Nir:     So first of all flattery will get you nowhere. I’m still happy to-to talk with you. And I think you’ll be forever in many minds be this pioneer who called us — who called the field geroscience and-and made us really geroscientists. Which has n — lots of advantages. One of them is that we have to distinct ourself from antiaging. [laughs]

Gordon: Mm-hmm.

Nir:     And that’s a good — and that’s a good way to-to do it. So thank you for your contribution and your leadership and your thoughtfulness.

Gordon: So Nir, When we first met, we were reviewing grants together and I was stunned at how detail oriented you were and analytical as you dissected these grant applications. But obviously you’re also a big thinker, big picture person. So I guess my first question is the big picture question. What do you think the major challenges are in the field right now?

  Nir: For me, there are three challenges. One is, how can we delay our aging now? I call it the Dorian Gray effect. Dorian Gray stopped aging when he looked — when he looked at himself in the mirror, he knew that he’s aging. And by the way, that’s what happened to me in Zoom time. Okay.

            I’m looking at myself. And I’m saying, okay. I’m aging in Zoom. But I’m actually much younger. Okay. But how to do it? That’s one challenge. The second challenge is what we call the wolverine or-or maybe the fountain of youth.

   Take an old person. And put him in a pool. And he goes up young. And I want to tell you this is the biggest challenge we have although, clearly, in animals, we can take old animals and make them healthier. Even if we don’t extend their life by much, we can make them [health ] — but I think the biggest promise — and I think what will happen — it’s only 50 years a-away.

   But what will happen is that maybe we start doing something when we’re in the — when you’re 20 or wh-when you’re 30. And you’ll come once a month, so one a year. And we’ll have this treatment that will  rejuvenate, you know, your systems. And you will age maybe but age much, much, slower. And I think, in each level of those, we have a story and we have promise, okay?  One of the things that excites me most from this perspective, not from the science perspec — because always science excites me more. [laughs] But from this perspective is the promise of the  TAME study that will be launched soon I hope, it’s been delayed but the funding is — looks like it’s there,

            But the TAME study is going to demonstrate that we can do kind of a Dorian Gray. We can maybe delay aging and, therefore, delay age-related diseases, a cluster of them, significantly. But the major reason I’m doing that is to get an FDA indication that would allow aging to be a preventable situation.

Gordon: I-I definitely want to talk a lot about the TAME study and in-in-in some detail. 

Nir:     Yeah.  I want to say, for the other two one of those,  wolverine/fountain of youth seems to be —  we can do good things  at least proven in animals for senescent cells. Okay? I think removing cells is of benefit. And there are lots of studies now – I don’t think we know that it works in human. But I’ll be surprised if it stopped working in human.

Gordon: Yes.

Nir:     It’s a question of how to do it.

Gordon: Yes.

Nir:     And, of course, the third thing is something that we are thinking as a moonshot. But those moonshots, unlike sending somebody to the moon,  I think have a different time scale to them. And this idea of taking Yamamoto factors or something and rejuvenating and erasing the epigenome and maybe doing some other things to — secure the healthy work of the cells and organs and body is something that it can — everything can go in parallel.

Gordon: Yeah. Super exciting. And, the — I share your excitement about the field right now and all these possibilities. But I want to go back actually. I just want to know how you became a scientist.  maybe you could talk about the schoolboy Nir Barzilai and when you started to think about science and medicine.

 Nir:     Yeah. You know, it was weird for me because, when I was 13, I walked with my grandfather every Saturday. We had this walk. And he would tell me what he did when he was young which was quite incredible.

Gordon: Mm-hmm.

Nir:     But I’m looking at a 68-year-old man who by the way, he died when he was 68 — uh, who was fat and slow and bald and not energetic. And-and I-I know that most of us do not think that we are going to look like our grandparents.

Gordon: Mm-hmm.

Nir:     They think that the grandparents got you know, who knows where they’re from? We have no idea. But that’s not us. And for me, it’s something that I couldn’t leave, not only that. I was in Israel then. I went to the army. I became a medic. I wanted to be in the medical profession. I went to a really great, uh, medical school. My mentors were Nobel Prize laureates. I went to the best,internship and resident. But —

Gordon: Mm-hmm.

Nir:     — all the time, it was kind of interesting. Everybody was let’s see the cholesterol level. Let’s see the blood pressure. And I’m looking. And I’m saying, just a minute. There is something you can get right now that has nothing to do with these measurements. You can see it: who’s old and who’s young. You know that it’s the old that are getting  problems. So why are they old?

