How to Die at an Old Age | Prof Nir Barzilai

Feeling good, wanna feel great? Longevity starts. Don't hesitate, too much noise. What do you choose? Trendy hacks, conflicting news, Skip the myths. Come hear what's true from world class experts. Straight to you first and third Thursdays, 7pm Science Health and our team. Brain to heart, from food to rest. Live the talk on living your best. Thursdays at seven. We'll see you there. What is the story with sunlight versus oral supplementation?

First of all, indeed, sunlight is the major source of vitamin D because we can produce it in a physical reaction in our skin. If you give expose your body to very high doses of vitamin D, you trigger countervailing factors that actually reduce the active vitamin D in your body.

They rarely measure the levels of vitamins in the individuals and I know it's hard to do that and I know supplement companies don't want to do that. There's not a lot of effort to optimize vitamin levels in the individual. So some people are taking too much or they're already high and they take some and they go higher. Other people don't get up to the range. And so, you know, I think it'll be really interesting if you can stratify who's responding and what the levels of vitamin D and the responders are compared to the levels in the non responders.

Welcome to the National University of Singapore Yong Lulin School of Medicine Healthy Longevity webinar. Thank you for being with us and thanks to the team for this very nice introduction video. A new approach to really attract your attention. Professor Heike Bishop Ferrari, beautifully presented during our last episode. Do you want to learn more about the dual health study how to use supplements? If you should titrate the vitamin pills to vitamin levels measured in blood. The episode is being recorded and available in our YouTube channel. Today Professor Nir Bazilai is with us, a dear colleague and friend talking about how we could die young at very old age. I think he will tell us more why we should die young. Please use the Q and A function and send us the questions, remarks and comments. We are starting with a short introduction by Sharaka Pimpin, a PhD student and she is also moderating the questions for today.

Hey Young. Hi. Nice to meet you. Hi. Could you tell me more about yourself? So my name is Shara and I'm currently doing my PhD at the Healthy Longevity Translational Research Program here in NUS. My academic background is in biomedical science and the past few years I've worked in different places like clinical diagnostics, biotech startup and academic lab. So you can say I've been everywhere, and I've done a bit of everything.

Oh, wow.

That's amazing. So where are you mostly based at? Yeah, I can show you around. Let me show you here. Awesome. So I spent most of my time here in the stem cell culture room, where I grow neural stem cells. And the goal really is to keep these stem cells happy and healthy so that I can study their behavior under different conditions. Oh, that's great. So could you tell me more about your research? So, my research is about neural stem cells, and I find neural stem cells super fascinating. And that's because they are the sole source of neurons in the brain. And this process is called neurogenesis. And it's super important in keeping our brain sharp, helping with learning, memory, and overall cognitive function throughout our lifetime. But as we age, neurogenesis declines. And one of the reasons is because these stem cells, like any other cells in the body, they age. And so they become less active, more prone to stress, and basically stop working altogether. And when that happens, our brains are unable to form new neurons, and that can affect our memory, overall cognitive function, and increase the risk of developing neurodegenerative diseases like Alzheimer's disease. So my research focuses on understanding how neural stem cells age and more importantly, what might we be able to do to reverse it. But there's another layer to this. So I'm also really interested in circadian rhythm. So, circadian rhythm is our body's internal biological clock, and they are key regulators of these stem cells. So when circadian rhythm is dis. Disrupted either by poor sleep shift work or even natural aging, they can affect the way these stem cells behave, and this can lead to a decline in neurogenesis. In fact, both disrupted circadian rhythm and neurogenesis decline have been shown to occur concomitantly in Alzheimer's disease patients. So in addition to my research, I also want to explain whether realigning circadian rhythm in these aging neural stem cells can potentially restore, Potentially rejuvenate and restore their ability to produce new neurons again. Wow, that sounds like a lot of work. So I guess your time is mostly spent on research. Well, yes, I guess a big chunk of my time is spent on research, whether it's culturing cells, running experiments, and. And even analyzing data. But I always make time for other things in life, too. So I'm actually the chair of the Young Scientist Club, where we organize events, seminars, and workshops that help to promote a very vibrant community to build our young scientists to become not only technically equipped, but to be confident, purpose driven and visible. So yeah, I also enjoy doing science content on my IG, so I do a lot of fun reels on PhD, live lab hacks and just the general ups and downs of a PhD student. And when I'm not doing that, I'm at the gym working on my gains. Thank you so much Cheryl for taking us around. How can we learn more about you? So my Instagram account is right down here. You can give me a follow. I post a lot about fun reels and yeah, and lab hacks as well, so you can give me a follow. I'll also be moderating the Q and A for the later part of the webinar. So if you have any questions or any thoughts, don't forget to just drop them down below and I'll see you there. Thank you.

