Dr. Nir Barzilai: Can This Drug Slow Aging? The Science Behind Metformin

Mark Hyman, MD

Dr. Mark Hyman is leading a health revolution—one focused on using food as medicine to support longevity, energy, mental clarity, happiness, and so much more. Mark Hyman, MD is a practicing family physician and an internationally recognized leader, speaker, educator, and advocate in the field of Functional Medicine. He is the founder and director of The UltraWellness Center, Founder and Senior Advisor for the Cleveland Clinic Center for Functional Medicine, a fifteen-time New York Times best-selling author, and Board President for Clinical Affairs for The Institute for Functional Medicine. He is the founder and chairman of the Food Fix Campaign, dedicated to transforming our food and agriculture system through policy.

He is a co-founder and the Chief Medical Officer of Function Health. He is the host of one of the leading health podcasts, The Doctor’s Farmacy with 150+ million downloads. Dr. Hyman is a regular medical contributor to several television shows and networks, including CBS This Morning, Today, Good Morning America, The View, Fox, and CNN.

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Full Transcript

Automatically generated. Please forgive any typos or errors in the following transcript. It was generated by a third party and has not been subsequently reviewed by our team.

Dr. Mark Hyman:
Coming up on this week's episode of the Doctor's Farmacy.

Dr. Nir Barzilai:
Remember Paul Simon had the 50 Ways to Live Your Lover. There are 50 ways to be centenarians. We're trying to discover all of them.

Dr. Mark Hyman:
Welcome to Doctor's Farmacy. I'm Dr. Mark Hyman, and this is a place where conversations that matter and today we're going to learn about longevity science. It's one of my main passions and it's why I'm so excited to bring you today's conversation with one of the top leaders in the field, Dr. Nir Barzilai. He's the director of the Institute for Aging Research at the Albert Einstein College of Medicine and director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health Nation Shock Centers of Excellence in Basic Biology of Aging. He's just a rockstar when it comes to longevity science. He also studies the family of centenarians that have provided incredible genetic and biological insights on the protection against aging. Several drugs are developed based in part on these paradigm changing studies. He's now leading a really important study looking at metformin called the TAME Trial Targeting or Taming Aging with Metformin to prove one way or another to the FDA that aging can be delayed and allow for next generation interventions.

He's co-authored over 300 peer review science papers and is a recipient of numerous prestigious awards, including the 2010 Irving S Wright Award for Distinction in Aging. He's also the 2018 recipient of the I-P-S-E-N Longevity Award. He's on the board of many incredible organizations and he is a founding member of the Academy for Healthspan and Lifespan, the Longevity Biotech Association and the Healthy Longevity Medicine Society. He's co-founded Cobar and Life bioscience and is featured in prominent papers, podcast, TV programs, documentaries, Ted Talks. He's consulting for the Singapore government, several international banks, the Vatican, the Milken Institute, and the Davos Economic Forum. And his book age later was published in June, 2020. Now we get into it, really into it. In this podcast, the way we think about aging and disease is rapidly changing and Dr. Barzilai and I begin our conversation exploring why he's moved away from the term anti-aging.

Together we explore the ways aging and chronic disease are closely aligned and what is at the root of accelerated aging. We're seeing in so many people today. Dr. Barzilai is one of the two people who spent the most time studying centenarians or people who reach a hundred years old, and we dive deep into a vast array of his learnings, including why having a longer lived healthy population would actually be good for the economy. He also shares some very interesting and surprising characteristics of centenarians and breaks down what can and cannot be attributed to environment and lifestyle factors. We then dive into Dr. Barzilai 's research on the drug metformin and how it's being used to target aging and prevent age-related disease. We discussed metformin's effects on the gut microbiome on muscle mass and delayed aging, and I share my current thoughts on it if it's something I would consider taking.

Dr. Barzilai also shares his thoughts on whether the intake of phytochemicals and other natural compounds might provide similar benefits to metformin without taking the drug. And we close our conversation with Dr. Barzilai's personal longevity routine. If you're interested in living to a hundred and beyond like me, this is the conversation for you. Now let's dive into my conversation with Dr. Barzilai. It's so great to have you on the Doctor’s Farmacy podcast. Nir you're a legend in the field of longevity science. You're doing groundbreaking research that is going to inform all of us about how we should live our lives, how we should think about the biology of aging and what kinds of things we can do to help extend our health span, our lifespan. And you're not just some biohacker doing this on Instagram. You're a scientist who spent your life studying this and has been inspired to do this for a number of different reasons. And one of the things I'd love you to start talking about is your grandfather. You recall him as a very robust, healthy, younger man who was able to do incredible feats of health and fitness, and yet when you knew him, he was older and he had diabetes, it was decre, and you're like, what the heck? So maybe share how maybe that was part of the inspiration for you being interested in this field of longevity science.

Dr. Nir Barzilai:
But first, I mean, thank you for the flatter really, get you nowhere, but look, same with you. You are pioneering your own way and all of a sudden we find ourself in the same boat because aging went from hope to promise and now we have to realize the promise. So we merge now and it's really important for me to make sure that we are kind of synchronizing more. So thank you. And yeah, my grandfather, so

Dr. Mark Hyman:
You're from Israel, right? And you were

Dr. Nir Barzilai:
Kind of, I think the bottom line is when we were kids and we looked at our grandparents, we were like, where did they come from? I mean, what happened to them? You never really see yourself as Uhoh. That's how I'm going to be right?
By the way, I found that this has changed because there's so many younger people who are really interested in aging. But that was for me and for me, even through medical school, I always said, okay, so cholesterol in diabetes, you can bring me a hundred people and I wouldn't know if they have high cholesterol diabetes, but I know that who's old and who's young, and that was the phenotype that was much more interesting to understand and can we do something about it? There's also when I went through my residency, I had a professor and whenever we presented a patient, we said, so it's a 68-year-old woman. And he said, does she look older or younger than her age? And I thought, what that has to do with everything? And all of a sudden you started through this just simple question, understanding that there's a biology for aging, there's chronological age, but there's biology of aging and it actually has a clinical impact of what you want to do, who you want to give up on and things like that.

Dr. Mark Hyman:
Yeah, it's so true. We all intuitively know if you see a 40-year-old smoker has been smoking two packs a day and an alcoholic for 30 years, they look pretty rugged. And if you look at someone who's 65 who works out every day, who eats perfectly runs five miles a day, they look younger than that 40-year-old. So we know intuitively there's something going on and that the chronology doesn't actually always match the biology. So your work has really been to understand the root mechanisms of this change in the biology of aging and how we can impact that through lifestyle, through medication, through various compounds that we can study and use, whether it's dietary factors or herbal factors or peptides and all sorts of stuff that are available to us to think about how we influence this process. But what's going on now is this incredible revolution.
When I was in medical school, we never even talked about aging. It was like study diabetes, study, heart disease, study, dementia, study cancer, the disease of aging. But as you talk about the biggest risk factor for all of these things is chronological age. The older we get, the higher our risk is for all these conditions. And so now scientists are starting to think about, well, what is it the root cause of these diseases that maybe unifies them? It's almost like the unified theory of aging and disease like Einstein. See the picture of Einstein behind your head there. I know you're at the Albert Einstein College of Medicine, and I think he talked about this kind of unified field theory once this unified field theory relates to aging and how do we think about these key factors that are causing this acceleration of biological aging and the diseases of aging?

Dr. Nir Barzilai:
So our practice and our leadership has brought that to declare that there are hallmarks of aging. And let me tell you what are hallmarks of aging in my mind because there's no total agreement, but to be a hallmark of aging, you have to show that something is wrong with aging. And when you correct it in animals or in people, actually you get an increase in health span and maybe decrease in mortality or increase in lifespan. This is how you become a hallmark in a conservative way. And the reason we have hallmarks is because something interesting has been observed. When you correct one hallmark, you influence all or a lot of the others.

Dr. Mark Hyman:
Yes,

Dr. Nir Barzilai:
You can improve autophagy, which is our cellular garbage disposal that takes our junk out. You can improve it, it goes down with, you can improve it, but you get better metabolism, you get less genetic instability, you get epigenetics changes.

Dr. Mark Hyman:
Mitochondrial function improves, right?

Dr. Nir Barzilai:
Mitochondrial function,

Dr. Mark Hyman:
Inflammation goes down all of it.

Dr. Nir Barzilai:
So there are practical issues here. First of all for me, when it comes to what do we call RO therapeutics, which we used to call anti-aging therapy, we don't use anti-aging because we have jero science. It's a little another.

Dr. Mark Hyman:
I'm not anti anything, I'm pro health wellbeing.

Dr. Nir Barzilai:
But when you use RO therapeutics, we can take as an example, metformin or rapamycin or SGLT two inhibitor or even GLP one agonist, other drugs,

Dr. Mark Hyman:
Ozempic, in other words, in other similar drugs. If you

Dr. Nir Barzilai:
Go and look at what happens to those hallmarks of aging, they all change. And people said, are you crazy? What God created 12 different aspects of this? And the real point is that those drugs are doing something to stop aging. So they take basically an old cell and make it younger or an old organ and make it younger or a whole body and make it younger. And when he does it, there are lots of things that are corrected. And I remember when it came to metformin, we started arguing this is what it does or this is what it does. No, we can decide what happens first, but when you correct aging, you get a lot of effects. So this is one practical aspect. The second practical aspect that is really important because we want to advance the field biotech. I'm also an executive in the longevity biotech Association. There's a lot of biotech investment. And people would come to me, my job is to do help them due diligence and they come and say, Hey, which hallmark shall we target?

Dr. Mark Hyman:
By the way, what disease? That's the wrong question. That's the wrong question.

Dr. Nir Barzilai:
Which is your favorite hallmark? I remember this guy from Texas at five daughters. I said, who's your favorite daughter? He said, I'm not answering. I said, I'm not answering. But the

Dr. Mark Hyman:
Point is, that's great.