Gordon: Yeah.

Nir:     And do they have to be old? And 

Gordon: So you really came into medicine because of this observation about aging?

Nir:     I came to medicine because I wanted to be a doctor because my —

Gordon: Yeah.

Nir:     — father and grandfather were a doctor. But  the thing of aging was the most curious thing for me. So I thought that endocrinology maybe can explain a lot of aging. Maybe if you just replace all those hormones, you’ll be young again. And so my formal training was in endocrinology and metabolism.                                                                        

Gordon: Let’s go into your science now. you’re very well known for your incredible, productivity around exceptional longevity and this-this very rare group of humans that seem to be doing something right that maybe the rest of us are not doing. But  genetics is at the heart of your studies. And I want to start by asking, this is my profound ignorance, Nir. But it you know, we read recently that-that, from a Calico study, that the variation in human lifespan, you know, short-lived, long-lived, the variation in human lifespan — only like seven percent of that variation is accounted for by genetics. First of all, do you believe that? And then, secondly, I want to connect that to your — to your work on exceptional longevity. And is there a contrast between those two things?

Nir:     Yeah.  Yeah. Exactly. Exactly. So look,  I think the efforts mainly of demographers to kind of figure out how much is genetic and how much environment is a little bit funny even in their minds because, in their minds, okay, 80 percent goes to this side of the room and 20 percent to this side of the room when we know that it’s the interaction between the environment and genetics are important.

Gordon: Mm-hmm.

Nir:     Let me say it in a different way. Let’s say 7 percent is genetic. If we find what are those 7 percent, couldn’t we design a drug that will protect us against the other percentage

Gordon: Mm-hmm. Yeah.

Nir:     The second thing is some-some of those studies — I’ll give two examples. Some of those studies looked at the correlation between lifespan of parents and their kids. Okay.

Gordon: Yeah.

Nir:     So my grandfather I mentioned, he died from a heart attack at the age of 68.

Gordon: Mm-hmm.

Nir:     My father also got a heart attack at the age 68. And he got a stent and triple-bypass. And he died at 84. So —

Gordon: Hmm. Yeah.

Nir:     — the lifespan —

Gordon: Yeah.

Nir:     — don’t-don’t seem to match. But obviously, they got the same disease at the same age. Okay.

Gordon: Mm-hmm.

Nir:     So the genetic was actually part of it. And —

Gordon: Hmm.

Nir:     — the genetic cause of hyperlipidemia — which I have, and I’m — I’ve been treating it for all my life. So I hope –

Gordon: Mm-hmm.

Nir:     — I hope to prevent it. A-another example is from identical twins. Identical twins have 25 percent genetic contribution to their longevity. It’s a bit more than 7 percent. But it’s still — it’s still not that convincing. But this —

Gordon: Yeah.

Nir:     — is the problem.   I’ve studied these phenomenon with intrauterine ligation where we get pups to be small for their gestational age. And they get — 

Gordon: This is — this is mice, Nir, or rats?

Nir:     This is — this is rats actually.

Gordon: Mm-hmm.

Nir:     This is rats. And they get age-related diseases. I mean, amazingly, a-a-animals don’t get diabetes usually. You really have to try hard.

Gordon: Hmm.

Nir:     And they get diabetes when they are three-and-a-half months.  There’s a hypothesis — a Barker hypothesis. It came from an unfortunate experiment in World War II where  people had famine. And they were born small. And they got into lots of trouble, young-younger on diabetes, hypertension.

Gordon: Yeah.

Nir:     So identical twins — a lot of them are born not symmetrical, but one of them is small for gestational age. And if they are  less than five pounds — and a lot of identical twins are less than five pounds — they get an aging mechanism that we think is epigenetic that doesn’t reflect the rest of us. So I don’t think this is a real good model. But I would say it now from the opposite side. In our centenarians, it looks like that it’s more 80 percent genetics and 20 percent the environment. In fact —

Gordon: Mm-hmm. Okay.

Nir:     — from environmental perspective, where 60 percent of the men were smokers, 30 percent of the women were smoker,  overweight or obesity, more than 50 percent of them, exercising even modestly, you know, just walking —

Gordon: Yeah. Yeah.