Thank you. Shara. That's beautiful. I see you smiling behind the scenes here. So for all the junior scientists who are watching now, how beautiful is it to do a PhD and then in longevity to being even dying younger, as Professor Nirbazilai will mention. That gives me the time to introduce Dr. Nir Basilai. He is a leader, I would say the leader in Geoscience at Albert Einstein College of Medicine. He is a professor in the Departments of Medicine and Genetics and the director of the Institutes for Aging Research and the director of several centers on the basic biology of aging as well. He has still time the author of over 350 publications. He is leading the international efforts to approve drugs targeting aging Targeting aging with Metformin. You also might have heard the TAME trial is a specific study conceived by Dr. Bazilai to improve that we can use a single drug and use that to combat multiple diseases associated with aging and get FDA approval for targeting aging itself. That's not all. Dr. Bazilei is the co founder and the president of the Academy for Health and Lifespan Research and on the Board of Directors of afar, the American Federation for Aging Research, where he co leads its biomarkers efforts, TAME and the Superager Initiative. He is an executive of the Longevity Biotech Association. You might have heard of LBA and serves on the council of our HLMs, the Healthy Longevity Medicine Society. He also book Age, Health Span Lifespan and the New Science of Longevity. Nia, as always, it's a pleasure to have you here and I will give you the floor for your presentation.