Dr. Nir Barzilai:
You can target one hallmark and you improve the others. But that also means that the hallmark, you can do the mitochondria, but you actually have influence not on things that are associated with mitochondria, but other aging thing. In other words, the fact that one hallmark effect the other means that some of the indications for drug development are going to be increased. So I gave you an example why those hallmarks are important. They're not done by the way.

Dr. Mark Hyman:
There was nine now there's 12, maybe 13.

Dr. Nir Barzilai:
And not only that, please understand this. We say hallmark, and you might understand, I'm not talking about you, mark, but others might understand that this is mechanism, this is the mechanism for aging. They're not necessarily the mechanism for aging. We still have a lot of things to do in order to understand what and what comes first and what's the combination. But those are practical things that we know that we can fix and have an impact. And that's a good start.

Dr. Mark Hyman:
Yeah, it's sort of like physics. We know there's atoms and electrons and neutrons, and then there's like quarks and boin particles and things we haven't really discovered yet. We keep learning. So I agree,

Dr. Nir Barzilai:
But once we discover atoms, we already had a lot of advance, right? Yeah,

Dr. Mark Hyman:
Exactly.

Dr. Nir Barzilai:
Without the neutrons.

Dr. Mark Hyman:
I just want to drill down on what you just said because it's so important and it speaks to the problem with the traditional science and traditional medicine, which is reductionist. What is the single pathway? What's the single target? Which drug do we develop for inhibiting or affecting this particular pathway? And what you just said was revolutionary is that these are all interconnected. It's a network and it's a network effect. And these are all connected in a web-like fashion that all influence each other and are often redundant. So if you actually influence A MPK, which is a lot of the work you're doing with metformin, you're also reflecting autophagy and DNA repair and NF kappa B and inflammation and P 53 cancer genes, and you're just doing so many different things that are redundant. And if you hit one of the other hallmarks, you're going to do similar things.
And there's so many ways to influence these that they're very redundant pathways. So it seems to me that biology, whether you believe in God or not, how we designed evolution, the body was designed with so many redundant systems that we're all designed to correct and repair and rejuvenate our system. So in a sense, what's so exciting to me up about the hallmarks of aging is it's explaining for the first time these kind of fundamental laws of biology where everything is connected. The body has this innate healing system, it has a profound and incredible healing regenerative repair renewal system, and that's what we're trying to target and activate. So we don't treat diseases anymore. We treat these fundamental root causes. And I would even go further to say what are the root causes of the hallmarks of aging people? It's a little bit still reductionist. What's causing the hallmarks of aging?
What's causing mitochondrial dysfunction? What's causing exactly causing DNA damage? What's causing deregulated nutrient sensing? And people say, what's your favorite hallmark? I actually have one. I think the meta hallmark, and you can correct me, the scientist here, I'm just the doctor, is I think that one of the meta hallmarks is the deregulated nutrient sensing because it influences all the others in such a profound way. And if you regulate that, which is really through food and our way of eating, what we're eating, when we're eating, how we're eating, all those other pathways that relate to the hallmarks speech, Kimberly influence,

Dr. Nir Barzilai:
First of all, by the way, when you edit this podcast, you should take out my stuff because you summarized it so beautifully. But then at the end you did what I kind of made sure you wouldn't do. Who's my favorite daughter?

Dr. Mark Hyman:
I know, I know, I know. And I'll tell you. Well, that's why I want you to correct me.

Dr. Nir Barzilai:
And I came from metabolism, so I don't object it, but the last paper that we all have, the slide, the last slide that we have went from seven hallmarks to then nine hallmarks to now 12 hallmarks. And those 12 hallmarks are saying actually there are three groups and one of them are the ones that are more likely to be the initiators and the others are going to be the responders.

Dr. Mark Hyman:
Yes, that's what I'm saying. Yeah.

Dr. Nir Barzilai:
So like genetic instability and prota might be more important than metabolism. It's their failure that might lead the metabolic failure.

Dr. Mark Hyman:
Interesting.

Dr. Nir Barzilai:
I'm not judging, I'm just saying what it is.

Dr. Mark Hyman:
There may be a hierarchy in what you're saying.

Dr. Nir Barzilai:
There is a hierarchy and yeah, we want to understand the hierarchy and we want to see if we missed any of the promoting. But I also want to say that exactly that when, so every one of us has hallmark or hallmarks, and we all try to do this picture to take this picture of hallmark and say, but ours is in the middle just like you did. Metabolism is correct to everything. And the answer is exactly what you gave before. When Anna Maria Cuervo, my dear colleague here at Einstein Codirector when she said, I think autophagy is in the middle because that leads

Dr. Mark Hyman:
To

Dr. Nir Barzilai:
Everything I say, well, why autophagy decline with aging?

Dr. Mark Hyman:
Yes,

Dr. Nir Barzilai:
Exactly. There's something that leads the autophagy to decline with aging. Tell me what it is.

Dr. Mark Hyman:
Yes, it's the cause of the cardio

Dr. Nir Barzilai:
MTOR that's target for rapamycin increase with aging. We want to decrease it. Why does it increase with aging? We don't know that.

Dr. Mark Hyman:
Yeah, yeah. It's exactly right. I think we like to be simple in our thinking, but biology is infinitely complex. Physics is actually complicated, but it's knowable. Biology is almost unknowable. I mean, when you think about there's 37 trillion cells, and I think a billion reactions in there every second or something, it's like 37 billion, trillion chemical reactions happening every second in the body. It's mind boggling. And I think that most, and you

Dr. Nir Barzilai:
Even ignored the microbiome, which more sense, right?

Dr. Mark Hyman:
Yeah. I mean there was a hundred thousand terabytes of information just in your biome. And I was on a panel with Stan Hazen at Cleveland Clinic once talking about the microbiome and health, and I said, Stan, how much of our metabolites in our metabolome are from our microbiome? In other words, how much of the molecules floating around in our blood that regulate our biology come from metabolites produced by the microbiome, which is from their genetic expression? And he's probably a third. And I'm like, whoa. A third of all our stuff in our blood comes from the microbiome. So we're really, I think in the dark gauges in a way, we're just sort of opening the door. I think with AI and the machine learning, we're going to be able to ingest so much information and begin to see these patterns and connections and learn more. And I'm very excited about that,

Dr. Nir Barzilai:
But I really want to do it more positively. Not that what you describe is true, but okay, microbiome, will we know that sauerkraut and kimchi changed the microbiome and improve the health no matter what is, okay, so yesterday there was really the best biomarker. I'm in a group that is a consortium of biomarkers, and we had a meeting yesterday at the Buck Institute. It was a meeting that was supposed to be a hundred people, but 250 people showed up. Lots of people couldn't register. I'm just saying it was a big deal. And people actually started saying, oh God, we have all those biomarkers and what do we do? And we have to have causative biomarkers in order. We have to understand aging first before even we get to biomarker. And I said, look, to diagnose diabetes, you need just one measure, and that's hemoglobin A1C. That's all you need. Okay? Do I know everything about diabetes? Not, but it's not that biomarker are useless unless I know more. Okay, that right, right. So I think there's a way, obviously we're moving on no matter.

Dr. Mark Hyman:
I agree a hundred percent, a hundred percent. It's true. You don't need to know how something works in order to actually treat it. I mean, if you eat better, we know it creates thousands and millions of changes in your biology and you eat crap, you feel bad. If you eat good food, your body gets healthy. You don't have to know how that works. But it doesn't mean you shouldn't exercise or eat healthy or do the basic things we know. So I completely agree with you, not like we have to have everything figured out before we do anything. Although sometimes some doctors and scientists are like that. So this moment is kind of an exciting moment. You've been working at this for decades and decades. It's almost like all these billionaires somehow got the longevity bug and want to not die. So they're pouring billions of dollars into this space, which is good for all of us, and it's actually allowing the research to really accelerate.
And you're one of the ones who've been saying for a long time. And I want to dive into a lot of the work you're doing, particularly around the super agers and the centenarian study. I want to dive into the science around metformin and what that is because a lot of people out there are taking this diabetes drug for longevity, and I have some concerns about it. I know you're the expert in it. You're doing a study to show once and for all what we know and what we don't know. And I want to get into that. But can you talk about this centenarian study that you've done that is about these super ages, what you've learned and how you sort of found that many of these people don't get sick, they just kind of die. There was a really important paper about the compression of morbidity that was published I think in New England Journal 1980, which talked about people who exercise, didn't smoke and were optimal body weight, lived long lives and then just died.
They had this rectangular of the survival curve. They just basically fell off the cliff, whereas people who didn't exercise weren't their ideal body weight. And smoked had this a long, slow decline, meaning their health span was a lot shorter than their lifespan. And this is what you saw with these centenarians where they sort of kicking along and going dancing at a hundred years old. And I just had a friend of mine, Norman Lear died today, and I was with him his hundredth birthday, and he was kicking up a storm, he was making jokes, and it was fantastic. And I was like, wow, this guy's just great and very sharp and

Dr. Nir Barzilai:
Kissinger, Kissinger who wasn't dancing, but he was mentally, he was really sharp. Yes. So absolutely. You described exactly, it's not only that they live longer, they live healthier. It's not only that they live healthier, they have a compression of morbidity. Like 30% of our centenarians don't have a disease, they don't take any drug, they just don't wake up in the morning

Dr. Mark Hyman:
In one day.