Nir:     less than 50 percent vegetarian, 2% percent. So-so for our centenarians, it’s clearly more genetics. And lastly, our offspring of centenarians were — which are part of longitudinal study —

Gordon:  Mm-hmm.

Nir:     — we-we had the paper that kind of really nails it because we have all the data on the offspring in our control environment. We knew what food and what proportion of food they are eating and how much alcohol and how much cigarette they are smoking and the micro and the macro nutrients and their BMI and everything else.

Gordon:     Mm-hmm. Mm-hmm.

Nir:     And between the two groups, they were totally identical, totally identical. However, their cardiovascular disease prevalence was almost half as low.

Gordon: Yeah. Yeah.

Nir:     So you almost match the environment at the very — at the age where it counts, not at centenarians but when they are 65 to 75.

Gordon: Mm-hmm.

Nir:     And still, you see that genetics plays a protective role because they get half of their heart attacks. And by the way, it’s true for Alzheimer, for-for other things that we are monitoring.

Gordon: So this is, one really important contribution you’ve made is to be studying the children of the supercentenarians, the centenarians. Just before we get into that, how many people make it to 100? What proportion of the population?

Nir:  Oh, it’s actually hard to know. It depends what method you do, but when I started, it was considered that one out of 10,000 —

Gordon: Mm-hmm.

Nir:     — is 100 years old and that there are more of those because they are a little bit bionic. There’s more people with, uh, you know, pacemakers and —

Gordon: Sure.

Nir:     — artificial knees —

Gordon: Sure.

Nir:     — and stuff like that. But you know, we tried to look at that through the vote-voter registry in the Bronx where Einstein is.

Gordon: Mm-hmm.

Nir:     And we found the duration of centenarians is one to 1,000 until we realized that we have like a 100 people over the age of 150  and a thousand over the age 130.

Gordon: [laughs]

Nir:     In other words —

Gordon:  In other words —

Nir:     — you know, we have to know that there are voters —

Gordon: Mm-hmm.

Nir:     — out there that are using some other instruments. But it’s really hard to know and to even validate the real age.

Gordon: Mm-hmm. I see.

Nir:     But I would say one out of t — I would say it’s rare. It’s — from genetic perspective, it’s rare enough

Gordon: Yeah. And then, super centenarians  over 110? Again — [because] that must drop off to a remarkably small number of people.

Nir:      A huge drop off. I mean, look. Even in centenarian, you lose 30 percent each year. Okay. So —

Gordon: Hmm.

Nir:   –your chances of being that  is really, um, not so high.

15:50

Gordon: So-so for the non-geneticists out there  just describe how you — how you — how do you find genes that are associated with longevity or exceptional longevity using this structure that you’ve used this control group of younger individuals or children? just unpack that a little bit for us.

Nir:     Right. Let me just say — let me before that just say another thing because I want to eliminate some other possibilities for their longevity. I kind of told you from the environment perspective they haven’t really reacted  like

Gordon: Yeah.

Nir:     — that’s not the reason. In fact, in our paper, we have control of their cohort. Okay. That’s called enhance one. And we see that they’re a little worse than their cohort even. So —

Gordon:  Hmm.

Nir:     — [that’s nothing.]

Gordon:  Hmm.

Nir:     The second question for us is, you know, we know that there are genes for Alzheimer and cardiovascular disease and cancer. Maybe our centenarians just have the perfect genome, I call it. You know, they just don’t have —

Gordon: Mm-hmm.

Nir:     — any of the nonsense. So the first experiment we did which is just cool and easy to explain, we had 44 centenarians —

Gordon: Mm-hmm.

Nir:     — that we had the whole genome sequence, okay  no control, no young control, no — just them. But there is a resource that’s called ClinVar. ClinVar accumulates all the mutations that are associated with diseases. And we wanted to have those that are most probably causing disease. And we said, you know, at least we’ll see. If they don’t have any of those mutations, they have pretty good genome. We were not ready for the fact that 44 centenarians had over 130 mutations that should have made them sick.

Gordon: Mm-hmm. Wow.

Nir:     And among them, as an example, are two people who have — two men who had APOE4 mutation.

Gordon: Mm-hmm

Nir:     And the textbook will tell you they are demented at 70 and dead at 80. And they’re 100 years old and not demented —

Gordon: Hmm. Incredible.