Thank you very much for this introduction. As I told you Andrea, all I'm hearing is how old I am because all of you will have that much if you stay young for long enough in Particular you Shara. That was a terrific presentation. I'm going to ask Andrea to nominate you. The academy has, is going to have like a fellowship for people like you who have not only a great scientist in, in training, but also have the ability to communicate and, and you'll help us do what I'm going to show you in a second also guys, I'm committed to NUS for many years now, more than a decades. I'm a friend of Yapsen Chang Yudin and I was with him as he conceived bringing the leadership that you have now. And I've been around and let me just tell you that because aging is going to be such a thing, health span, longevity are going to be so important and you're such in the cutting edge in your team and how the government looks at it that we in the United States now are jealous. I don't want to say jealous. We're envious, you know, jealousies we want to take from you. Envious is no, you should have it. But we also want to succeed because as you know, we have a lot of challenges in our research. So with that let me, with that introduction, let me just start and I want to start. I'm going to make some provocation. I hope that I'll be done in 20, 25 minutes. But you know, in our field we're using many terms and those terms are here. But not only we're using those terms, those terms are confusing people are not using. Regeneration is something else for many people. We also have kind of the same mission and vision and we thought, you know what we should reorganize or rethink or rebrand who we are so that we have a better message. And with this message we can come and say hey, we are doing something really important. Maybe you're not realizing that and do the phases where we really go, you know, we go eventually to the WHO and to the United Nation and that we're becoming more influen influential when we don't use all those terms or differences in vision, mission. So the question we had and when I say we, it included Andrea's organization, Healthy Longevity Medicine Society, the Longevity Biotech Association. Afar we asked, you know, what should we call Alsace Self? We ask even if, if we should have a new name, maybe there's something here that's missing and that would be great to come with a new term and pretend that it's new. But that's the future. And for that we got, we got a branding company and realized that doing it with professionals is really Very important because a lot of us think differently but they have an objective way to assess where the wind is, what to do next. And I'll jump just ahead because this is something that they've done and just tell you that no matter who we are and no matter how you adapt it to your organization, the mission is, our purpose is extend global health span. How it's accomplish a rigorous intervention, scientific, rigorous intervention to target the biology of aging. What do we provide? We provide improved quality of life, preventing or delaying onset of age related disease and making healthy who benefits accessible to all. Our ultimate goal in our vision is the future of growing old means living longer in good health where people and families and society thrive through longer health spans. Our vision of success is reduce disease burden and equality access to benefit aging. And how will we get here? By science. And that's what sets us apart. And we want this template to be important for everyone because it took every word here, took a lot of research and a lot of agreement to say, hey, that's who we are. The interesting thing that happened in this process is that the rebranding company by the name, their name was Padilla and we paid them a lot of money and they did a great job. They said look, the best thing that, that that can help branding is when you have an enemy. And they said your enemy is anti aging. Basically it's people like Brian Johnson or all those profits that do research on them and do crazy things and they're important because they, because they, they have attention. But if they are, if they are the anti aging is the enemy. Actually the best word that you could use is geroscience because that's how we distinct ourselves from anti aging but by having science. And this is, this is a very simple, you know, I'm going to stop the, stop this idea here. I'm just going to throw to you because this is a campaign that basically takes geroscience, redefined it and taking it to and it's going to be defined differently to scientists, to the public, to the politicians, to the biotech and pharmaceutical company. Because it's not going to be geroscience alone. It's going to be geroscience and extending your health or geoscience and medicine to stop aging and things like that. So I just wanted to tell you it's part of a revolution, right? It's part of a revolution. But it's going to be important for us to have all those terms and we'll have a slides that will be available that you can modulate and use. I don't want to go over things that are obvious, but in case somebody here hears it for the first time, you know, aging is biology. There's biological and chronological age. This biology, it's what drives diseases. And we can target aging and delay it or reverse it in several way and stop it. And really I think the revolution that we're doing is spending time on our health rather than treating disease. By the way, until today it was maximizing. Okay, but Andrea had the term optimizing, which I adapted because, because, for example, what do you mean maximizing? Do we, do we tell a 90 year old to run the marathon? Maybe not. Every age needs its own optimization. Sometimes it's more, sometimes it's less. So I, I like this term and I think that's, that's really the revolution we're leading. So now I'm going to talk about two different things shortly to kind of make the point of how to die young. And by the way, Andrea, how to die young is, is really not. We don't want to die. We don't, we want to stay young and die very old. That's, that's why. But so a few decades already I'm doing several studies with the population and this is our poster child. Those are four kids that were born between 1910 and 1920, several blocks from where I'm now talking from in New York. And what's unique about them is they all reached over the age of 102. She died at, she died at 102. She was the little sister. The rest were really upset and all the rest leave to 110, 107 and 109. So it exemplify immediately that there are people who reach a really incredible age. And not only that people reach incredible age, but there's a genetic component to them. I actually think that Most people are 100 years old, needs, needs help and needs genetic help. And I'll try to convince you about that. But really the major point I want to make around this research is that they don't only live longer, they live healthier. Here we're taking two studies. The one in black and red is other centenarian study, Tom Perls from New England. And the green and blue is our study. And what we show here is that all our population started, started healthy. Those who are not centenarians start to accumulate diseases. Those are diseases that we could verify after the age of 60 and by the age of 80, maybe 10% of them don't have a disease. Those centenarians have their health span extends by almost 30 years. In our group at age hundred, 30% don't have a disease. Okay? So it's not only that they live longer, they live healthier. At least this population, there's an ability of people to get to 100. There's ability of people to live longer and die, basically. And really, this is really the point here. It's not only living longer and healthier, it's the fact that there is a compression of morbidity. And the interesting thing in those people is they're sick weeks at the end of their life. We're sick years at the end of our life. In fact, the center of Disease Control, which doesn't exist anymore in the United States, looked at the medical cost in the last two years of life of somebody who died at the age of 100, and it's third of those who died at age of 70 and those who were 100 in my study, that when they were 70, they didn't get, they didn't go to the doctor. By the way, this Data is from 1993, and it's been like that until they measured it. So we started talking about this concept that's called longevity dividend. And this concept has grown and I think it's important for you to tell, to tell you guys so that you can defend the