Dr. Nir Barzilai:
It's actually interesting, the C, d, C, we all know what's the C, DC after covid? The CDC is looking at the medical cost in the last two years of life of somebody who dies after the age of a hundred versus those that die when they're like 70 and it's third the cost. So there is longevity dividend by those example of Lear of Kissinger. People who just live on have very few medical records and then they die. Like everybody, how come Lear died? What happened to him? And that's very typical. But I want to say something else that, because it's an economical thing that I think we should always include when we talk about health span and even lifespan. Because Andrew Scott, who's a professor of economy in London School of Economy, said, guys, what are you talking about? You're totally underestimating because you are saying you're looking at medicine as people in the hospital. Okay, I'm looking at medicine on people outside of the hospital. So if they're not in the hospital, what are they doing? They're traveling, they're shopping, they're buying houses for the kids. And the economical value of just a little increase in health spend is absolutely amazing. And by the way, if we don't do it, we're going to bankrupt the governments anyhow. So I think this is very important. I

Dr. Mark Hyman:
Think the data on that was interesting. It was like 37 trillion for every year, and if you did 10 years, it was like $367 trillion add to the economy. And again, based on that compression and morbidity study, if you are doing bad behaviors and lifestyle, you're going to die long, slow, painful, expensive deaths where is if you live long, you're going to die quickly, painlessly and cheaply.

Dr. Nir Barzilai:
Exactly.

Dr. Mark Hyman:
So you were talking about these super ages in the Arian study, and what are the key takeaways that you've learned from this work that you've done for decades? Because you and Thomas Pearls were the only few who've actually done this and looked at these people,

Dr. Nir Barzilai:
Right. So let me say few things before highlighting something. I want to say a few things. First of all, we have three hypothesis. One is that it was interaction with the environment, which is not true with centenarians. Half of our centenarians were over overweight or obese, even as centenarians, 60% of men and 30% of women were smokers. Exercise even moderate exercise, house cleaning and biking and walking. Less than 50% of the people vegetarian, a little over 2% of the people. In other words, as a group, that's not what they've done. And let's not be confusing because you exactly tell people what to do as far as exercise, nutrition, sleep, and social connectivity. But that's not it. That's the point. So the second question was, okay, hey,

Dr. Mark Hyman:
Although it's a good bet, if you take care of yourself, you're going to do better. So

Dr. Nir Barzilai:
I'm saying absolutely, it's important to note it's good for all of us, but they're distinct by the fact that they didn't do it, so they had something special. So what is something special? So the second hypothesis was maybe they have we all, now that we have Xs and lots of us are doing genotypes. So 23 and me, we have lots of things that are associated with disease. We have snips changes in the DNA that are associated with Alzheimer's and with heart disease and with cancers and all that. Maybe one out of 10,000 just have perfect, we call it perfect DNA. Okay? You don't find it. And in fact, when it's already more than a decade that we had the sequence, the whole genome sequences of our first 44 centenarians, okay, no control, nothing, just 44 centenarians. And we went to this database clean var, and we asked how many of those variants that are pathogenic variant, which means you'll get the disease, okay, if you have that, you'll get the disease. How much do they have? And to our surprise, 44 people had 230 SNPs. In other words, they had five or six SNPs that should have made them sick, including we have centenarians who have a E four genotype. If you're homozygous for a E four genotype, you're most probably going to be demented at 60 and dead at 80, and they're a hundred, and they're not demented.

Dr. Mark Hyman:
I had one of those, she was 93-year-old dentist and was still working, and she was a OE double four.

Dr. Nir Barzilai:
Okay, so that's the point. So the third hypothesis, which we're really supporting by many ways, is that they have actually genes that slows their aging. In fact, they slow their aging to such effect that if you have some of the junk stuff, it doesn't matter. It doesn't

Dr. Mark Hyman:
Matter. Yeah. Yeah. That's amazing. So basically you found that there were certain genes that they had that were protective genes. And the question is based on those protective genes and discovery of those, what are those genes and what can we do about it? Because just for people as background, they've listened to me. They know your genes are fixed. You can't change the genes that you have, but you can change the expression of those genes, how they're modified by what we call the exposome. Everything you're exposed to throughout your lifetime, your diet, your thoughts, your feelings, your microbiome toxins, your gut microbiome said everything influences your gene expression. So these SNPs, these variations in the genetic code are not mutations, they're just variations, but they highly influence our health and what we do. So what have you found are the most relevant SNPs that actually extend life and then increase health? And what can we do for those of us who may not have them? How can we optimize those variations?

Dr. Nir Barzilai:
Good. So let me give you an example. I would say that there's, remember Paul Simon had the 50 ways to leave your lover. There are 50 ways to be centenarians. We're trying to discover all of them, but there are certainly things that are leading, and I will take one example because I think it's very important, and that's that 60% of our centenarians, 60% of our centenarians have something that impairs the actions of growth hormones. Okay? 60% of them.

Dr. Mark Hyman:
Yeah, that's like that Villa Baba, those little Ecuadorian people who have really short and they have these growth hormone deficiency and they live forever.

Dr. Nir Barzilai:
Those are the Lauren Dwarf, right? Yeah,

Dr. Mark Hyman:
The D, yeah.

Dr. Nir Barzilai:
They have a growth hormone receptor deficiency, and they don't get diseases. We don't know if they live longer. On the other end, in my studies, 12% of our centenarians have a deletion of exome three in the growth hormone receptor.

Dr. Mark Hyman:
Interesting.

Dr. Nir Barzilai:
The interesting thing in that though is they're much taller than average, although they have this mutation, they're much taller because it's kind of a mutation that when they go through puberty and there's high growth hormone level, it's hyperactive. But when growth hormone drops, then growth hormone goes down. IGF one, which is a peripheral growth hormone, is down. Okay? So there's interesting variation. In other words, if somebody stall and said, I heard that you don't need growth hormone. I said, no, you might have mutation. That is good. Don't be discouraged. But basically, and even in our centenarians, few things, our women centenarians, most of the centenarians are women. The ones with the lower half of growth hormone IGF one, it's the growth hormone that we can measure. Half of the women that have the lower IGF one leave twice as long. They're already centenarians. Okay? Centenarians have 30% chance of dying every year.
But those with the lowest leave the longest, also, those with the lowest have better cognitive function. Those with the lowest don't have any difference in physical activity. Because the question is, does IGF affect muscle? Well, it makes the muscle may be better, even if not stronger. So those growth hormone mutation is really important. Now, what we did, because we start researching animals, we go to humans, now we have to go back to animals. So we took animals and gave them an antibody. Again, the IGF receptor that was developed for cancer didn't work. Cancer is much more complicated than aging in my mind.

Dr. Mark Hyman:
And insulin is an insulin growth factor. One is a big driver of cancer. So

Dr. Nir Barzilai:
Exactly. So it made sense. But when we take animal and we give them the IGF one antibodies, they live longer and much healthier. So this is an important system. Now let me explain it in a way that people understand when we go, evolution is about having children. So growth hormone, our body stronger, we have more muscle, we're able to get better partner. I don't know. It all works well.

Dr. Mark Hyman:
Okay? Yeah.

Dr. Nir Barzilai:
Okay. Now we get to the age of 50, which by the way, life expectancy through of most of a hundred thousand years of evolution was between 20 and 30. So we didn't get to enjoy 50 so much, but when we get to enjoy 50, then we started to go into aging, and now it really makes no sense for us to spend our energy in growth when we're actually starting to break down. So I think that there's a hypothesis in aging that's called the antagonistic biography. The things that are good for you when you're young are against you when you're old. And that's a perfect example. And we actually proved it by looking at this very good database from the UK Biobank. And we showed there that everybody young, when they have high IGF one level, they have less diseases, less mortality, and after the age of 50, it totally switches. Everybody with high IGF gets into a lot of trouble. So I'm pretty sure to tell you that this is important, and I'm pretty sure to tell you that that means that for elderly people to give them growth hormone is not a good idea.

Dr. Mark Hyman:
Okay? Yeah. Yeah. I was going to ask you about that. There were some studies. There was one in New England Journal published a number of years ago showing how it improved so many biomarkers and improved muscle mass and health in many ways. And in the whole a t aging field up until recently was really pushing growth hormone. I was very always concerned about it because of its increased risk of cancer and diabetes. And so I'd love your perspective on that because it sounds like wow, growth hormone is a good thing in some ways. It increases your capacity for exercise and fitness and wellbeing and sexual function and everything, but there's a dark side to it.

Dr. Nir Barzilai:
And by the way, we'll get to Metformin, but remember that because it's the same story. I don't think metformin is good when you're less than 50 unless you have diabetic. Because there trade-offs, you have to realize that now we're talking about the biology of aging that is different than the biology of young. And so we cannot assume that everything that was good for young people is good for old people so we can develop it.

Dr. Mark Hyman:
So we often look at IGF one levels, and there's a lot of people out there in the sort anti-aging field that are looking at that and go, oh, your IGF levels one, let's get that up. And I think to me, it's a big concern because one of the might amend my favorite hallmark is the deregulated nutrient sensing. And the first part of that is deregulated insulin signaling. And I think insulin is, and we're going to get to this with metformin, but as people know my work, I've talked so much about insulin resistance as the biggest driver of so much of the phenomena of aging, heart disease, cancer, diabetes, dementia, muscle wasting, and just aging itself. And it seems to be one of the primary drivers, and it seems to be why we're seeing an increase in chronic disease because our diet is really inducing excess insulin signaling, and it's why we see increased rates of cancers in people with the insulin resistance. And it's a big factor with obesity. If you're obese, you're more likely to get breast cancer or prostate cancer, colon cancer, and many other cancers. So it's a really interesting complicated story, but I think it's like what is the right way to approach this? Should we be trying to reduce growth hormone as we get older? Is this something that we should be targeting saying these centenarians have lower IGF one and lower growth hormone. That seems like an interesting avenue for potential

Dr. Nir Barzilai:
Research. So by the way, metformin lowers IGF one. So for example, metformin does it. Not every drug is doing, but I gave the example, there's already an FDA approved, no, it's not FDA approved, but there's IGF receptor antibody in humans that, so we have that. It's safe. It was used in trial, and it's kind of available to think about therapy for aging. So one of the thoughts that we had even in our study, it seems that the major benefactor for low IGF is women who had cancer in the past or tumor, any kind of tumor in the past, when they have low IGF one level, they kind of live forever. So the question is, should we women after breast cancer, which by the way they age, okay, another reason to have RO therapeutic is to treat cancer survivors. We give them chemotherapy and radiation, we accelerate aging, and then they're older. So for example, should they be receiving IGF antibody? I talked with the companies that are doing that as an ideal, but unless aging will kind of be more an FDA approved indication, I think the pharmaceuticals are very reluctant to start doing that. Another thing that lowers igf, just that I know those fasting regimens are also lowering IGF, some of them,

Dr. Mark Hyman:
Well, because lowering insulin signaling, but other things, exercise and keeping metabolic healthy and actually reducing sugar and starch in your diet also, will that reduce IGF one as well?

