if we're doing geroprotectors or environmental. And I'm saying that because anti aging is not who we are. There is a tension between the people who call themselves anti aging and between the people who are geroscientists. We want to come from science and we want to do our clinical studies in a way that somebody will know that it's placebo control. And so there is a proof rather than a hope. And it's usually hope. It's even not promised with lots of the products out there. What helps us is that we geroscientists have what we call hallmarks of aging. The hallmarks of aging are something that change with aging, and if you fix it, your animals live healthier and longer. That's how you become a hallmark. And those hallmarks are interconnected to each other in a sense that you can target one but have effects on the other. If you take an old cell or old organ or old body and make it younger, you get improvement in lots of things. So you capture those hallmarks. And the drugs that are actually gerotherapeutics are going to do the Same. They're going to change a lot of the hallmarks. And if they don't, I would be suspicious that they're not really gerotherapeutics. You know, statins is good for heart, but if you give statin to animals, they don't live healthier and longer, and it doesn't really touch any of the other hallmarks of aging. So statins are good for prevention of cardiovascular disease, but we should prevent cardiovascular disease by preventing aging, mostly. So those hallmarks are generally sites of intervention and they're biotechs. Increasing number of biotechs, $12 billion investment in biotech, four and a half billion of that only last year, are choosing hallmark and targeting this hallmark and trying to find an indication for disease and eventually for aging itself. So this is what allowed us to proceed and to start in developing drugs that are truly gerotherapeutics.

And are there any today that are.

Well, there's one drug that is certainly a gerotherapeutics. It's called metformin. It's a drug that's used for diabetes. It's a drug that was used 70, 80 years ago to prevent flu, malaria, inflammation. And then it was discovered that it lowers glucose in people as well. And so it was hijacked for diabetes. It can prevent diabetes, by the way. So it's been out there and we learned many things about it. We learned that in clinical trial, that's controlled trials, okay, where half of the people getting and half are not. It prevents diabetes, it prevents cardiovascular disease, it prevents cognitive decline. And there are association studies, a lot of them, that shows that there is less cancer. All kinds of cancers are decreased. There is less Alzheimer, and there's even less mortality. People on metformin not only have half of the mortality of other diabetics, but they even have less mortality than non diabetic patients. And I'm sorry, I should have started by. If you give it to animals, they live longer and healthier. So there's no doubt that this drug is there. But this drug needs a prescription and the FDA hasn't approved it to prevent aging. And that's a trial that I'm leading that we're going to start soon. A trial where we've been working with the FDA and we want to show them that we can prevent aging. What do you mean by preventing aging? It's not a disease, but we're going to delay a cluster of diseases. And if we're successful, then we'll ask the FDA to approve it for a use of prevention of Aging.

And what's the knock on Metformin like, given your confidence as a scientist in it? You know, are there other scientists who, who would say, well, good for you to go do another clinical trial? But, you know, we don't think it's going to work. Are there critics of metformin?

I don't think there are critics in the metformin among the geroscientists. And in fact, the TAME is important because a lot of the investment in the biotech to target hallmarks. That's one important thing. The other important thing is that they know that there's an FDA effort to get aging as if it was a disease or a preventable condition. So it's the opposite. People are very supporting tame. We have a huge coalition and there are people who are not scientists or not doctors that will tell you, I took metformin, I had diarrhea. It's a terrible drug. And it's true, it's happened to several people, but it's the safest drug. I don't know that there is a safer drug than metformin ever. There have been billion years of use. We know everything we want to know about metformin, and nobody dies with metformin. In fact, they live longer. So that's the downside. Okay? The side effect of metformin is you live longer. Maybe you cannot afford it.

You're obviously a believer there are some side effects, but in your opinion, pale again, obviously a longer life.

Most people don't know that they are on a drug. Okay, Most people. Some people have side effects when they start the first week of use. And it's usually they feel bloated, they might have diarrhea. And only 3 to 6%, something like that, will have persistent diarrhea after a week and will stop the drug. The rest will not have any side effects.