Nir:     — which kind of shows that, if they s — if they have slow aging, they can escape some of those diseases. And of course, Alzheimer — you can born with APOE4. You’re not demented when you are born and where you are 10 year old or 40 year old. It takes you — it takes the biology of aging to bring this disease  

  — out. So if you can —

Gordon: Yeah.

Nir:     — if you can escape it long enough, you don’t get  this disease. So I just wanted to take off the environment and the perfect genome out of the equation. Now to tell you and I think — I think we’ve done this-this gene — you know, the fact that we — that the genome was sequenced was such a breakthrough. And it-it’s very important. But then, we did something really silly. What we did is we took one mutation at a time and one disease at a time. And we said, are they correlated? Let’s look at one wrong sequence for diabetes. Okay.

Gordon: Yeah.

Nir:     And let’s see of all people in the world — let’s take 100,000 people and see if there is a connection when, in fact, we are not built of one change at a time. [laughs]

Gordon: Hmm. Mm-hmm.

Nir:     We are built for many changes in a  at a time. Some of them are upstream. And some of them are downstream. And the biology is complex. And although we use this to find significant findings, what we are doing now is actually  finding all the differences between long-lived individuals and those without longevity. Okay. So [they’re young] —

Gordon: Yeah. Yeah. Yeah

Nir:     — and unrelated.

Gordon:  Mm-hmm.

Nir:     Okay. That’s not offspring — are unrelated. But what we are doing with computational, with AI, is putting them into pathways. And then, we are asking, what are the difference in the pathways between those —

Gordon: Yeah.

Nir:     — those with longevity and those without? And the interesting thing is we are getting what we got from animals all along :

Gordon: Mm-hmm. Mm-hmm.

Nir:     — the IGF insulin signal pathway, mTOR pathway, you know, MAP-kinase pathway. In other words, we — when we do it this way, we get confirmation that the-the models you’re studying, Gordon, are  as we claimed, [laughs] that aging is conserved, tha even the longevity part is really conserved. And I think that’s one very important contribution to remember, that we are — we are relevant in all our models.

 Gordon: Isn’t this amazing?  I can’t believe we’re having this conversation! When I started working in C. elegans, a tiny little microscopic nematode, I never thought we’d have anything, you know, significant to say about human aging. And actually, when your longevity gene project — isn’t it like 24 years ago it started? 

Nir:     Yeah, in ’98. Exactly.

Gordon: So in- in ’98, what was your thought processes? So you’re-you’re — I guess you’re reading some of these papers from-from worm people and fly people. Maybe you’re going to conferences at that time talking to them. I mean, did-did you really foresee that the stuff that they were doing would be relevant to-to your thinking about human aging?

Nir:     So l let me tell you a funny story. The only thing… look,  the fact — Gary Ruvkun, Cynthia Kenyon had their papers. And it was fabulous. The concept that one gene changed life span was just-just the most fabulous thing. But for me, it was  the wrong gene. It was the insulin-signaling pathway.

Gordon: Yeah.

Nir:     And I’m-I’m an endocrinologist. I’m actually a diabetologist. I’m seeing patients a couple of times a month. Okay. And the problem with type II diabetes, they are insulin resistant which  what the nematodes were pretty much.

Gordon: Yeah.

Nir:     And not only that, they’re insulin resistant where the — in patients, their main problem, they have abdominal obesity. They have lots of intra visceral fat and the nematodes had fat in their intestines too.

Gordon:     Yeah.

Nir:     And I remember organizing this symposium in the American Diabetes Association meeting and bringing Cynthia Kenyon. And it could have been great except she’s done   a real faux pas [laughs]. She basically said in the diabetes that, if everybody will be type I diabetes, they would live longer —

Gordon: [laughs]

Nir:     — at the time that it was hard to maintain them alive. [laughter] So — okay. But-but, you know, it’s not only the insulin signaling. It’s the IGF signaling pathway.

Gordon: Yes.

Nir:     And-and it was — and-and I’ll tell you — I’ll jump ahead and tell you 60 percent of our centenarians have some functional alteration in the IGF-1 signaling pathway — 60 percent.

Gordon: Wow.

Nir:     It’s the most common genotype. I think it’s almost a genotype – it might not be the only one. But it’s really relevant. And it’s consistent with the fact that, you know — that the d — the small dogs live longer. And the ponies live longer.

Gordon: Yeah.