Dr. Nir Barzilai:
I don't know if it does much of it. I don't know if it does as much. I don't know. I have, if

Dr. Mark Hyman:
You become more insulin sensitive, do you have less IGF one?

Dr. Nir Barzilai:
Well, not necessarily. It's from an insulin signaling. They share a hybrid receptor. But from a clinical point of view, the relationship between insulin level and IGF one are not really great. So I'm not sure. I haven't seen a study that I can quote even though it's

Dr. Mark Hyman:
ING question. Interesting. Now I want to talk about something else that you found in your super ager research, and that has to do with some of the other common traits that they have. You mentioned the really low levels of IGF one, but they also had high levels of HDL or high density lipoprotein cholesterol, which is people refer to as the good cholesterol, but there's no good and bad cholesterol. There's just different functions of the cholesterol. And I remember years ago I had this old guy who was like a pathologist from Quest Lab who came, gave a talk and he said, I realized we have all this data on people and we really don't know what the phenotype is because we just get their lab data. We don't know actually what happened to them. He wanted to research what affected longevity, and he decided to look at HDL.
And he basically went and found all these people who had a high HDL in the Quest database, and then he tracked all their death certificates. And he found this incredible correlation between high HDL and longevity now, which is fascinating because when we looked at certain drugs that are the CTP inhibitors and others that actually seem to raise HDL, they actually have the opposite effect. So naturally having it may be good pharmaceutically, elevating it may be bad. What's your thought on this whole thing? And there's new versions of these drugs that are about to come out as well that may, we don't know. So I find it very fascinating. And I think the things we do know is that sugar and starch lower your HDL, and that exercise increases it and good fats, and also like coconut oil and saturated fats will increase your HDL. So we know some ways to modify it, but I'd love to kind of hear your perspective on

Dr. Nir Barzilai:
This. Right. So we discovered very common genotype, but by the way, what I'm describing are functional genotypes that we know there are lots of snips that they're everywhere, and we don't know if they're functioning. I'm talking about functional genotypes. And we found functional genotypes on the CTP. That's one of the gene that control those cholesterol, HDL, lower triglycerides. And another thing in a gene called APO C3. And the pharmaceuticals was very interested in our research. And actually Merck has developed, Pfizer failed another, Pfizer didn't develop a right drug. It was a drug problem. It caused hypertension. It was something else. Merck developed a CT P inhibitor and a company that, what's their name? They used to be isis, but then they had to change the name, the Ionis. Now Ionis develop an antagonist to APO C3. Both are changing. And by the way, they didn't develop it for longevity. They developed it for lipids.

Dr. Mark Hyman:
And APO C3 will have, your triglycerides will go up if you have APO C3,

Dr. Nir Barzilai:
Right? No, right. But our genes are inhibiting the CTP and the APO C3, they have to be lower. And so those drugs that are inhibiting, those are coming out to the market with Merck. One of the interesting thing, our centenarians who had this mutation in CTP, they're distinct from other centenarians because they had an incredible cognitive function. This was better even than heart disease or anything else

Dr. Mark Hyman:
If they had lower A OC three functioning.

Dr. Nir Barzilai:
And so I asked Merck on the CTP, I asked Merck when they did their study to look at cognitive function, and they didn't have any association, but I think that they had the wrong population with the wrong test. If you do cognitive function on 50, 60 years old, you're not going to get much change in cognitive function. You need some for the test we have. You need some other population. So I'm still thinking that this CTP will come in, people will start thinking about it, and I'm thinking, when this CTP will come in, I'm thinking I'm going to take it because the cognitive function signal was pretty amazing.

Dr. Mark Hyman:
It's interesting. I actually have done my genes and I have the good version of the CETP and the bad version of the A PO C3, and it tracks my HDLs higher, and my triglycerides are also higher than I would expect given my diet and lifestyle. I mean, they're not stupidly high, but I'm like, why is my triglycerides a hundred given what I eat? And I can get it lower. But it's just so fascinating to see how we're going to be able to track our genotypes and then see what works for us and create this personalized approach to health and longevity, which is where it's all going really fast

Dr. Nir Barzilai:
In a total surprise. I have one by 23 and me, I have one of the IGF receptor genotype that I

Dr. Mark Hyman:
Published. Oh, okay. So you're going to be doing this a long time then, huh? We're going to keep going. We'll do another podcast when you're a hundred.

Dr. Nir Barzilai:
Yeah, let's do a deal like this.

Dr. Mark Hyman:
And the other thing that you found was something else that was in the super ages called high levels of MDIs. Can you explain what are MDIs, what that is, why it matters and what you found?

Dr. Nir Barzilai:
So this is kind of a surprise, and I have to say I have a guy, the dean of gerontology at USC. We went to medical school together. By the end of medical school, we published together like eight papers. And we are collaborating ever since, though he's a pediatrician, but he's the head of gerontology now because I influenced his life so much. But we were looking, we had a grant together and he was looking at partners for not the IGF, but there's IGF binding proteins. It's a

Dr. Mark Hyman:
Complicated Yeah, IGF p3, right?

Dr. Nir Barzilai:
And he kind of fished a peptide that eventually was known as human in. Human is coming from the genome of mitochondria. So we have at some point of evolution, early evolution, our cells were kind of miserable and pathetic and we needed some energy and we got this bacteria and mitochondria is really SI of bacteria. And we adapted to be symbiotic, and that's the source of energy. But those mitochondria and we often forget, have their own genome,

Dr. Mark Hyman:
DNA, right? Their

Dr. Nir Barzilai:
Own

Dr. Mark Hyman:
D. And this comes from your mother,

Dr. Nir Barzilai:
It comes from your mother, right? It has your own DNA, and also it has mutations on your DNA. But it's not only that this DNA produces peptides that eventually you can measure in your blood. And when you give those peptides, they do stuff. So human in is one. So we started actually a company to try to develop at least good part of the things when you develop those peptides, when you develop the peptides, you actually have to have them act longer and you have to find things that are more with higher efficacy and stuff like that. So we developed a bunch of those peptides. And on the way we found really interesting things. I'll give just one example. One of the peptides that we developed, we looked at genome of Asian, Korean, Chinese, Japanese, and they had 8% of them had mutation in this peptide.
And when Hasi measured those peptide activity in the lab, they weren't so active. Now those people, those 8% had 30% increasing risk of having diabetes. So by the way, genetics is so important now because two thirds of the drugs that FDA approved last year were based on genetic studies. It's no longer that you work on mice or nematode and say, let's develop a drug. It doesn't work anymore. Regeneron, all the pharmaceuticals, they want to see population that have overactivity, underactivity of this peptide and have a disease. And then you can develop the drug fast and more effectively. So it's very important for us to get signal from population that also showed you that, by the way, it's called motzi, this gene. So it's very important to show that there's relationship between genetic study and actually diseases in humans. So you have more confidence that there's a causality here.

Dr. Mark Hyman:
Yeah, so interesting. A lot of people are using peptides now, like motzi human in, and you mentioned earlier when we were chatting before the podcast that MOTZI can be helpful, but then you develop antibodies to it, which may have other adverse effects we haven't understood. So a lot of people are playing with peptides. Do you think it's safe? Do you think it's risky?

Dr. Nir Barzilai:
No. Look, I understand frustration of people, and I think that the frustration leads to shortcut. And when you say maximize your exercise or diet and stuff, you're not really causing harm usually. But when you're taking peptides that you don't still understand everything about them and you manufacture in a way that's probably doesn't make sense. They're companies that are happy to give you these peptides. But actually, for example, in the Mo Sea, it was hard to find actually a solution that will hold this mo sea without getting them to clink together. And we couldn't get them any blood level. So there's so many things with those peptides that you cannot assume I'll order a peptide and inject and it'll be thing. I think it's, it doesn't make sense from this sense. And then it can be dangerous because we don't know how much, and generally drugs, there's too much for drugs and too little for drugs. So I think it's a wishful thinking. And I wish, look, we are playing, we, both of us, I mean, we went to medical school and the first thing they teach us is do no harm. So we are conservative, we belong to the half that will actually do something for people. But most doctors,
Let's do no harm. So let's not. And then by the way, the next day they teach us rightly that there's no always a never in medicine. So what about using a drug that saves a hundred people and kill three? How do you weigh it? Yeah, exactly. I, it's important for us to stay conservative. It's important for us to say we need clinical studies. We need a real development and kind of stick to it, because otherwise, I think the chances of doing harm are really

Dr. Mark Hyman:
Much. And it's so personalized too. I mean, I just remember a story of a young man, I think his name's Fagan Bottom, who basically was a medical student and developed this very rare cancer. I forget the name of it. And there was no treatment for it. You probably know this guy. And he, he's basic, and he was this super fit football player. And then he just became emaciated, went through multiple brands of chemo. They told him he was gone. He was just ready to get his affairs in order. And he decided, well, I'm a medical student, I'm going to start to research this. And he looked at the proteins expressed in his blood and used very basic scientific techniques and found this huge spike in mTOR. And he was like, mTOR is good because it helps you build muscle, but overexpression can cause overgrowth not just a muscle, but of cancer cells and other things. And so he said, well, I'm just going to try rapamycin one of the drugs that actually inhibits mTOR and it completely cured his cancer. And he's amazing, healthy, great guy now. And he continues to take this drug. So it speaks to some of these pathways that are at the root cause of cancer. He's not taking chemo. He wouldn't do radiation. He didn't do surgery, but he used sort of molecular medicine to understand what his particular tumor was doing and what he could do to modify it. So I think we're just incredible

