#087 Human Longevity 101 — Dr Nir Barzilai

Doctor Nate Barzilai is professor and founding Director of the Institute for Ageing Research at the Albert Einstein College of Medicine and the Director of the Paul F. Glenn Centre for the Biology of Human Aging Research and of the National Institute of Health's Nathan Schoch Centers of Excellence in the Basic Biology of Aging. Essentially, he's an OG original gangster in human longevity research. When describing him, David Sinclair writes, not only is he a world leader in aging research, but also happens to be one of the best science communicators on the planet. Barzilai is also the author of Age Secrets of the Healthiest, Sharpest Centenarians. He has over 270 peer reviewed papers and also co founded Cobar, a publicly listed biotech company developing mitochondrial therapies for aging. In his quest to fight aging, he he's consulted or presented to institutions such as the Vatican, PepsiCo and Singapore's Prime Minister's Office. He also leads the tame trial which is looking at a cheap and commonly used diabetes drug called Metformin to see if it can slow down the process of aging. Metformin first gained interest in the longevity space when people began to notice that diabetics on Metformin seemed to have lower mortalities than diabetics on other drugs. In fact, diabetics on Metformin had lower death rates than similar people who didn't have diabetes and so were not on metformin. Just to be clear, that means that diabetics on metformin who have a serious medical condition, which is one of the big four killers in the developed world, appear to have lower death rates than non diabetics who aren't taking Metformin.

That's crazy.

In his TAME trial he's investigating if giving Metformin to older adults can delay the progression of age related diseases. Barzillai is part of a movement in longevity research or geroscience who aim to treat aging as a disease in itself instead of treating one disease only for another to take its place.

If you cure cardiovascular disease, you'll get two years of health span and lifespan extension. But what happens to the people that come to the hospital and they have a heart attack and you give them a stent or you do a bypass in two years they'll get Alzheimer's or cancer or diabetes because you never treated their aging, you just treated their heart and that's why you don't get much bugs for your money if you just switch one disease for another. It's only if you target aging that you're going to delay all of those diseases. And that's the only way to proceed now. Except not everybody realizes that.

I think one of the most interesting or curious points in your book Age later was that you said that you were advising, I think the Prime Minister's office in Singapore and someone, and I don't know whether it was a joke or how serious it was, but someone suggested, why don't we put metformin in the water supply?

Well, yeah, no, it's not a joke. I said, I want to be prepared. So tell me, tell me what you want to answer. And they said, should we? You know, it was a really good question. In fact, it was a terrific question. Okay, the answer is no. Okay, the answer is no. But, you know, maybe it'll happen one day. Okay, it's good, it's good to discuss that. Discussions like that happen on statins. You know, should we just put statins in the water? I mean, those things come from time to time. By the way, there's no comparison to the effect of metformin then statins, okay, there's no comparison. Metformin is going to have much bigger impact than statins. But, you know, statins are a good drug and people are asking those questions. It's fine.

I guess one of the things we still won't know even from your tame studies or until the future is what effect metformin might have if we give it to a very young person for the rest of their life. If you give it to someone in their 20s, is that something you're curious about?

Yeah, this is a very interesting point. There's the UK Biobank, okay, that is really collection of huge, huge of clinical data with genetic data, with biomarker data, with outcomes with diseases. And I'm going to answer your point, but I'm going to make a different example. And we use the UK Biobank to ask a specific questions. If you have high IGF1, which is a growth hormone, that's how we measure the effects of growth hormone. Is it going to be good for young people and for old people? And the answer is high IGF level are always good for young people. They have less mortality, you know, less all kind of diseases. It's always bad for old people. Okay, we called it antagonistic pleiotrophy. Things that are good for you when you're young can turn against you when you're old. When we go through aging and there is a breakdown with aging, we need to stop growth and start stopping the breakdown. To get this energy back to growth is not good for us. Why Am I telling you this example because it's going to be the same with drugs or if we give growth hormone, okay, we give it only in young and not in old. Okay. And the same with metformin is we know that metformin after the age of 50 in trials had good effects, but do we know that at age before that it has, it doesn't have bad effects. For example, metformin lowers IGF1 level. It's not good to lower IGF1 level in young people. Right. So your question is absolutely right. When are we giving drugs is very relevant. And I would, I would, you know, really tell your friends, okay. If you hear it and you think, wow, I should take Metformin now, I'm not sure it's safe. Okay? There are trade offs, and part of the trade offs is the age. So I wouldn't ask you to do that.