Nir:     And those nematodes live longer. And-and-and the [bar-key] mice live longer. And-and it was very consistent with that. But this is – just for the story’s sake, I —  the human data —  we just figured out the human data recently with an aging-cell paper not long ago where we resolved this issue. But the data that was existing for IGF was very confusing. Some showed that IGF is good. And some showed that IGF is bad. IGF —

Gordon: Mm-hmm

Nir:     — is the insulin growth factor.

Gordon: Yeah.

Nir:     Insulin growth factor 1 is really one of the major effector of the growth hormone system. Okay. Just —

Gordon: Yes. Yes. And that-that explicitly makes a connection to the small-dogs/large-dogs thing.

Nir:     It — right. Exactly.

Gordon: Yeah.

Nir:     So-so when I wrote my first grant on the IGF system, it’s one of the grants that I said I’m writing it. I can write it. I can justify it. I really don’t believe this shit. [laughter] But this is actually maybe the only dr — you know, we all write grants. And we-we-we-we discover important things no matter what. But our hypothesis is usually not right. This was the hypothesis that I didn’t believe turned out to be right. [laughs]

Gordon: Yeah. No. It’s  an amazing story.   Let me — a little bit more about  the sort of the methods around studying humans and studying human genetics. I know most of your work has been in-in animals and in endocrinology, 

    But you’re very well-known now for these discoveries and exceptional longevity. Tell me the story of the Ashkenazi Jews and-and why they are so important to your studies.

Nir:     Yeah. Look, it’s not only that there are few centenarians. It’s also hard to recruit them. And we tried to find basically a shortcut. And the shortcut in genetic research is, if you a have more homogeneous population.

Gordon: Mm-hmm.

Nir:     So rather than go in New York City where there it’s one of the most diverse — or the diverse, I think I just read – the most diverse 

Gordon: Hmm.

Nir:     — in the world where there’s so many genes and there’s so much noise that you have to account, go to a single population. And that time, the single population was the Icelandic population. And they really were having major discoveries. Like up to 10 years ago, they were the population where you had discovery. It’s only f —

Gordon: Mm-hmm.

Nir:     – 500,000 people.

Gordon: Yeah.

Nir:     But they’re all brothers, cousins. Right.

Gordon: Yeah.

Nir:     And the other population that was exemplar are the Amish. Okay?

Gordon: Hmm. Hmm. Mm-hmm.

Nir:     The Amish population have 100 founders. So they’re also pretty much relatively inbred. And so for me, the next population — population that I’m one of them and I had connection, was the Jewish population. And the majority of Americans — American Jews are — like more than 90 percent are Ashkenazi Jews which means they come from Eastern Europe.

Gordon: Yeah.

Nir:     And because of an unfortunate history, there is lots of inbreeding and also,  death bottlenecks that made this population European but very homogeneous genetically. We know that, because-because, when you have such a population, some of the rare  heterozygosities can become homozygous,  

Gordon: Mm-hmm.

Nir:       just because you’re the same population. So diseases like Tay-Sachs and some hemophilia are more prevalent in Ashkenazi Jews just to exemplify how unique they are. Now — so genetically, it’s homogeneous. And we actually retrospectively went and showed that we would need —  it’s g — it’s mutation — it’s genetic — it’s genotype specific.

Gordon: Yeah.

Nir:     But sometimes, you need 20 times more people, sometimes 50 times more people to get the same effect. So —

Gordon: Right.

Nir:     — I had to recruit, you know, in,   [laughs] exponential magnitude more people —

Gordon: [laughs]

Nir:     — to get the same effect. So this thing has helped a lot. Now —

Gordon: Is there a social component to this,  you know  in terms of — w — recruitment, for example, and r — then retention, you know, why peop — why people would stay in your program? Is-is-is — that part of this population as well that’s strong?

Nir:     Yeah, absolutely. But the reason is even different. You know, in the United States, most of the Western World, the poor people live 15 to 20 years less than the rich people. Okay. Or I would say differently. I think it’s the level of education.

Gordon: Mm-hmm.

Nir:     And the level of education of the Ashkenazi Jews in our study is very homogeneous. Okay? 

Gordon: Hmm.

Nir:     They — th-their income varied. But the education is the same. They all have access to healthcare. So we didn’t have to adjust for one of the major factors that are  associated with impaired longevity.

Gordon: Yeah. Okay. Got it.   So in studying this population you find genes. Tell me , I mean, you’ve hinted at this already. Obviously, the IGF signaling pathway is a strong component. What other individual genes have-have come out as being major players?