Is this something that you would take daily then?

Yeah, I'm taking it daily. You know, for the trial which I described, the TAME trial, the targeting aging with metformin, we had this argument of they're elderly, give them less. You know, let's be safe. And some who said, you want to prevent aging, give them more. Okay, and what we've decided, most of the clinical studies were in a dose of 1500 milligrams. And we decided that's our dose. If you get to 1500, okay, if you get less, it's okay.

What is it targeting that you think generates its success?

I already alluded to the fact that at the end, metformin corrects all the hallmarks of aging. That doesn't mean where does it work first it has to get into the cell, and it usually binds to the oxidative complex of the mitochondria. And they do two things. One is metabolic, they improve metabolism, and one is they decrease oxidative stress and some other things, but that's kind of what's going on. But other effects of metformin that happen either because we fixed aging or before they're, or because they're not related to the mitochondria or some other things.

So we don't precisely know how it might be working, but.

Well, we know how it works for diabetes, and we know that it works with aging by improving the hallmarks. But what in this process is most important, what comes first and what is a result? We will argue about that.

And are there other drugs, molecules out there that might have similar benefit as metformin?

You know, probably from our knowledge, the most important thing that we notice this year, in the last couple of years, is several companies are doing this drug that is this SGLT2 inhibitor. It's used for diabetes. And investigators have noticed that people who get this drug, not only their diabetes improve, but their heart condition and kidney condition has improved. When you give this drug to animals, they live longer and healthier. You know, we are talking about repurposing drugs that are in use. And the third drug is called rapamycin. Rapamycin is increasing the health span and lifespan of animals the most of any other drug. That doesn't mean that it's going to be as effective in humans, but it's a promising drug. And there's an effort to have some rapalogs, those are derivative of rapamycin in clinical trial to show their effect on variety of diseases and aging.

So, for example, you're using metformin, formin yourself. Would you consider rapamycin or, sorry, the SGLT2, are those primetime enough that you would even personally consider them?

No, I'm not considerate personally, but I hope that there'll be trials with them in order to again show in one study that we improve many diseases of aging. I'm not recommending to anyone to take those drugs because we don't want to hurt anyone and we certainly don't want to kill anyone on the way to success and without doing the trial. It's all about promise. It's not realized yet. So I'm not the one who's telling you in order to go to the doctor and get those, I'm just telling you what they've been Showing and why we think they're gerotherapeutics and why I hope that they'll be soon available in a pharmacy next to you, and that's

why you're more confident in metformin. If I were to headline this, because we have have so much evidence, certainly we know it's a safe drug. Right. Versus these two other ones where we just simply don't have the data.

Right. I would say the only reason I'm interested in the TAME trial is it's a tool to get an FDA indication. Okay. Let healthcare providers start giving it, let pharmaceuticals come in and develop better drugs and combination of drugs. Another thing is there is a question whether the combination of drugs is good or antagonistic. It could be additive, it could be synergistic, and it could be antagonistic. So I wouldn't tell people, just take more drugs. We know from animals, the longest living animals are those that are treated with the combination of rapamycin and metformin. So I think there's indication that it's additive. We'll see if it holds in humans.

So where we are now of what's out there, and obviously you're looking at metformin, but that seems to have the most promise and in fact, closest to market with respect to potentially FDA confirmation of it as something indicated for aging.

Right. I think this is the most mature, has chances of succeeding and have chances for the FDA to start thinking maybe we can prevent aging. This concept is not something that is inherited. You know, there's conservatism and it takes lots of talks and perspectives, persuasion. But we asked them, if we do this study, we don't want to do the study, and you'll tell us, hey, we wanted you to do something else, tell us what to do now. And we kind of agreed of what we're going to do.

When will the trial be concluded?

Well, the study has to start. You know, we had that delay with funding issues, so we'll start it when we can. I hope in the next few months

if it is successful. I mean, could we be in a world where everybody is on metformin? Like, it seems like statins too, are more and more recommended.