What is your opinion in general on young biohackers who experiment with things like metformin and rapamycin? I mean, are any of these kind of safe to take in a medical context? Of course not in terms of medical advice that you're giving, but just in general, are any of these compounds proven to be good for a young person to take to extend their lifespan?

Yeah. Well, you know, first of all, the answer is no. But look, for me personally, you know, as an mds, we learn the first day to do no harm, Right? And we're always on the edge of doing more harm than good. Right. I mean, it's always a balance, but that makes us very conservative. Okay. The second thing in medicine, you know, is there's no always and not never. So we become also unsure of ourselves, okay? Which is a little bit a problem. Now I'm playing the game that I'm leading a major clinical trial, okay? And my duty is to say, don't take anything before there's a clinical trial. Okay? That's, that's what I say usually. And I'm not calling here for anyone to be in metformin, but I am concerned about young people who don't understand that the mechanism of aging is and the targets for aging are different between young and old people, and that there are trade offs. So I'm looking at three things from a treatment perspective. One is the Dorian Gray state, where Dorian Gray was not aging, but when he looked at his mirror, he saw his real age. Okay? The mirror didn't hide his age. I'm pretending that I'm Dorian Gray, okay? I'm looking now at myself and I'm saying, maybe it's chronological age, but I'm much younger actually. So, you know, I try it, it works well for me. Okay. And those are the drugs of like metformin and rapamycin. Those are the Dorian Gray drugs. Okay. Try to delay aging. Right? Now, the second scenario which is the hardest is the Wolverine or the fountain of youth. Okay, let's take you old, put you in a bath, you're getting out young. Very, very difficult to do. I would say, however, that there are drugs like senolytics that at least in animals, improve their health, not their lifespan, but improve their health. In other words, when I say if you target aging there, it can stop and reverse. In this sense it does. But the third scenario is the most interesting. It's the Peter Pan, okay? Peter Pan was forever young. Okay. The idea that we will take a 20 year old or a 30 year old and give them a treatment once a month or once a year and erase their aging, okay. So it's delayed significantly and they don't get old. I think it's going to be the easiest thing to do in 50 years. Okay. I don't think we're near there now. There's no model that we show that it's going to work, but this is probably where we are going for now. We have to block aging as it comes on us. And this is good and we can do it and we should do it, but it's never going to be is let's just stay young.

There's another, I guess, fourth option which is more of, you know, with things like the metaverse and virtual avatars and robotics and other things. It's whether we can at some point escape the biological and physical confines of being a human and somehow upload our consciousness into something else. Is that something you think about or do you think that's just sci fi?

Well, I think about it as a curiosity, not as a medicine. Okay. I personally, if you tell me, you know, you'll become an avatar, you know, it doesn't, it doesn't, it doesn't attract me really. It doesn't attract me. I'm afraid that there are things that people are taking that are going to change yourself. You know, one of the problems, if you're going to renew my neurons, you first have to download the information, my memories, my personality, and pass it to my new neurons. If I'm going to be a different person, I'm not really interested in that, okay? I'm, I'm, I'm interested in my life and not on somebody else life. So the this science fiction is cool. Look, technology and robotic is going to help us a lot. It is helping us already. So I'm looking for a technology that will help me age, but I'm not looking at myself being something else because it's not attractive to me. And, you know, and I can see why it will be attractive to people, but it's not attractive to me.

Do you have any grasp or any thoughts on how far we'll be able to extend our lifespan? Are there some biological absolute limits to what we'll be able to do with all of our preventative medicine and any other therapeutics we design? Is there a hard limit, do you think, anywhere?

Well, I think the Mac. Our maximum lifespan as a species is about 115 years. We, we argue about it because there's somebody who live to be 122, but you know, statistically it's 115 years and we die before the age of 78 now. So they're 37 years to realize without needing even to discuss that, okay, it's not going to happen. It's not going to happen in one day anyhow. That doesn't mean that our maximal lifespan has to be 115 years. On one hand, there's the second law of thermodynamics that says that we have things that have limited life, okay, and that there'll be a limit no matter what we do. But I don't think that all of them means that we cannot go past 115. The example that I gave you of maybe at the age of 20 we can rejuvenate, I think is one way probably to say that we might get over 150. Right? You know, just as much as I told you, we got to the age of 78 and we got bad deal, cancer and diabetes and stuff, you know, we'll go to 150, there'll be new diseases that will make us miserable. Okay, it's going to continue like that. But, but I don't think that. I think that now when I'm, I'm saying if you're asking, do we have a lifetime capacity? Yes. And if you're asking me is that going to stay. Not necessarily.