concept, because many people are saying, hey, isn't it too, you know, isn't it too expensive to get so many old people? But this is the point that Andrew Scott, who's a professor of economy in London's business school, is saying, okay, so those guys, he says, are not in the hospital, okay, that's the medical cost. But what are they doing? They're traveling, they're shopping, they're building houses for their grandkids. So they're bringing an economical value that is immense. They also own 40% of the economy. So every year that we can delay their aging has a huge, huge medical benefits. So the idea that what we're doing will bankrupt us is really the opposite. Okay? The only solution for us is to make people healthier. Okay, I'll go fast over a major finding. So we had with those guys three hypotheses. One is that it's the environment. You know, they happen to do what we know we have to do now by optimizing our health. Okay? The second is that maybe, maybe they were born with a perfect genome in the sense that we have lots of SNPs that are related to Alzheimer, to diabetes, to cancer, to other diseases. Maybe they just one of 10,000 just don't have that or that they have genes that basically slows their aging or make them resilient to the effect of aging. So as far as the environment, I'll just tell you they were obese. A lot of them were smokers. Physical activity, even moderate, like walking and bicycling in very, very few of them. Vegetarian, very few of them. So the message here is not for you to be fat and smoke, okay? But for them it really didn't matter. You know the woman that I showed you in a picture who died at 110, she smoked for over 95 years. She started smoking since she was 95. When I saw her first, she opened the door and she was smoking at hundred. And I said, helen, nobody told you to stop smoking. And she said, you know, all the four doctors that told me to stop smoking, they died. If so, you know, so they are unique in this thing. Okay? The by the way, it's similar to, to people who lived at their time. We could. And they're either worse or similar to people who lived at their times. Okay, do they have the perfect genome? Again, I'm just giving you a snip because it's a little bit more complicated than that. But when we had a whole genome sequences for our first 44 centenarians, no control, just 44 centenarians, we said what could we do with the data for now, by the way, it was so expensive. What could we do with the data now? There was a database that's called Cleanvar. There is still a database like that in evolution. And at that time they identify 15,000 variants that were pathogenic. When they say pathogenic, it meant you most probably have this disease. So we just ask, maybe our centenarians don't have any of those variants. We were certainly not ready to see that not only they had variant, but everyone, you know, we have over 230 variants. So every one of our centenarians had like between five and seven variants that should have made them sick. And they're at hundred and they're not sick. And if you're asking what are those variants? They're variants that some of the penetrance is incredible. Look, we have centenarians who have APOE4 homozygous for APOE4. They should have been demented at 60 and dead at 80. And they're 100 years old and they're not demented. Okay? And so on. Many, many of those variants. So the point here is that they have something that slows their aging Enough to protect them from the effect of many variants that come at an with an aging disease. By the way, we just to give you a sense of the genetics, so we have the genotype of all this population and we have now over 3,000 people, out of them 850 centenarians. And we have whole exome sequencing of them. And we were looking at rare variants because. Because longevity is rare, right? It's one out of thousand. We looked at variants that are less than 1% difference. And so those are. We're looking at the difference between this variant and doing basically what's called a Manhattan's plot. But I think what we're doing now in genetics, that's better, it's not only the variance, but its association with a certain network because we're not built from one variant at a time. Each one of us have many variants up and downstream important variants. And so it's important to associate it with a network. The one thing we didn't do is to actually look at the literature and see which are more likely to be related to aging because then we're not unbiased anymore. So this, we use the tool, but not in what I'll show you now. Basically, when we did the analysis, the three pathways that came up is what we kind of expected. A new mtor, insulin, IGF signaling, map, kindness signaling pathway. In other words, whatever we knew from animals, whatever we targeted in animals actually was the difference between centenarians and people who are not going to be hundred years old. So just that, you know that aging is really global, by the way, there are specific genes. It's more complicated than, but simply we basically get the same differences genetically that we know are important from all the years. We've done studies in animal, you know, lower models, rodents, monkeys. I want to give just one, one example of the IGF signaling pathway. I'll make it fast because I see that I'm going a little slower than I thought. But in nature, the small dogs live longer, the ponies live longer. When we mutate, either in nematodes or in mice so that we change the expression of hormone, all the dwarf models are really living longer. Even if we measure the major growth hormone that we can there, by the way, there are many growth hormones, okay, there's only one growth hormone, but IGF1 is the growth hormone that is really more most relevant when, when we look at the clinical outcome. So we have centenarians, and those centenarians are going to die at rate of 30% a year. But those with the lowest IGF1 level live twice as much as those who are not. So even when you're centenarians, the level of your growth hormone is important. And I'll just tell you that 60% of our centenarians have some genomic features that inhibit the actions of growth hormone. And I think in order to understand that, we actually went to the UK Biobank where they had 250,000 people who had measurements of IGF1 and the rest of their medical records. And what you simply see here is that it's age dependent. When you are young and you have high IGF1 level, you have low mortality, low dementia, low diabetes, low vascular disease, low osteoporosis. Okay, but when you're old, it flips. When you have high IGF1 level, you have more mortality, dementia, diabetes, vascular disease and osteoporosis. So when you are young, it's important for you to have growth hormone, but when you start breaking down, you need to shift the energy. Okay. You need to deal with a breakdown and it doesn't make sense that you'll invest in growth. And that's really a very important thing that we see in our centenarians. And there's much more of what we found. I'll just tell you then, when we took IGF receptor antibody and treated old mice, they lived longer and they lived much, much healthier. So I would just say about centenarians that we have through afar, a project that's called the Superager initiative, where we're trying to get a much bigger cohort. Two of our finding have been translated into drugs that passed phase three studies. We have much more longevity genes that we're looking at and we want to validate in a bigger group and find all the longevity genes that we could turn into medicine. Okay, I want to now spend few minutes on gerotherapeutics and everybody who's treating, everybody who's a longevity doctor will optimize. Andrea, I change here. Optimize too. Will optimize exercise, diet, sleep and social connectivity. Okay, Supplements needs much more studies because most of the supplements are not being studied like a drug. We don't have outcomes for that. And there are so many other problems that Andrea probably have told you or tell you. And so I don't want to talk about it, but I just want to talk about the possibility of repurposed FDA approved drugs. So what am I talking about? The FDA approved drugs are not drugs that approve to aging because there's no such pathway. The reason. So what we're taking is we're taking data on drugs that were given to animal and showed that the animals live longer and healthier. So it's not all the drugs that are available. It's also already a selection of drugs and we have about 14 of those. And the reason that we think this is important