Dr. Nir Barzilai:
Story. It's an incredible story. I forget the name of this guy, but incredible

Dr. Mark Hyman:
Story. I think it's Jason Fabo. He wrote a book. It's great. So I think that's so important. So now I want to sort of shift to talk about your work around metformin because I think it's really interesting. And I think as we talked at the beginning, there is no silver bullet or there's no magic trick here that is going to fix everything. And I think people are always looking for, what's the pill I can take? What's the supplement I can take? What's the peptide I can take? It's going to fix it all, and I don't have to worry about what I'm doing and how I'm living and whether I'm drinking or eating bad or exercising. And that's really not the purpose of this, but you're doing something that's really important, which is you're doing a very rigorous clinical trial on a compound that seems to have some evidence that it may improve many of the biological factors in the hallmarks of aging.
And this called Metformin, which is a drug developed in 1957 to treat diabetes. It's been around for a long time and it's one of the first line therapies for it. And you're doing this not just to study metformin, I think, but you're doing it to actually show that we can treat aging itself. And if this is successful, which I hope it is, I think it will shift the whole field of the NIH and of the focus of longevity research, which is what I hope it does. But I kind of want to just sort of set the stage for a minute and talk about why we think this is so, and I think there was a paper in 2014 with 78,000 diabetics who were studying this group on metformin versus non-diabetic controls. And it seemed that there was about a 15% lower survival time in people who were not taking the metformin. And there were some challenges with that study. There was another study published in 2022 that was another observational study, but completely contradicted that study, which was the Danish registry case control study where the metformin monotherapy group increased mortality, I think by 50 something percent compared

Dr. Nir Barzilai:
To nondiabetic.

Dr. Mark Hyman:
Yeah, compared to non-diabetic. So one study showed that if you were a non-diabetic, your risk of death was greater if you weren't on metformin. And the other study showed the opposite in quite a significant way. So I think that's kind of like it needs to be answered, and this is why you're doing this clinical trial. Well,

Dr. Nir Barzilai:
No, look, I think that was a destruction. I think it was a discussion. But let me say first I want to correct something.

Dr. Mark Hyman:
Oh, please. 20

Dr. Nir Barzilai:
1920s and 1950s. Okay. Metformin is an extract of the French lilac, so it's kind of nutraceutical, but it's not. It's modulated. You need a prescription, actually, you don't need the prescription. You can go in Amazon and get it for a lot of money. Really, it's not a lot of money, but it's 10 times more than it costs. And at that time, why did people use it? Because people noticed that people who takes this French lilac extract, it was treating arthritis, it was preventing fluid. It was even preventing malaria. It had lots of benefits. And at that period, people noticed that people who had diabetes and took this drug, it lowered their glucose. So it was kind of hijacked for diabetes, but actually it had all those other properties that were ignored. Now since it's used for 80 years for diabetes, there are lots of other studies that showed, and by the way, without studies have showed that it prevents mortality in variety of studies. Okay, I'll get to those studies. So in clinical studies, those that you mentioned are not clinical studies, they are association studies.

Dr. Mark Hyman:
Yeah, they're just population studies where they look for correlation, but it doesn't prove cause and effect. And they showed the opposite.

Dr. Nir Barzilai:
So clinical studies, there was the UK PDS, there's lots of evidence that metformin decreased mortality, but even or supporting of that, people on metformin have less. First of all, there's the DP, they had less diabetes. Non-diabetic patients get less diabetes. People with diabetes have less cardiovascular disease, they have less cancer, they have less cognitive decline, they have less Alzheimer and a big effect in clinical studies. So for me, it's not about proving metformin, it's not that at all. The reason I'm doing tame is for the other reason that you said we have to show to the FDA that we target aging, the biology of aging, and we prevent age related diseases.

Dr. Mark Hyman:
Yeah. The study is called tame targeting aging with metformin,

Dr. Nir Barzilai:
With metformin. And really the idea is not to repeat the studies that were done. And by the way, because metformin is FDA approved, so it's safe because there are so many other studies. A lot of doctors are repurposing metformin based on data that they have.

Dr. Mark Hyman:
I allow a lot of people who are taking metformin for longevity. And I

Dr. Nir Barzilai:
Exactly. Metformin is repurposed for PCOS. Metformin is repurposed for pre-diabetes, which all of them are not FDA indication. We repurpose drugs all the time. So the idea is to show the FDA in a clinical studies that a cluster of diseases that include cardiovascular disease, cancer and cognitive will be delayed or prevented in a certain period. It's a hard concept in the sense that we are saying we're targeting aging, so we are agnostic to what disease you're going to get. If your mother was diabetic and you are obese, you're going to get diabetes. But I don't know, we're going to change your aging. And for every disease that you're going to get, you're going to get the point over time, and we're going to show that metformin will delay that based on existing study. So it's all about how we prove to the FDA that aging is that we can prevent

Dr. Mark Hyman:
Treatable. It's treatable,

Dr. Nir Barzilai:
Right? Well, we can prevent diseases. And by the way, they agreed, they don't buy that we can do something with aging. But they said if you have a trial that shows that you can prevent all those old related disease, you should bring it on. And we don't care. We kind of don't care to call it aging a disease now because we know what to do. But this is really the main point. But it has consequences. First of all, this is there were really great team that planned how to do this study, and this is a template for the industry. You don't need many patients If you were developing a diabetic drug, now you needed 12,000 people in a cardiovascular study. Also, to prove safety, we're talking about 3000 people between the age of 65 and 80. Because we're not looking at diabetes. We're looking at every disease basically.
So you're going to get one after 65, you're going to get one no matter what. We need only 3000 people. The second thing is pharmaceuticals are waiting for that in order to jump in and get into buy those biotechs in aging and develop drugs because they need an FDA route, they need a business plan and business plan developed with FDA. And also for us, healthcare providers don't have to approve any drug. That's not FDA approved. Now, it's easy with metformin because it's the cheapest drug in the US formulary, but for industry, no doubt that some of the first drugs that will come will be as expensive as GLP one now, right? As any drug for a few years. But for the public, having metformin is going to be really an advantage immediately.

Dr. Mark Hyman:
Yeah, I mean, I think it's important. I want to talk about the mechanism of action because as we sort of talked about earlier in podcast, about how all the hallmarks are connected and how there's so many redundant pathways and how affecting one of these pathways can affect other pathways. So from my understanding, the main action that we understand of metformin is to activate one of these, I call 'em longevity switches, the deregulated NU and sensing pathways. And one of them is A MPK, which detects low nutrient energy levels in the body. And when you activate that, it creates a cascade that inhibits inflammation, that activates sirtuins, which improve DNA repair and improve mitochondrial function and inhibits mTOR and maybe has other mechanisms of action in the microbiome, which may be interesting to me. I know how that exactly connects into all this. Maybe the mechanism is that it optimizes your microbiome.
So I'd love you to talk about some of these. And I also want to dive into one of the, what I think are potentially a risky aspect of metformin. The things I just mentioned are all positive that all beneficially impact the hallmarks of aging, but it's the inhibition of something called mitochondrial complex one. And this is one of the most important steps in producing energy in your cells and to build muscle. In some of the studies I've seen you actually giving metformin will limit or prevent any increase in muscle mass and muscle density gain when you take metformin and you exercise. So if you do weight training, it kind of blunts the effect of weight training, which kind of is worrisome to me as I think about frailty and aging and building and keeping muscle and preventing sarcopenia. So maybe you could talk about some of these mechanisms, how they all interconnect, how you think they influence all these phenomena of aging. And then maybe chat a little bit about this concern that I have and whether I'm right or wrong.

Dr. Nir Barzilai:
So I think it's best maybe that I'll give an example and follow it because I got involved in that at a certain time. So when you take a group of 75 years old, and this is a study by Charlotte Peterson in Kentucky, and she had the grant because she said if I exercise and give metformin, I'm going to get even better response. And so she took those 75 years old, half of them exercised, the other half also exercised, but they were also on metformin. And by the way, when they exercise, whether you're on metformin or not, you build up more muscle, but you build significantly less muscle when you're on metformin.

Dr. Mark Hyman:
This is the master's trial you're talking about?

Dr. Nir Barzilai:
Yes, the master's trial. So basically the paper was like metformin inhibits muscle size. So that's where scientists have to come in because I'm reading the paper with interest, including all the supplements and supplement two shows that they also did an assessment of muscle function for different things. And those four different things were not different between the people on metformin and without metformin. So if the people with metformin had bigger muscle, what does it mean? Does it mean that really for every gram of muscle, metformin is actually doing better? If we think in the Einstein way, that's really what it means.

Dr. Mark Hyman:
Wait, I lost you there. Can you kind of explain that again? I didn't make the connection.

Dr. Nir Barzilai:
If you and metformin have smaller muscle but you have the same power, then every gram of muscle is better.

Dr. Mark Hyman:
I see what you're saying. So you don't lose muscle function, but you lose muscle

Dr. Nir Barzilai:
Mass. Okay, so then I said to Charlotte, can I look at the muscle? And I did several things with the muscle, including the transcripts and the transcript shows. I think what we kind of knew

Dr. Mark Hyman:
The transcript is basically all the things that are transcribed in the proteins, right?

Dr. Nir Barzilai:
I'm sorry, I shouldn't assume, but

Dr. Mark Hyman:
I'm a doctor. I get it, but I don't think anybody was on transcript.