Nir:     So the major players that come — that came out — and I call them major players because they were already translated into therapy.

Gordon:  Hmm.

Nir:     One of them is a SNP — a functional SNP in a gene that’s called CETP, cholesterol ester transfer protein. By the way, this gene does not exist in mice and rats, [laughter]  and in many other animals. But when this gene is inhibited — and  you know, it has to do with cholesterol ester transfer. I don’t want to — I don’t want to bore anyone although I’m very excited about telling you this. But, when you inhibit cholesterol ester transfer, what happens that you can measure is that HDL cholesterol, the good cholesterol, goes up.

Gordon: Mm-hmm.

Nir:     And triglycerides are going down. Okay. It has nothing to do —

Gordon: Yeah.

Nir:     — with LDL.

Gordon: Yeah.

Nir:     And it was interesting for us. And the reason we looked at this gene is because our families of centenarians had very high HDL level and very low triglycerides.

Gordon: Okay.

Nir:     And we found that this functional mutation or change — y-you know, mutation is usually less than 1 percent. I’m kind of,   I’m kind of changing just for you to know from mutation to SNP just because they’re I’m not saying it exactly right. But you understand what I mean. But a functional change in the CETP gene was — went from like 8 percent in our population to 20 percent in our population.

Gordon: Hmm. Hmm.

Nir:     And it was kind of going on [laughs] — it-it has a linear increase with age. In other words, the more —

Gordon: With age. Yes.

Nir:     — the more people survive, the more of them had this SNP. Now —

Gordon: Got it.

Nir:     — Merck was interested – the CETP target has also a long history. But Merck was interested in that and developed a drug that went through a phase 3 trial. It’s not a drug that they are selling right now. They are looking for some opportunities. But The results of their study showed that people who took this drug had much lower cholesterol and much less cardiovascular diseases, a phase 3 trial.

Gordon: Hmm.

Nir:     Similarly  we found almost the , really the same story in another, uh, gene that’s called APO3 — APOC3 — sorry.

Gordon: Mm-hmm.

Nir:     And APOC3 — it’s also kind of a cholesterol gene also associated with low triglycerides and high HDL. It also goes from like 8 to 10 percent to 18 to 20 percent,   some overlap, But that really means that almost 35 percent of our centenarians have one of those. And there’s a company that at the time was called Isis (they needed to change their name. They’re Ionis now.) But they also had a drug.  And I think they are going to sell that. It’s  an antisense for the APOC3. And the effects were pretty tremendous. So I’m just — I think the moral of the story, [laughs] — thinking as I told that — is that people say, “Uh, you’re doing genetics. Well, good for you. We don’t have these genes. We need gene therapy to do it.” No. The genetics is to find a mechanism. Well, when you find a mechanism, you usually can find the drug. You don’t need to do —

Gordon: Yeah.

Nir:     — CRISPRs. People are saying —

Gordon: Yeah.

Nir:     —   CRISPR? No. You don’t have to do CRISPR. 

MUSIC INTERLUDE

Gordon:  Okay. Let’s talk about drugs. Uh, when do you think we’re going to treat people, at what portion of their life with some sort of aging intervention m-most likely to work?

Nir:     Uh, can I ask you, are you taking anything? [Bec –]

Gordon: Uh, no. I’m just taking exercise.

Nir:     Well, that’s-that’s a — we-we have a gerotherapeutics and geroprotectors. So you’re doing a geroprotector.

Gordon: [laughs]

Nir:  Because I’m taking metformin. Okay?

Gordon: Okay.

Nir:     But frankly, my doctor put me on metformin because, at some stage of my life, I was pre-diabetic.

Gordon: Mm-hmm

Nir:     and I’m not anymore. But I didn’t stop metformin. [laughs] And he didn’t stop it for me.

Gordon: [laughs]

Nir:     and I’m — you know, I’m kind of — I’m saying it now. I wasn’t proud initially because we are very few doctors. You know, Eric is one of the —

Gordon: Eric Verdin? Yeah.

Nir:     – Jim Kirkland —

Gordon:   Mm-hmm.

Nir:     — and Tom Randle. And-and you know, when you’re a doctor, you realize that th-the first — the first day in medical school, they teach you do no harm. Okay.

Gordon: Yeah.

Nir:     So you’re very conservative. You really don’t want to do anything. Okay.