is because FDA drugs first of all need an MD involvement and we do, we want to be responsible. Look, we're going to do great, but we don't want to kill anyone on the road to success. So I think it's important that mds will start at least and any MD can repurpose drug. But mainly if it's an FDA approved drug, there is a safety, okay, it's safe. And you know, exactly, you know, every drug, every drug ever invented is going to save hundred and kill three. We have to get better at choosing the hundred and not killing the three. But, but we have to go on and if we have a safety record, it's going to be easier. Drugs are efficacy and also we have lots of data on them. That's why we're looking at them now. In order to decide if this is likely to be a gerotherapeutic, I suggest we look at two parts. The preclinical part is that they are doing something cellularly to the hallmarks of aging. Okay. And we know it's important because the hallmarks of aging are interactive. You can target one and affect the other. Right. A drug like metformin or rapamycin change all the hallmarks of aging pretty much. So we want to have data that it affects the hallmark of aging. And also we want to show in a clinical trial, in a, in a, in an ITP kind of trial that caused longevity. Okay? So I think we take care of the geroscience here from a clinical perspective. We want to see that the drug that actually was developed for another cause will in clinical study decrease multimorbidities in, in other words, will prevent other diseases of aging. We also want to see that this drug that was developed for another purpose changes not the disease specific mortality, but the overall mortality. And out of those drugs Here there are four drugs that we're quite certain that they get 11 to 12 points that we're quite certain that they could be repurposed and they could be starting to be used in clinical medicine. And Those are the SGLT2, metformin, bisphosphonate and GLP receptor agonist. Specific questions about them I'll say later. I'm going to just finish with some examples. But just to make point that People during COVID It was noticed in nine papers around the world that people on metformin had less hospitalization and death from COVID which led to a clinical study, when I say clinical control study, that showed that if you give metformin within one to three day of COVID it decrease hospitalization, death and long Covid. The point that I'm making is those drugs, you think metformin is changing metabolism? No, but it's changing immunity too. It's also changing the resiliency of the body and inflammation. So. So all of those drugs actually have effects on Covid in some clinical studies. Just to tell you it's not what the specific drug is thought to be doing. It's part of their effect on aging. For example, when you take SGLT2 and you give it to animals, they live longer. This is from the itp. So those are the three centers and this is, is the overall IT work. It works in males but not in females, which is very common in the itp. And just we have to be aware of the fact that drugs are sex specific. Although this in this case, it doesn't work like that in humans. Okay. It's as effective on women. So let me show you an example of another SGLT2 inhibitor. And this SGLT2 inhibitor was developed for diabetes. And when it was given to diabetes, they said, hey, it prevents kidney disease and it prevents liver disease and it also prevents cardiovascular disease. So now they took, they took patients with kidney disease and they gave them the drug and the renal specific outcomes. The cardiovascular outcome and the death of any cause have decreased between 30 and 40% in only 32 months. They started separated quite in the beginning. And this is on 4,000 patients, that half of them are implacebo. There are many other studies like that on SGLT2 giving it to cardiovascular disease and showing that diabetes is prevented or the cardiovascular disease is prevented. But there are tons of clinical studies that suggest that this is a gerotherapeutics. I could go on not only about SGLT2. I could tell you that metformin decrease heart failure, that bisphosphonate decreased cardiovascular disease, that GLP1 decreased renal outcome. I mean, we know that they do other things and the same in mortality. SGLT2 decrease overall mortality. Metformin decreased mortality of people with embolism, Biphosphonate decreased mortality in ICU, GLP 43% mortality. And so we are accumulating this data. There's so many data that we can do better. And I'll show you what we're doing. But listen, those drugs can be repurposed. It's legal, okay? Metformin was repurposed first for obesity. There are much better drugs than that. But people on metformin usually lose some weight. It's the first drug of choice for pcos. It's the first drug of choice for prediabetes. It's now the first drug of choice in the United States for people who get Covid. And it's now a drug that often used for macular degeneration. So why not for aging? So our challenge is to take all those studies, okay, for the four drugs and say, hey, how are we, how are we trying to implement it? And there are many considerations here because in a way, first of all, let's take out people less than 50, okay? Because all the studies have started in people over the age of 50. Usually actually their age is 60, 70. So let's take them out and look at it more as a secondary prevention. People that already start aging but not getting disease or even they have one disease and decide what are we going to protect them against? Okay, this is what I'm showing you is not true. It's, it's not done. It's just an effort to do that. But maybe we'll have a patient will decide that what age we're going to do it. And we'll have a patient and depending on its clinical features and risk, will decide which drug we're going to give them. I just want to say that based on that, we have the FAST initiative, what Andrea said, the biomarker initiative of AFAR that now goes to ARPA H where basically we're going to take clinical studies that ended with those four drugs and more rapamycin 2, and do omics on all of them them, okay? And basically every one of those drugs will do something in the omics, proteomics, metabolomics, everything, everything. But whatever they do specifically, they're all going to affect aging. And those will be the biomarkers that we need. Because it's not only that what tells you your biological age. It's biomarkers that change within in a short time because you want to have patients in your clinic that in three months you can show them you became younger. Okay? That's the idea. And so this is, if the timeline holds, it's 18 months away where we have biomarkers that can tell you what it is. And also for biotech, biotech needing a phase two study to see that actually they're going the right direction before they spend billion of dollars On a phase three study study. I just want to end and not forget that it's not only about the elderly, okay? People who survive cancer are aging. If we give them chemotherapy and radiation. Kids get heart disease, women after breast cancer, some of them are really aging fast. HIV gets disease 10 years before their cohort. Down syndrome is something that we need to treat disabilities. You know, people on wheelchairs are not exercising and not dieting. So that's a thing. Actually globally, for example, if we want to go to Mars, we're not going to Mars before we solve aging, okay? We're not getting there healthy or returning at all. In agriculture, the aging of fruits and vegetables are really something that is being researched because we need a bigger shelf life, especially with global warming on fresh and vegetables. So there's a lot of reasons to do our research. And remember this concept of longevity dividend. Look, metformin is the cheapest drug in the formulary in Singapore and around the world. It's no cost and will probably increase healthspan by many years. Okay, but there are other treatments that are expensive and maybe initially. But remember when healthcare providers are looking at how much longer people stay healthy, they'll be ready to pay also for maybe more expensive drugs. It will be a really good analysis for them to do and maybe even very expensive drug makes sense for healthcare providers to do just in order to have less hospitals or decrease times at the doctors. So I want to. I'm aware of the 33 minutes that I spoke. I want to again thank you guys. Thank you for inviting me. It's very exciting to talk to your group there and I'll stop my sharing here.