So do you think if you were able to delay these nine hallmarks of aging, we're using the Peter Pan model, we're able to delay them. Do you think there's theoretically no limit on how far we could go? What I'm asking is that, do you think that will be a hard stop somehow we cannot delay things enough.

I don't think that I don't see how immortality happens without the fourth scenario that you suggested. Right. That we are so dependent on technology that we are out of the, we're out of the game anyhow. Right. Also, you know, when I'm thinking personally, so let's say the earth is going to survive for 12 billion more years, which is debatable, you know, I mean, some people are even getting into hundred thousands years. But if our world, if Earth is going to stay, you know, I'm, I'm becoming some, I'm, I'm becoming a little bit tired sometimes, right. I mean, I had enough. I, I, I really don't want to go through 12 billion years of president elections and stuff like that and all the politics and stuff like that. You know, it doesn't, doesn't. 12 billion years doesn't sound really great for me now. I think for most of us, what we want is we want to live healthy for a long life and die one day or not wake up in morning one day. And I think that'll be very good goal and very good life too.

So in terms of what is available today, is there anything you would think of that if you could start a trial today and then fast forward 100 years and see what the results were of it? What would pique her interest in terms of that?

Well, I would work on this mechanism that erase aging in stem cell. And I don't want to get more complex, but it's really different to take a stem cell and rejuvenate it, or take a cell that is already established and has a purpose, okay. Neuron or liver cell, and rejuvenate them. Okay. We're not there yet, Although there are some experiments that suggest that we could do that, but we're not that yet. So that's where I would go. But even better if we could really rejuvenate old cells, not just young cells that keep them young, but rejuvenate old cells without hurting anything, that would be good. The, the only problem is that when you use those yamamake factors, when you do these rejuvenating factors, when you do it in models, they are prone to cancers. Okay. And so the safety is always going to be difficult. And you have to find out which are the things that will do that without causing cancer. Where are the factors that will do it without causing cancer.

Another part of all this story is of course with budget and money and what kind of funding you can get. I had two questions. The first was how much interest have you seen from investors from funding bodies in this space. And the second question was if you did have unlimited budget, is there a study you would design today?

So the interest of investors is huge. You know, biotech had a very bad year last year, but there is exponential increase in the funding in longevity biotechs. And in fact again together with Jim Mellon in the UK and some other people, we established the Longevity Biotech association, which is basically the association that's going to help the industry and its special needs. Some of the special needs is if you want to do aging, it's more of a long, you need more Runway, you need more money. Okay. People should know about it, should be educated and we should help them. We need to help the regulation. We have to make sure that there's enough gero scientists that will give advice to companies. You know, if you want to target one of the hallmark, we can set you up with experts so you can understand what it does and why it pays to do that. You know, things like that. So yes, the biotech I would say are going to push us harder. There are also trade offs for that because I cannot get postdocs anymore because they go for better salary to those biotechs. Right. And work there. And I'm not worried only about my research. I'm worried that there won't be a new generation of geroscientists if everybody goes to the biotech right now. So the biotechs are definitely there now. If you're asking me where, where would I spend the money? And again there are two ways to look at that. One are moonshots. Okay, let's do something like I told you, let's do some rejuvenation. That will start early. Let's just do that. And this might be good. It's a moonshot, it will take time. It's not going to help anyone in the meantime. And we need help right now. Okay. And so if anything I will do with my money is I wouldn't do only tame. I would do tame. Like studies have a paper now out showing nine other drugs that could be gerotherapeutics. Let's do tame like studies for all of them. Because another reason we'll need the money is we need to see which biomarkers change with age with, with therapy. We have biomarkers to tell you your biological age. But those biomarkers are not necessarily going to change with treatment like cholesterol and hypertension. Right. Those are markers that you know if you treat them, you'll prevent cardiovascular disease or stroke. Right, but that's not, that's not the case for us. So we need those biomarkers. We need many clinical studies to do that, to do that safe, not to kill anyone on the road, get biomarkers and accelerate what we can do to the public.

Right now, we talked a little bit about the advisory work you've done with the government of Singapore. And I wanted to just ask broadly, how much political interest is there in the kind of research that you and others do? Is this something that your people are regularly reaching out to you about?