Gordon: Yeah.

Nir:     The second day, they’ll tell you there’s no always, and there’s no never. Okay.

Gordon: Mm-hmm.

 Nir:  So you can give a good drug, and it’ll be bad too. Okay.

Gordon: Mm-hmm. Yeah.

Nir:     So you are confused — you are conservative and confused. And I’m always saying people at the FDA went only to those two days in medical school because they don’t — [laughter] they don’t let us move at all. But I think — I think we have to understand that we really, in our evolution of doctors, we always —  we’re just doing a little bit more good than bad. [laughs] And we got forward with that. But we also killed a lot of people. And probably, we’re still killing people. So I think — I think we have to be conservative. And that’s why I’m saying, you have to have clinical trial —

Gordon: Mm-hmm. Mm-hmm.

Nir:     — in order to make a judgment. Look, metformin is a drug that’s been around so much, billions of years of use, a very safe drug.  Any doctor can repurpose metformin. Okay.

Gordon: Yeah.

Nir:     It’s the right of every doctor. But if people ask me, “Is there proof?” I said, “No. There is no proof for the study that I’m doing.” [laughs] Although —

Gordon: Yeah.

Nir:     — there is a proof to each component of the study but not the study the way I’m doing it. So I’m very reluctant as carrying this obligation to say, “Well, I’m taking metformin.” But on the other hand, you know, we are getting at the age where we see that it’s slow. And we know that there’s a promise. And what should we do, you know?

Gordon: Mm-hmm.

 Nir:     Sacrifice our aging -? 

Gordon: Mm-hmm.

Nir:     — our healthspan ?

Gordon: Yeah. [laughs] Well,  so actually, we did a study in-in — nematode worms with Patrick Phillips and Monica Driscoll quite recently with metformin. And you know, you probably remember that Monica published many, many years ago metformin extending lifespan in worms. In this most recent study, we were looking at different strains of wild worms and different species of wild Caenorhabditis. 

36:01 And we-we saw really diverse effects. And so it simply didn’t work in some strains and species. And maybe it was even detrimental in some. And that points  obviously to genetic background being really important in the response to drugs. This is probably no surprise to anyone. But it does get to this question about how do you —  ahead of a clinical trial, how do you actually structure it? Is there a way to find a subgroup of people who will respond to the drug in aging and-and those that would not? I mean, that would be fantastic to know, right, because, if we just take a random population, we may not see the effect size that we’d like to see.

Nir:     Right. But-but look, our preliminary data that is very substantial — okay. So I’ll give you two examples. The study that’s known as the DPP, Diabetes Prevention Program, took people who were normal glycemic but had, you know, risk for diabetes —

Gordon: Mm-hmm.

 Nir:  — obesity, family members at risk. But they were, it’s important to know, they were not diabetic — and gave them either metformin or lifestyle changes that in-include exercise and diet. And it was a five-year study. But it was stopped after four years because both lifestyle and metformin significantly prevented diabetes so delayed —

Gordon:  Yes.

 Nir:  — delayed diabetes. And the effect was 30 percent. Okay?

Gordon: Wow.

Nir:     So you’re asking, well,  why it’s not 100 percent. But most of the drugs — you know,   like the cholesterol lowering agents that are really considered good have —

Gordon: Mm-hmm.

Nir:     — have 20 percent effect in a population. By the way, it’s 20 percent over the observed years. Okay?

Gordon: Yeah.

Nir:     Okay. So — okay. But basically, when you have an effect that is over 10 percent, it’s not a private event. It’s a very common event. Okay. You can say that, at this period, that most of the people are going to benefit from metformin.

Gordon: Yeah. Yeah.

Nir:  And-and the ef — and-and the effect — you know, the number of people that we chose for this study was based on the DPP. Even the amount of drugs we’re taking is based on the DPP. Similarly, there was a U.K. study — it was called UKPDS — where metformin was, in diabetes, was compared to other three classes, one class of drug but three drugs that are called sulfonylurea and insulin.

Gordon: Mm-hmm.

Nir:  And only metformin significantly decreased cardiovascular disease.

Gordon: Yeah.

Nir:     And I can go on on-on more and more studies. It’s a — it was also a 30 percent effect. If you look not at clinical study but if you look at 250 studies about cancer and metformin use, it’s a 30 percent effect for all cancers except prostate cancer.

Gordon: Mm-hmm. Hmm.