Thank you so much. Nia, it's always a pleasure listening to you. Near first, a a question maybe many of the audiences have. Should I choose my partner based on the genome of the family history? So how many centenarians should I actually have in the family?

Yes. So if I knew that my mother in law is going to be 100 years old, I wouldn't marry my wife. But it would be mistake. It would be a mistake. So I by the way 23andMe has some of the longevity genes. I actually found that I have one of those IGF genes myself. But and another interesting thing again, there are centenarians who come to me and say what is there for me? And I'm like thinking you're it. You know, I don't have anything for you. The whole, the whole reason to do the research is not only to have your information but really for drug development. Right? Because once we go and really show that this affects cellular aging and that we give it to animals, they do something and it goes to pharmaceuticals and they develop drug. We have just another tool for the people who don't have these genetics. Okay, so that's what we to.

So. But you said that there are already two drugs based on the research you did with the centenarians. Can you, can you tell us which drugs these. These are?

Yes, yes. Early on we saw I showed data of Rare genotype below 1%. But when we started, there was a striking phenotype to the families of centenarians. By the way, we have not only their, the offspring, but we have their. Not only the centenarians, but we have their offspring. And they're longitudinally being studied. Okay, 1400 people and I'll tell you, we're doing it for 10 years. And the offspring of centenarians have half of the cardiovascular disease, half of the cognitive decline and half of the mortality compared to the people that they're living with their spouse, basically. So, so this is also apply, but where was I going?

Which two drugs?

So the phenotype that we saw was very high HDL level, sometimes 150 HDL level and very low triglycerides. And there were two functional genotypes that changed. One was an APO C3 and the second is CTP. Is CTP. Both were inhibitory. Now the CTP inhibitor was developed by Pfizer but stopped because the drug was. Was bad drug. And Merck actually developed a CTP inhibitor based in part of our studies. We think it's going to be important for cognitive function. They haven't tested it or they tested it on a young population so they didn't have tools to test it. And the APO C3 was developed by a company that was called iCist. They had to change the name. They're Ionis. And those drugs went over phase three trial. But remember, those drugs have designed for lipid, not for age. There is an abstract that CTP inhibitor actually prevents cognitive decline, but it hasn't been published yet.

Great, great. Thank you. Let us talk about tame. I think that many are curious when TAME is starting or not starting. I already said in the introduction, you conceive, so who is giving birth to it?

Yeah, exactly. That's why conceive is important. Look, first of all, let me just tell you TAME is about the fda, okay? TAME was about the fda. We designed TAME because we have enough data to know that the results that we expect will, will be significant. Okay. As I Said anybody. Metformin is also already being used for longevity and many other remedies. Right. So it's for the fda. Few things have happened since some of that are funding. You know, pharmaceuticals are not funding TAME because they have nothing to gain. The government was ready to do the biomarker part, but not the TAME itself. We had a billionaire that was going to fund it and he lost his money and then covet start and we said, oh, we are lucky that we're not doing time at time of COVID although retrospectively we would have saved maybe lots of people. Then evolution came and kind of regressed about that. So we have enough money to do some version of tame, but we're waiting because ARPA H might do it and also Lilly might do a TAME like study with one of those MPICs. So the template is there and I believe it will happen. But again, it doesn't mean that we cannot start using those tools because in our world of getting drug out, it's a very linear timeline. We're not going to accelerate anything. We have to do things. In part.

Yeah, I agree with you. So it really built the blueprint, so the framework how to do the trials. So now the question is, should we do it with GLP1 agonist or SGLT2 inhibitors, et cetera? So that's the question. But thank you so much really for building that framework. Also here during the webinars, we very often have discussions about how much evidence do we actually need to use these kind of drugs, drugs where we have a good understanding about their safety and risk profiles to give them in health, longevity, medicine, clinical practices. So how much of label should we actually give and how much research we do to give it them on label? If we are in good conversations with the fda, can I have your opinion around that?