Yeah, it will be like that. Look, even in diabetes, metformin works in 70, 80%. Okay. What metformin is doing is public enough. It will work on the population, it will not work on everyone, and probably not everybody will tolerate metformin. So it's going to be one drug out of several options and several combinations.

What's your guess of how much Health span. Might that buy you? Like, where are we going over the next 30 years?

Yeah, I think that that's very important. So we hope that with this study will show that we increase healthspan by a year or two. Okay, that's in a clinical trial, that translates to huge economical effects. If we're healthier a year or two, the cost of the last two years of life will be decreased significantly. We called it the longevity dividend. But it's more than that. An economist from London School of Economy, Andrew Scott, a friend, published a paper in Nature Aging where he said, just a minute, you're totally underestimating because it's not only the medical costs. In fact, in his paper, he took my data on tame, on the Metformin trial, and he basically showed that, you know, we have 3,000 people on the trial. Half of them are metformin. So it's 1500 people on metformin. The economical value, if it'll work the way we said, if we'll delay diseases by a year or two in this four or five year period, we will add an economical value of $150 million, when the study itself is more like $50 million. So we are making $100 million for the economy. But the point is, if you target aging and prevent heart disease and cancer and Alzheimer's and all that, then you're adding a lot of value to life. And this is economical value. Forget the fact that people want to be healthy anyhow, right? I mean, that's clear. Everybody wants to be healthy. So that's the thing. But, you know, I have another study of. I have 750 families of centenarians. And it's not only that they live long, they are healthier for 20, 30 years longer, and they have a compression of morbidity. In other words, they are sick for very little time at the end of their life. So we have example, okay? We as a species can do it. We can live healthy for longer and die.

Okay, yeah, that's what I was getting at. If you buy two more years, does that mean you'll still have a long agonizing death or you get more health span and it's short and quick at the end, Right.

The data that we have suggests that we are contracting morbidity and not only extending health.

Spanish that's extremely interesting. Where is life expectancy going to over the next. I mean, obviously subtract out wars and accidents, but if people are living in prosperous economies, will they be living north of 100 in 100 years?

So our maximum lifespan as a species is 115 years. Somebody lived to be 122. But statistically, it kind of plateaus at 115 years. First of all, it doesn't mean that in the future this has to be the limit. Okay. In fact, we should already work as if that's not necessarily so. But we die before the age of 80, so we have 35 years to realize that we should start doing right now and improving it. And it's both with medicine and with the environment. And we need it not only because we have elderly, but we have people who survive treatment for cancer that are getting sick and old really early on. There are kids who survive cancer and have heart disease when they're 35 years old. People with HIV have diseases 10 years before they appear in their cohort. Poor people, debilitated people, disabled people. And certainly if we want to go to Mars, we have to deal with aging first because we're not going to get there without getting cancer or heart disease and we'll never make it back. So it's important for many reasons to start and target aging, and we have the tools to accelerate it right now.

It's fascinating, and that was amazing. Yeah. Thank you for touching on all these points and have a wonderful rest of your day.

You too.

That was our Host, Shawn Francis, CEO and Chair of MedCan in conversation with Dr. Nir Barzilai, the world's foremost expert on metformin as a therapy for aging and the founding director of the Institute for Aging Research at the Albert Einstein College of Medicine.

We'll post links to that clinical trial targeting aging with metformin at our website@eatmovethinkpodcast.com

say hello or send us a tip or a suggestion by emailing us at infoatmovethinkpodcast.com Eat MoveThink is produced by Ghost Bureau.

Senior producer is Russell Gregg. Jasmine Ratch is managing producer.

Social media and strategy support is from Chantelle Guertin and Andrew Imax. Christopher Shulgin is executive producer.

Remember to rate and subscribe to Eat Move. Think on your favorite podcast platform. Follow our host, Sean Francis on Twitter and Instagram. Shawn C. Francis. That's Sean with you and Medkin at Medkin Live.

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