Nir:     Okay. So when you have a 30 percent effect over an observed years, this is a public player. Okay.

Gordon: Yeah.

Nir:     And, you know — and then, there’s the side effect because 180,000 people in U.K., that were studied with, you know, those without diabetes, those with diabetes on sulfonylurea and metformin. People who took metformin who were diabetic more obese and had more disease to start with had lower mortality over five years than people without diabetes. [laughter]

Gordon: Yes. Yeah. It’s amazing.

Nir:     Which, by the way, it’s — you know, when Rich Miller says, “Hey, you know, I don’t get ITP metformin or the effect of metformin are low,” and he tested it also with your nematode — yeah. That’s in mice. And that’s —

Gordon: Mm-hmm

Nir:  That’s with the dose that you give them that was —

Gordon: Yes.

Nir:     — their dose response. Okay.

Gordon: Yes.

Nir:     But we already know in humans that the effect is greater.

Gordon: Mm-hmm.

Nir:     Even compared to normal, look, metformin versus sulphonylurea in human,  is 50 percent less mortality. And from non-diabetic, it’s 17 percent. So it’s more than Rich Miller’s  [laughs] —

Gordon: Yeah. Yeah.

Nir:  statistics]. So —

Gordon: And —

Nir:     — some of those drugs and I think, look, we can expect that maybe rapamycin — maybe metformin is better in humans, and rapamycin is less than what we thought from animals. It-it could be, you know. But that’s –

Gordon: Yeah. No. It makes perfect sense. It makes perfect sense. Do you think that, how do you see biomarkers playing out here because maybe we can improve even these numbers by appropriate dosing?  And maybe that’s a response to the drug that we can track with biomarkers, whether it be epigenetic or protein or other-others. Do you think that’s likely?

Nir:     So-so remember, the biomarkers are not interesting only to distinguish between biological and chronological age. We want them to change with therapy. Okay. We want —

Gordon: Mm-hmm.

Nir:     We don’t want to do a phase-three trial for 100 drugs and spend trillions of dollars on them. Right. We want, in two months on a phase 2 study to see, are the biomarkers changing? Okay.

Gordon: Yes.

Nir:  That’s our target.

Gordon: Yes. Yes.

Nir:     And I picked actually proteins as the most likely biomarkers. Also, listening to Harvard who said, look, you’re not going to cha — to change methylation in nine months or even more than a year of treatment. And we measured 5,000 proteins by aptamer on 1,000 of our people in the longevity study, half offspring and half control. And we asked, what’s changing between ages 65 and 95? And there are many proteins. But the ones that are really incredible to me are break — proteins that show breakdown. For example, collagen, extra-extra cellular metrics,  even degranulation of platelets or breakdown of some cells because I think that it’s the breakdown that we want to stop. We can stop it with many treatments. But that’s what we want to stop. So —

Gordon: Yes.

Nir:     — we-we now had actually a-a conference in the NIH supported by Mayo and AFAR and other  people. And I brought in some ideas that we’re going to accelerate because there are some — the-the DPP  for example, that I told you about —

Gordon: Mm-hmm. Mm-hmm.

 Nir:  — they have samples where we can actually look at the effect of both lifespan intervention and metformin —

Gordon: Yeah.

Nir:     — by omics. Do omics of everything, proteomics, metabolomics, you know, methylation, whatever —

Gordon: Yeah.

Nir:     — and really try and see what happens in those studies. Also, there’s another drug, SGLT2, that I think is really a very important gerotherapeutic in humans. You give it to diabetes. But you prevent heart disease. You prevent kidney disease. You prevent —

Gordon: Mm-hmm.

Nir:     — all causes of mortality. ITP has shown that it elongates the lifespan of Rich Miller’s mice.

Gordon: Yeah.

Nir:     So I think that’s the way to go fast.

Gordon: Very promising. Very promising. I mean, d-d — we’ve seen recently in mice with Frank Hannity’s lab that we actually can see a compression of morbidity and, in this case, with the metabolite. That’s what’s going on with these human results. Right. You’re really reducing the period of sickness. And-and that-that has an enormous, social and-and economic effect down the line. , Nir, this has been fascinating. Thank you so much for your time.  I’ve learned a lot. And-and thank you for your-your public outreach and your advocacy at the FDA and other places for this field. And I hope to see you soon.

Nir:     Thank you. Me too. 

 SHOW OUTRO

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