Well, Andrea, we're working together on this on those two issues. And it's kind of. It's kind of a consensus building around it. But those four drugs that I showed, there are more drugs. And by the way, there are drugs that have changed mortality in humans, but they didn't come from the animals. Okay. Brian has several drugs like that. So those drugs, I feel they've done better than TAME because TAME is changing cluster of disease. We didn't want the study to stop because there's a cardiovascular effect or kidney effect. Right. We wanted the cluster to show that all of aging change. Those drugs actually had clinical studies that had the power to show effects on several outcomes. So I feel very strongly that the whole evidence that their gerotherapeutic is out there, tested by thousands and thousands of people. Their results are incredibly, they're clinically significant, not only statistical significant. And so we should move on and we have to be maybe in gero medicine, we have to have some, some papers that leading to the thought and to encourage how people in longevity should start using them more aggressively. I would say.

Yeah. And hopefully with the registry because there might be of course the effect of age or a risk stratifier. So you might know of the studies of metformin that if you are giving it to young animals but also to younger individuals and you are exercising them, that might actually have a negative effect on the musculoskeletal system. So what's your thought about the risk mitigation when somebody should use a certain drug?

Right. I think what we're going to do, we're going to have different drugs and then find the personal medicine experience and what's good for what people. Look, look, we have a problem that you learn from the X prize. Really The X prize said, okay, immunity, cognition and muscle. A lot of the drugs that we're using are not good for the muscle or I should be careful. They might be good for the muscle, but not if you check muscle volume. Okay. They're not going to increase muscle volume. Metformin and rapamycin are not going to increase muscle volume because they're MTOR inhibitors. But they actually Metformin. We did a study like that change the biology of muscles. So the muscle can do is smaller but can do more. But we are stuck with the fact that it depends where we do. We have trade offs and so we have to play around the trade offs, maybe use several drugs or as you said, if it's bad for the muscle, then we have to exercise more. Right. Or something like that. But we have to. But this is a challenge that we have and we'll have to manage that and learn as we go. Register.

Yeah, registry. That's what we need. I really want to go to Shara because there are many questions from the audience. Nir, if you can please close this session with the answer to one question. What you would advise youngsters to do now and if they should, should actually enter the longevity field. But first, over to Shara.

Hi, thank you Prof. Andrea and Prof. Nia for such an insightful and engaging talk. We've received a number of great questions from the audience and I think I'll begin with a very fundamental question. What in your opinion is still considered young? And I think this is most relevant because People are thinking about taking some of these drugs and perhaps you could advise at what age they can take ju. Protective drugs, for example, like petformin and stuff.

Stuff.

I, I was hoping for this question because I get it a lot. I realize it started with Peter Attia, who took, is very influential, and he took metformin in his 40s and exercise and, and you have to understand that we have this concept of our antagonistic pleiotrophy. Things that are good for you when you're young are not good for you when you're old. But it's also the opposite. Things that are good for you when you're old are not good for you when you're young. Young, right. So for example, I said IGF1 is really good when you're young, but it's really bad when you're old. If you look at variety of outcomes and death, metformin actually lowers IGF1. Okay? So it's good when you're old, but if you're young and you're doing it, it's kind of silly, right? Because IGF1 is good for you, especially when you're exercising. If you're measuring VO2 max. And by the way, VO2 max is a provocative test. We're not, we're not doing VO2 max in our life. We, we exercise and we don't do VO2 max. But if you take Metformin, Metformin is going to lower your VO2 max. Okay? That's how it works. Inhibits, you know, the mitochondria, right. The, the complex 4 in the item in the mitochondria. So, so it's not good when you're exercising and, and you're young. So I. Now that's metformin. I don't know for all of those drugs how good they are when you're young, but I'm thinking that before the age of 50, you probably should optimize the other things. And all the studies of the drugs that I told you were on people over the age of 50 and many of them much later. So I think this is the audience where we are thinking of starting those drugs and if those drugs are good at all for younger people, I'm not sure. I think maybe, and I think some of them will be, will be good, but not all of them.

Okay, thank you very much for that question. I think there were a lot of audiences who are interested in these genes that delay aging and all. And I think one of our audience want to ask, in your experience, did you find that the genes that delay aging and those that have been shown to protect from age related disease. Are they one and the same or if there's any difference, how do you distinguish between these two?

So, so let, let me just say so sometimes we have statistical significant difference between centenarians and not right. But the numbers that we have are not large because we are, we have hundreds of people and now genetic studies are on tens of thousands of people. That's why we need to have more. But we found a way to overcome human here to overcome that. We have this program project where we're making the genetic discovery and we're passing it to Yu Shin Su who's a, a great investigator. I don't know if she was here but, but you should invite her. And Yushinsu has a whole lab that express express the mutated genes in cells, in variety of cells. And see first of all are they resilient? If she puts them in radiation or in hydrogen peroxide, are they better cells? Also what is exactly their action? And once we understand more about what is this mutation, if it's really relevant to our aging, it goes to Laura Niederhofer, another great person who's going to set a genetic model of a mice to see if they're doing better and then to Paul Robbins who is going to develop drugs for that. And we have several successes in that. So what I'm telling you there is a way to move forward with information about the genes even if you don't have the population studies that understand exactly who and what and how come and of them by the way, some of what we're finding is just false positive. You know we have 12 incentenarians and two in, in normal. So it's low numbers anyhow. So 12, two can be, you know, in the next 100 you can be equal 100 people. Right. So we, so we need to go and find on a cellular level if we're talking about something important and, and, and that's a way to go about it.