Yeah, we are working on that too. And again, the uk, there's Andrew Scott in the London School of Economy that published a paper this year that was amazing. I've been part of a group and part of papers that showed if you extend healthspan by a year or two, what does it mean to the medical cost in the last two years of life? And it's quite incredible. You know, if you get healthspan and people are not going to the hospital, you have a huge benefit. But Andrew Scott said, Just a minute, just a minute. But that's not everything that happens because if those guys are not in the hospital, what are they doing? They're traveling, they're shopping, they're buying things for their kids, for the grandkids, okay? The economy, the economical value, you're totally underestimating. And it's a saving of 300 or something trillion dollars in several years. Okay, like, unbelievable. If we could save that, we could also have money to save global warming. Okay. Like, it's, it's, it's really quite impressive. And this is a thing that we have to educate the government. So I'm involved in lobbying in the United States. For me, it was a little challenging. The good news for me was longevity is something that politics is an issue. But there are some things that everybody can agree. In fact, even the most right or left wing want to show that they worked across the aisle. So longevity is a good thing on the other end. In the United States, science became controversial because of the vaccine, right? We had a president that said, don't do masks, don't do vaccine. It'll go away, right? And giving scientists bad name. So I told our lobbyist, we have a problem with science. And they said, no, you misunderstood the politics here is because you forced somebody to take a vaccine, okay? But if you're going to develop a medicine and yeah, if you want to be sick and die early, fine, you don't have to take the medicine. That's okay.

Have you noticed that countries with a more upside down population pyramid. So a lot more old people compared to young people. Are they showing more interest in the kind of work you're doing? Because for them, it's just more important, I guess.

Yes. The Asian countries like Japan, because they're old and have almost no new people coming up, and China, because they prevented the second child for decades. Right. So they have huge of old people. And I think that's a very important motivation to improve the function of elderly and to decrease old Spanish. That's very much necessary for them. And I cannot say that they're biting or I don't see. Look, it's hard to get into some of them, but although they should be desperate, I don't know that I'm helping them much. Look, with Singapore, I was trying to tell the Ministry of Health and it was when Trump says, america first, right? And I said, well, in longevity, let's do Singapore first. Okay. But then you realize Singapore is a relatively very small country. Okay? They don't want to take the tasks that are easy for the United States to do. They can be the first, second, but not the first. Okay. I think. I think UK is playing a game like that in part two. Okay. Although UK politically is much more ready and accepting for geroscience. I don't know if you want to talk with Tina Wood, who's leading the longevity from a social and parliamentary perspective, but they're ready for that. They kind of understand the problem and where it's coming.

The last question I wanted to ask is, throughout your career, have there been any habits or ways you've approached problems or things you've done that have been helpful for you to get you to where you are today?

Look, there are two things that happen in my life that I think helped me to be successful. The first thing is I went to the army and I went there like everybody else has to go there. But the army, not for everyone, but for a lot of people and certainly me, is a place where you go when you're 18 and in the first day, you're nothing. You're a zero. There's a guy who's two months older than you than telling you when to brush your teeth and when to eat and when to go and make your life miserable. Okay? You're zero. And in three years, I became the chief medic of the Army. So there was an opportunity for me for growth. After three years, I had my office, my secretary, my car. I did inspections in helicopters. You know, it was a whole lifetime. And this whole lifetime gives you this generic perspective. That, okay, I've done it once. I'll do it again. Okay. I think young people are growing much slower in this way, and they're playing part of the crowd, and they don't know that they didn't have this experience that I can go and make a difference, okay? And once. Once you've done it like that, it becomes generic. I could go to another country and start my research. I could go to the NIH and get my grant because I said, okay, I get the game. Okay, I'll play the game. The second thing that was helpful for me, and I'm saying that because it's a personality issue. I never met a stranger, okay? It's very helpful for me. I like people. I want to talk with people. I want to know about people. I want to help them. And if there's a cost together, I want to do it. Okay? So if you're introvert, no matter how smart you are, it's hard to be a leader. You know, it's hard to be a leader. It's hard to be a collaborator. So I think those, if I have to choose, those two things are things that help me today. And as I said, there's no advice. One was the life circumstance, and one is a personality. And when people are asking me, what should I do? I always say, I'll tell you what I would do so that we can take it off the table and talk about what you should do. Because you're a different person with different experience with different personalities. Right.

I hope you enjoyed that episode.

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