Dr. Nir Barzilai:
No, I know

Dr. Mark Hyman:
It's a written transcript of a paper. No, it actually has to do with the DNA replication and transcription of proteins. Yeah. So

Dr. Nir Barzilai:
This is where the paradox is in order to build muscle, you need mTOR. Okay? So if you need mTOR, you already know that if you use rapamycin, which is a strong mTOR inhibitor or metformin, which is also a major inhibitor, which is really important for the aging of maybe the rest of your body, you're going to pay with a muscle. So we showed on one hand that the transcript of mTOR related genes are really decrease. On the other hand, we found that other genes that are important for aging, such as for autophagy and for inflammation of the others are getting better. So basically you have a muscle that is smaller but is better in quality when you're

Dr. Mark Hyman:
Interesting.

Dr. Nir Barzilai:
Look, I think the reason that's a controversy, and so by the way,

Dr. Mark Hyman:
Well just mitochondrial health is such an important feature of healthy aging. It's one of the biomarkers mention of aging look

Dr. Nir Barzilai:
Targeting. So metformin does what you kind of described, let's call it the metabolic, the MP kindness pathway. By the way, metformin works also when in animals they don't have a MP kindness. Okay? It's kind interesting, weird. And metformin also ends when you don't have mitochondria in a row zero cell. So it's really much more complex because it's doing some things. But what happens on the mitochondria, yes, you increase the transport of electrons and by that you also decrease oxidative stress. And in this pathway you also decrease inflammation and other parts. So actually it's important, but it's also important for another reason because if you look at VO two max, which is a really good tool to assess your health, if you have mitochondria,

Dr. Mark Hyman:
Lemme just stop there. I want to tell people what that is. That VO two max is basically a measure of your fitness and the higher it is, the longer you live. And it's really basically a measure of the function of your mitochondria and how quickly they can consume oxygen, how much energy they can burn in a minute. So Lance Armstrong has a very high VO two max, whereas a diabetic might have a very low one. And it's really a reflection of your mitochondrial health and your fitness and it's directly tracked longevity.

Dr. Nir Barzilai:
And this marker for metformin is not good because you have to understand, we're not acting, we're not on a VO two max in our life. It's like you come from metabolism. Remember we used to talk about insulin sensitivity and insulin responsiveness. Insulin responsiveness was take the insulin level to thousand microns per ml not relevant to our life and see how much glucose you can actually push them to the muscle, which is not as relevant as let's get your insulin level to a hundred microns, which is like after meal and see what's your sensitivity in. And you can have the increased response. I think the same thing people are not thinking about, but VO two max, I think metformin is doing lots of things. It doesn't prevent you to exercise. If you want to check if your VO two max, I think you're not going to be at VO two max if you have a good metformin, but I don't think this is really a measurement of health when you are in this drug, just like as you are not going not to take rapamycin ever because they inhibit muscle.
I think the more important point here is that when you are young, when you are old, those things help repair rapamycin and metformin, they touch a lot of the hallmarks. They have repair when you're young, they're going to lower your IGF one, they're going to lower your testosterone in several instances, all those things that we don't or your exercise capacity or your ability to do pushups and weight. So I think it's very different how we think of those drug when it comes to old body and to young body. And yes, they're tradeoffs. There'll be tradeoffs.

Dr. Mark Hyman:
I've heard of some people saying, I'm not taking metformin on the days I do my string training. Does that make sense?

Dr. Nir Barzilai:
I know. Or the same hour or hours. Look, this is my spiel. The major side effect of metformin is that you might leave longer

Dr. Mark Hyman:
And

Dr. Nir Barzilai:
You might not be able to afford it or something. But those drugs have good because yeah, if you are a sport medicine, if you're Peter Atia, then all you care is the muscle. But metformin just like exercise. Exercise is not about the muscle. Exercise, improve cognitive function and immune function and other things. So yeah, I'm not sure Metformin is good for bodybuilders, but it's also good for other things outside of the muscle.

Dr. Mark Hyman:
Yeah. Yeah. That's fascinating. That's fascinating. So it's such a nuanced story and you are right. There are so many benefits of metformin that are, we call pleotropic when a drug typically in medicine we think of a single drug with a single target. And anything we don't like is called the side effect. It's not really a side effect. They're just effects of the drugs. We may not or that we may, in this case, when metformin has all these side effects that are beyond lowering blood sugar that actually may extend our life, which is so exciting. So I'm very, very excited for the TAME trial, I think.

Dr. Nir Barzilai:
Sorry, I just wanted to, before you move from foreman.

Dr. Mark Hyman:
No, I'm going to keep going. I have more to say about it. But you go ahead.

Dr. Nir Barzilai:
I just want to go back to, you started by those two studies. There were not good studies. And I have to say I populated the first one I populated because it was cool. I knew that it's not a good study, but I thought it's kind of study that you show that people with diabetes on metformin might live even longer than people who don't have diabetes. The dentist study was a different study, a

Dr. Mark Hyman:
Twin study. Yeah.

Dr. Nir Barzilai:
But one of the, okay, there are few problems that we should know. First of all, the study didn't show the mortality of people on metformin, diabetic people on metformin versus not on metformin, which is for me, because yes, when you're diabetic, you're running into more problems. So just show first you have the data, you have the registry. And I know that they showed that there is less mortality that they just didn't want to put it in this study. But the reason there's difference in my mind, and by the way, the twins, the problem with twins, the twins a lot of time are born low for gestational age. In fact, one twin might be born is usually born smaller than the other twin. And this is kind of the barker hypothesis. Those twins, those small for gestational age can run into aging rather quickly. They get diabetes, they get hypertension before others.
So the twin study, if you don't adjust for birth weight, I'm very skeptical, is skeptical about it. But I think the major reason for the difference, I mean there are so many differences, but I think the one that explains a lot, one is in the UK where at that time obesity was 20% in the population, of course all the diabetic were obese, but also 20% of the other population were obese. When in Denmark, the rate of obesity was 10%. So basically it means that the Danish diabetics are obese when the rest of the population is not obese. So you took one of the risk factor that would adjust through insulin resistance and other right

Dr. Mark Hyman:
To those. So it's the devil's in the details. And the problem is most people just get the headlines in the newspaper and often the headlines get it wrong. And I read one study in actually the New England Journal, but abstracts don't represent what's in the body of the paper over half the time anyway. So it's like it's hard for the average person to make sense of it all. Well,

Dr. Nir Barzilai:
An example that's relevant to metformin, and actually it's a very important example. Look, there are nine studies in the Covid times around the world that people on metformin in half hospitalization and after deaths, and then there's a New England Journal clinical study where they gave metformin to people within three days of getting covid. And it prevented 40% hospitalization, 40% death. And then there's a follow-up study in the Lancet that it prevent long covid by 50% of. Well,

Dr. Mark Hyman:
It is interesting mechanistically because one of the drivers of that is uncontrolled inflammation. And one of the mechanisms of action is it inhibits this transcription factor, this thing that causes your genes to be expressed called NF kappa B, that influences cytokine production, which is a cytokine storm inflammatory signaling molecule. So basically if you take metformin, you're inhibiting the driver that causes your genes to produce all these cytokines. So maybe that's the mechanism, I don't know

Dr. Nir Barzilai:
Way more than that because it has effects on the immune cells on inflammation, but on the immune cells. But it also affects the whole body to sustain a terrible heart disease. When you're old, you need a body for that. But I think it makes the point that we talked about metformin and muscle and stuff like that, but look at metformin and covid. If you take it within the first three days, you can do much better.

Dr. Mark Hyman:
Interesting. Yeah. Okay. Well, I want to talk about a few more things about Formin. I'm not done yet. Okay. And you're the guy. So while I got you, I'm going to ask us about the microbiome effects because I've talked to some folks about this and I think there's some research in Israel around this and how maybe the impact on our gut and our gut microbiome may be playing a big role in some of these benefits. Can you share what we know about that and what it does to our microbiome?

Dr. Nir Barzilai:
Yeah, I totally agree. I think it's a potential important link, but by the way, I'm kind of the fence with microbiome and the aging aspects.

Dr. Mark Hyman:
It's one of the hallmarks of aging now, right

Dr. Nir Barzilai:
Now, changes in the microbiome. It just made it to a hallmark of aging. And I think it's maybe not strictly, it's not strictly my definition, but certainly I don't think there's enough models that show that you can increase survival with any manipulation of that. But there's certainly a study that showed that people on metformin had a change in their microbiome that had a benefit effect. There's more to the study than that. It's very compelling. It's not only metformin, which is another drug that in human prevents mortality, not related to diabetes, also has effect on the microbiome. So I'm pretty sure that microbiome are important, but that's kind of the thing we are saying. Is the microbiome changed by metformin in the gut or is it changed by metformin in the body? Because metformin changes all the hallmarks of aging, so it changes microbiome. So is microbiome a bystander? Is it important? It's kind of hard in this way to depict, but I want to say that there are drugs that change the microbiome, and I'm convinced that microbiome has a role. I don't totally get it, but it has a

Dr. Mark Hyman:
Role. Have they mapped out the particular bacteria bugs that actually are increased or improved? Akkermansia, for example, is

Dr. Nir Barzilai:
Metabolic. They had the whole genome. It's an old paper already, and there's more sophistication and maybe more studies of the, it's really not about the type of bacteria, but their metabolic profile. What's the metabolite that are actually absorbed into the gut? Things like that. So I think there's more sophistication, but I would take it as a fact that metformin changes microbiome.

Dr. Mark Hyman:
Okay. Now I want to play devil's advocate for a minute here and challenge a little bit the theory of metformin. Because there was a study that was done, very famous study called the Diabetes Prevention Trial, and it was decades ago, but it showed the impact of lifestyle compared to metformin compared to nothing for preventing the progression from pre-diabetes to type two diabetes. It was about a thousand pre-diabetics. And they found that if you took Metformin, it reduced the progression to diabetes by about 31%. If you did a lifestyle intervention, which by the way, at the time, and I knew people were in the trial, was a low fat intervention, which is not the diet you want to put a diabetic on, but they had other things like exercise and social support and so forth. They reduced the progression by 58%. So in this case, I'm wondering, is it possible to achieve all the benefits that we get from Metformin and even more benefits with more aggressive lifestyle intervention? And do we actually need metformin? You're

Dr. Nir Barzilai:
Assuming that they're doing the same benefits and not different benefits. But look, first of all,

Dr. Mark Hyman:
And I understand there's all these other kinds of influences, Metformin, besides blood sugar and diabetes,

Dr. Nir Barzilai:
And let's agree that exercise, all the lifestyle, exercise, diet and stuff have a major impact and could be maximized at every time. Okay, let's agree on that. This is my question. Look, I'm a diabetologist. I'm actually on Thursdays. If I'm in town, I'm seeing patients, okay? I'm not a geriatrician, I'm a ologist. And so psychologist 30 years in my clinic, and it's a fellow clinic. So I see quite a lot of patients. So first we tell them, okay, diet and exercise, we send them to diet stuff and we tell them how to exercise. How many people are doing that? 3% in the Bronx. Okay. I'm sure you have more success. Well, sure.

Dr. Mark Hyman:
I mean, it's not whether it works or not, whether you do it or not. Well, you have to take metformin in order for it to work. If you don't take it, it's not going to work. Right?

Dr. Nir Barzilai:
Right. Exactly. Diet. And I'm thinking, who needs metformin? Who needs metformin urgently? It's not us. Okay? Because we know how to deal with our health. It's poor people. Poor people are obese. Poor people don't have access to exercise. You don't give them money to buy trade off or to get into gym because they don't have gyms for nutrition. You want them to have more vegetables. Well get them more vegetables. You want 'em to have more fish. They don't like fish. So actually with Scott, with Andrew Scott, we did kind of this how many dollars metformin versus what you need to do to change lifestyle for a population. It's one, 200,000.

Dr. Mark Hyman:
Maybe I have a different theory, but Yeah, I hear you. I hear you. I hear you.

Dr. Nir Barzilai:
Yeah. So I think we need Jira protectors and Jira protectors will get better and they'll get in combination and they will enable us to go beyond the lifestyle. I have no doubt about that. And it's a consideration, but I wouldn't look. DPP was here in this area too, and I'm more used to show that, if you should say, does Metformin work on non-diabetic? Well, the DPP was non-diabetic. They were at increased risk, but they were non-diabetic. And it's a 30% effect and a 30% effect of every drug is pretty incredible. And the lifestyle intervention of the DPP was amazingly, it was very, very expensive. They did have to go to the gym to train them, to give them food, things like that.

Dr. Mark Hyman:
We actually actually created a program. I did a program with a Cleveland clinic at our center, which is a lifestyle change program. And we actually measured the cost of the program compared to conventional care, the outcome improvements. And we basically saw it was three times as effective and more cost effective by doing shared medical appointments essentially. So there's ways of delivering care and doing things that I think are not what we normally do that actually work. So it's not that we just haven't figured out how to get people to do their thing, but that's a whole nother conversation. The other thing I wanted to talk about is for someone like me or asking for a friend, my insulin levels too. My lipids are perfect. My body fat's 10%. I exercise all the time. I eat perfect, have a low glycemic diet. Am I going to get added benefit from taking metformin or have I already kind of tuned things up? Is there something that I should be thinking about? I want to live for a long time, and I'm sort of on the fence about it, and you don't have to answer, but I'm just like someone like

Dr. Nir Barzilai:
Asking

Dr. Mark Hyman:
For a friend.

Dr. Nir Barzilai:
I'm making point that I'm a data person. No, I don't have a data. And I wouldn't really recommend you unless you get into some trouble. If you tell me I'm worried about my cognitive function in spite of everything, I would say, maybe you should consider rapamycin metformin or something else that's coming. But no, I wouldn't look, it goes back. Your biological age might be less than 50, right? It's

Dr. Mark Hyman:
43. Yeah, so

Dr. Nir Barzilai:
So why would you take metformin? That's my point.

Dr. Mark Hyman:
And

Dr. Nir Barzilai:
It's not age. It's the biological

Dr. Mark Hyman:
Thing. Right? Interesting. Yeah. So I think it's interesting. I think we're clear. Someone has metabolic health issues. It's not a bad thing to do, and I prescribe it for those who need it. I think I'm not yet ready to prescribe it widely for healthy people who are looking for a longevity benefit. I want to see what the tame trial shows. So I'm holding out, so hurry up on that. The other thing I wanted to just bring up is other ways that we can have similar effects. And maybe I'm out of school here, but you mentioned that Metformin was from this French lilac, and we know there's a lot of things that actually also influenced the same pathway, A MPK, which has all these downstream benefits. We talked about obviously exercise, saunas, various phytochemicals, and there are a lot of things that have been found to have similar benefits to metformin like saffron, berberine, resveratrol, ginseng, resi, mushrooms, artemesia, black human seed, bitter melon, which is like a Chinese food tangerines, chlorogenic acid from coffee, capsaicin from peppers. So I mean, if we start to include all these phytochemicals as a way of regulating A MPK, you think that might have similar benefit? Can we start to look at those things?

Dr. Nir Barzilai:
Okay, so I'll tell you my worry, and I'll give an example. If let's say you take metformin and rapamycin and you increase the dose and you stop mTOR.
So for example, your plasma cells are totally mTOR dependent. Okay? So what I'm saying, if you add, we are assuming that if you have those longevity nutraceutical or drugs and you'll add them to each other, they'll be additive or synergistic. And in fact, I'm afraid that a lot of them will be antagonistic. Interesting. Or you'll get, and my worry is more our friend Brian Johnson, who takes 115 supplements, and we measured our green age together. And I'm three years younger than my age. He's four years younger than my age, but I'm not doing 115 supplements. So I think he's paying off. I think the supplements are problem. I always say they're great for the economy, okay? They're great for the economy. They drive a lot of business. But I would say that we don't know enough, not about the supplements, but how you add them together. And at what point, I said before, every drug, if you take a lot of it can be of a problem and can be a problem with a specific person. So I would just say, yes, we need clinical studies, we need more clinical studies even in animals to show whether it's additive or antagonistic exercise and metformin are antagonistic on the muscle, right?

Dr. Mark Hyman:
Right.

Dr. Nir Barzilai:
We have those examples. So I think it's a good question. There are all those things, and my worry is that people just wrote down the list and they're buying everything.

Dr. Mark Hyman:
No, don't do that. Don't do that. Don't do that. No. The point is that there's so many natural compounds in our food, and I think you can't get into trouble if you eat all these things. If you have bitter melon in your diet and you have saffron in your food and you have coffee in the morning, these are not going to be problematic. It's when you're taking pharmaceutical doses of these things that you're going to get in trouble. I also just want to, God, I'm going to want to talk to you forever. I know we have to end soon, but what are the top jar protective molecules and drugs that are under research Now, I think you've obviously focusing metformin, but there's NAD, there's rapamycin. What's your take on what are the most promising things out there?

Dr. Nir Barzilai:
So we published, and now I'm submitting another update paper. We did a paper on repurposing FDA approved drug that showed to increase longevity in mammalians, not in nematodes

Dr. Mark Hyman:
On worms, humans, power mammals, right?

Dr. Nir Barzilai:
We have a scale of 12, six belongs to the RO science, hallmarks of aging lifestyle and health span of animals, and six are human. And the four drugs that are, and this will surprise you. Metformin comes only second. Okay? The first drug is SGLT two inhibitors. SGLT two inhibitors is a fascinating story, but in short, it's developed to diabetes. Basically you peers your sugar, and that's why your sugar will be okay, but for some reason, people notice with whether you're diabetic and then non-diabetic, when you take it, you get less kidney disease, less heart disease, and decrease overall mortality. Checks out everything. You give it to animals, they live longer. Okay? So GLT two inhibitors actually, and I'm kind of considering maybe to switch from metformin to that for a while and see what happens. I think this is, and by the way, I'm taking it, I was pre-diabetic and I really benefited from it. But because you are not taking, I didn't want to say, just wanted. And the second is metformin. The third is etidronate or bi phosphonates. Bi phosphonates is a guy. Another example is we don't know where

Dr. Mark Hyman:
Osteo osteoporosis drugs.

Dr. Nir Barzilai:
Osteoporosis drugs. I heard about it the first time because it was a paper. Women in ICU on Biphosphonate, they don't die. And then they started to test animal. They started to test in human studies and in control studies. And there's decreased mortality for people on biphosphates, which we don't understand the mechanism yet

Dr. Mark Hyman:
There a lot. And it's not just because they don't break their hip and die from that, no, it

Dr. Nir Barzilai:
Could be action, but the bone has your bone marrow, there's immune cells. There's a lot of stuff that happens. And the third that we got is the ozempic, the GLP one inhibitor. Remember when I went into aging, the only model that we had was caloric restriction. We took animals, grew brothers, half of them ate whatever they want. The other were calorically restricted. They lived 40% longer and much healthier like our centenarians. So GLP one is a calor medic, and I would say that obesity drives aging, okay? Obesity drives aging. So to use GLP one, and people are using it creatively. If you're obese, they'll give you GLP one for a while and then put you metformin to keep on the way, things like that. But those are the four drugs that should be considered for repurposing in that order. Now based on evidence.

Dr. Mark Hyman:
So the first one is metformin, or what was the first one?

Dr. Nir Barzilai:
SGLT two inhibitors,

Dr. Mark Hyman:
But then the ozempic,

Dr. Nir Barzilai:
The second is metformin, the osteoporosis drugs, and then the ozempic.

Dr. Mark Hyman:
Okay, got it. But the thing about ozempic, I remember this study where is it the weight loss or is it the ozempic? Right? There was a study where they looked at gastric bypass in diabetics, and they essentially divided them into two groups where one group got the gastric bypass and the other group got the diet that the gastric bypass patients would have to eat after they had the gastric bypass. They both had the same benefit, exactly the same weight loss, exactly the same benefits on metabolic health. So is it the surgery or is it the diet? Is it the or is it the weight it loss. And I think that's important to think about. So just to close, I would love to hear what you're most excited about that's coming up in this field. And then two, what your personal regimen is for staying healthy and living a long time, given everything.

Dr. Nir Barzilai:
Okay. So let me tell you, I'm also the scientific director of the American Federation for Aging Research, and I drove three big projects. One is the tame, so we talked about it, okay? This is under the umbrella of the American Federation for Aging Research. The second initiative, we kind of talked about it, but it's the Super ages initiative. So I have 750 centenarians. Tom Pearls have thousand centenarians. It's not enough to do validation and to do discovery. So we're driving to recruit 10,000 centenarians and one of their offspring and somebody who's married to the offspring, triple things because we have to adjust for the diversity of the population.
So this is a main thing, and it's important because if you guys, anybody knows of a centenarian, you go to the far web and there's the super initiative, or you just put super initiative. We are sending the to spit, the DNA, that's all. It's a genetic study for now, but it's a community. The far community is not the sick people. It's the people who live longer and healthier. So this is a very exciting project. And the third project, it's called fast. It's about biomarkers, right? And biomarkers is a hot, hot new topic because we have what we call an omic way to look at them. We don't measure one biomarker at a time. We're measuring thousands or maybe hundred thousands at a time. And we have a project.

Dr. Mark Hyman:
You mean DA methylation or you're talking about something else?

Dr. Nir Barzilai:
No, everything. Proteomic, metabolomic, methylation, everything. And what are strategies to go to studies that already were completed in the four examples that I gave you? SGLT two, Metformin, GLP one, and get samples of the first year of the study before and after, and do all those omics and discover, first of all, what are the biomarkers for aging, different ages, what are the biomarkers of aging? Second, what changed specifically after treatment? Some of it will be specific for the drug itself, but then we'll have all studies and we'll ask what commonly changes with aging? Because it's not only, we're pretty good at telling you your biological age, but that's not important enough. We want, if you come to mark to treatment, we want to show that those biomarkers change if they don't change, and methylation don't change within a year, or if ever or not, all of them change. So we want to have biomarkers that you will use, and maybe in two months you would see where the trend is. And for longevity, biotech association not to spend money on phase three trial and fail, but get the signals like we get from cholesterol or hemoglobin A one.

Dr. Mark Hyman:
So what you're talking about are these sort of intermediate things that are easier to measure than whether you get a heart attack, a stroke, or cancer or diabetes or dementia or death. But that actually correlate with these things. And that you're talking about a kind of network of biomarkers that not just one that we're going to be using that reflect a larger pattern of dysfunction or function in the body.

Dr. Nir Barzilai:
So we are going to look to use hundred thousand, but we hope that maybe 10 are depicting everything okay. Or a hundred, I mean, it'll be eventually some are going to be enough. We don't want everybody to spend a thousand dollars per test, per patient to figure out what is not going to be necessary, but we hope to do reduction. That is significant.

Dr. Mark Hyman:
That would be amazing. It's sort of like the Immunos project from David Furman where he looked all the cytokines and he found four that were most highly predictive. And if you just measure those four, how close are we to that? How close are we to having a true biological age set of biomarkers that we can replicate and use with our patients?

Dr. Nir Barzilai:
I have an answer in May.

Dr. Mark Hyman:
Yeah,

Dr. Nir Barzilai:
As long as you don't ask me the year

Dr. Mark Hyman:
By

Dr. Nir Barzilai:
May.

Dr. Mark Hyman:
Okay. May. May, 2050. Okay. No, no.

Dr. Nir Barzilai:
There's a huge progress in the field. There's a huge progress in the field. But with the progress comes also problems. Okay? Becomes problems, comes noise. It's people who are, there are three different kind of people involved. The biologists, the doctors, and the computational people who talks different languages. We have committees that are dealing with that. It's not as fast. I call this initiative fast. It's not as fast as I was hoping

Dr. Mark Hyman:
It should be. Like the Manhattan Project for it is so important. I think it's so important. Well, this is amazing. Okay, well, let's follow all that. We're going to track all that, and we're going to put in the show notes, all of your papers, all the things we've talked about so people can follow up on it. But I want to know, what's your longevity protocol for you, NIR? What do you do to keep yourself healthy and everything you know about longevity, aging? We want to know what's your protocol?

Dr. Nir Barzilai:
So let's start with the obvious. I exercise every day, by the way, which is almost 365 days a year. I missed this week. I was on a plane, I usually don't miss, but exercise now, what? Exercise very briefly, I Peloton is my to go to, but I'm doing other things too. But twice a week I have a trainer that mostly works on my muscle and flexibility, and I think he's getting me. I'm always trying to maximize it and getting to a better place. But this is the regime. As far as eating, it's mainly intermittent fasting. Okay? I had dinner last night at seven 30. It's already one 30 here, so I'm 17, 18 hours. And unless I see the podcast and I talked lots of nonsense. I think I'm fine.

Dr. Mark Hyman:
You were good. You were good.

Dr. Nir Barzilai:
And that has improved my health tremendously, by the way, including my exercise capacity in a mysterious way. And by the way, again, this is not for everyone. It's better for men than women for some reasons, at least for weight loss. But some people are saying, I cannot do it. I get hypoglycemia. They don't. But anyhow, it's not for everyone. But it's

Dr. Mark Hyman:
Really great. If you're a pre-diabetic and your grandfather was diabetic, your metabolically probably do better with it. That's what

Dr. Nir Barzilai:
I got. Yeah, exactly. Right.

Dr. Mark Hyman:
And what do you eat when you're eating? What do you eat when you're eating though? You can't just have McDonald's and cola, right?

Dr. Nir Barzilai:
I'm, when I'm eating, look, it's all more aspirational, but I'm trying to cut on carbohydrates. I'm trying to eat more fish than beef. I'm kind of successful. It's very different than 10 years ago, let's say olive oil. But really, I think the intermittent fasting already cuts lots of the stuff that I shouldn't eat. And I'm not hungry in return. It's not that I eat more because of that. I don't believe that. And my weight has been good. The third thing is sleep. And so dark room for eight hours. I don't sleep for eight hours, but I try. It's actually by my Fitbit. It's interesting. Every week I sleep exactly six hours and 40 minutes on average. And social connectivity, that is important. It's not my problem. I've never met a stranger in my life, so I have this deficiency. But yeah, those are the things. Now, on top of that, so let me say that I take metformin. Everybody knows that they take metformin, but I do other things and the way I do other things, I have a longevity doctor, and I come with a longevity doctor, and I say, are

Dr. Mark Hyman:
Cheating on me?

Dr. Nir Barzilai:
What should I try? By the way, I'm on the council of the Healthy Longevity Medicine Society. Are you aware of this

Dr. Mark Hyman:
Society? No.

Dr. Nir Barzilai:
Okay, I'd love to connect you there. For sure. We need you because look, this is going to be right. I mean, we are going to be the medicine of the future. We're going to improve your health and not get the disease. It's going to be, medical schools will be taught differently. Totally. Yeah. So we need your input there. I'll contact you about
Later. But so the longevity, I sit with the longevity doctor. He says, why don't you try X? And I said, okay, if I try X, what should I test now and after? What will be the decision to go on? And so I tried. I'm not going to tell you what, but I tried other things. Some had effects, some had no effects. But I thought that I want to try just in order to, it's not an n plus one for anyone, but for me to understand what it is, what it means, what is measurable and things like that. And I get some information about that. Because of that, I don't care to share Metformin. I can share, because we have studies. This what I'm doing, I cannot share, but I am trying to

Dr. Mark Hyman:
Different supplements or different things You try.

Dr. Nir Barzilai:
Yeah.

Dr. Mark Hyman:
Yeah. Okay. Well, we'll stay tuned for when the data comes in. I mean, this has just been such a great conversation. I could talk to you for hours. I think everybody's learned a lot, and I think if people want to learn more, they can read your book age later, healthspan Lifespan and the New Signs of Longevity, they can follow you at Nearby Lie MD on social media. It's not hard to find them online. Just Google 'em and we'll put all the links in the show notes. But thank you for your work. Thank you for being so tireless and helping us figure out a way to actually understand aging and do something about it. We all want to

Dr. Nir Barzilai:
Live. Thank you. We're soldiers in the same war, and you'll win.

Dr. Mark Hyman:
We'll win. I love that.

Dr. Nir Barzilai:
We can also do another podcast between now and a hundred. Okay.

Dr. Mark Hyman:
Okay, great. Okay. Down, down. Well, after the Tame trial's done, which is what, another four or five years, right? Yeah. We'll come back. Well maybe sooner. We'll see what's up. But anyways, it's great to have you, and you have a fabulous, thank you very

Dr. Nir Barzilai:
Much. It was a pleasure for me to talk with you too. Thanks for the tough questions.

Dr. Mark Hyman:
Thanks for listening today. If you love this podcast, please share it with your friends and family. Leave a comment on your own best practices on how you upgrade your health, and subscribe wherever you get your podcasts and me on all social media channels at Dr. Mark Hyman. And we'll see you next time on The Doctor's Pharmacy. This podcast is separate from my clinical practice at the Ultra Wellness Center, my work at Cleveland Clinic and Function Health, where I'm the Chief Medical Officer. This podcast represents my opinions and my guest opinions. Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only. It's not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you're looking for helping your journey, seek out a qualified medical practitioner. Now, if you're looking for a functional medicine practitioner, you can visit ifm.org and search their find a practitioner database. It's important that you have someone in your corner who is trained, who's a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health.