All right, thank you so much. I think there are also quite a few audience that are wondering are they missing this centenarian resilient genes and stuff like that. So I think maybe the next question because you mentioned about personalized medicine, I think the question would be how soon do you think we can implement a gene sequencing as part of the pipeline to know if we have these centenarian resilience genes.

So I kind of said before, I mean 23andMe has folded but. But I think there are other companies who are collecting Important information in the genome. They had from the start they had those longevity genes in their panel and as I said, I, I discovered, discovered that I have one of them. So I, I think it can be commercially available. But remember, a lot of the genome has, a lot of the genotypes have low predictive value. Okay. Because again, they're interacting with SNPs upstream and downstream and it's different in populations. So I, I don't think they have enough predictive value now, but they probably will have predictive value as we have more medicine and maybe it will understand better the pathway and say, oh, this drug is maybe better for you. But I think now the information, I mean, it's good to be curious and I want all the information about myself, but I'm not sure there's a practical thing that is necessary now. But by the way, this is for those longevity genes. You know, there's a lot of clinical, very important clinical information in genetics. Okay. Besides it. But I'm saying for those longevity, I think it's a little premature.

All right, thank you. And I think because you also spend quite a bit of time talking about the drug, repurposing drugs for general therapeutics. I think one of the audience asked whether using FDA approved drugs is not a very safe and safe approach or, or what do you think about pushing the boundaries with more bold, novel therapeutics. That's something that is in the pipeline for you in the future.

Look there, there are a lot of drugs that are developing by biotech and they'll go through the phase one, phase two. I want to be here. Look, I'm doing biology of aging. My colleagues are, are lab people. A lot of them are lab people and they see that they give eight mice something and they do better and they say, oh, we should all take it now. Okay? And that's absolutely wrong. In medical school, in the first year, in the first day of medical school, they teach us to do no harm. Primum no notre. Okay? So we are really conservative, okay? Half of us will not give you Tylenol for headache because one out of 100,000, it affects the liver. Okay? The second day of medical school. There's no always a no, never in medicine, okay? As I said, those Drugs will save 100 and kill three, right? We now see that they don't want any Covid vaccination research because there's some side effects. But in the meanwhile it saved 60 million people. Right? So, but the point is that I am among physician, I'm maybe the less conservative, but I really Think that we should be careful in how we go on and not kill anyone on the road to success and just do it steadily as fast as we can and not do things that are crazy that, that can jeopardize our all effort. I, I always say my problem with Brian Johnson is that if he dies people will say Brian Johnson didn't make it. Why do you think you can make it? And I want to have it out there. No, I told you he's doing stupid things and you know, dangerous things. Again, the FDA approved drug have passed safety.

Okay.

We know more about them than any supplement. Okay. By volumes.

All right, thank you so much. I think we can end off the Q and A today with maybe a one short question. I think this was something that Andrea also asked just now. What would you tell young longevity scientists who wants to maybe optimize their health span today? What advice could you give us?

First of all, they're already doing fine because I think they're in a safe area of research. Okay. I think think aging research will grow, has to grow. There's going to be pressures from everywhere and we feel that even in, in the United States where science is suffering now actually aging is going on and, and probably with much more money that we, we had before. I think everybody understand the economical benefits and, and of course if you have a life that has a vision, that has growth and safety, it's good. Like if you're in vaccine, I would say you're going to get depressed and you should start Prozac or some, or something. So I, I think that's very important as far as health for young people. Again I, I think it's mainly optimize exercise, diet, sleep and, and, and, and social connectivity maintenance. Now social connectivity I think is less of a problem with scientists. Not all, but less of a scientist. I visited you guys. I think you're all talking with each other. Sleep for young people is binging on television and not going to sleep. Okay. So you have to go to sleep and find with, with elderly it's different. It's that they cannot, they cannot fall asleep or stay asleep. Right, Right. For diet, I think the, the point is that there are many, many diets and you have to find the right one for you. Okay. It, it's not a fit all. A lot of vegetarians are compensating less protein by more carbohydrate and they become obese and then they lose the benefits. Okay. For example, so you have to decide if it's for you or not. And for exercise there's lots of advices but don't give up on any part of your muscle. You know, do everything and flexibility. But flexibility is more for the elderly. Needs more but flexibility too.

Thank you so much.

Okay. Thank you so much. Nia. I think we have to ask you back to discuss our physical exercise regimes and the diet regimes, et cetera etc. Thank you so much Nia. It was wonderful to have you again on the on the show. We absolutely will stay in touch and thank you for all your contributions to nus.

Thank you. And to you too and it was fun. Thank you and thanks for the questions. They were great.

Thank you. You as an audience. You already gave lots of questions. We really want to hear from you your comments. What do you think about our new intro video? We really want to make this show most fun for for you. I will leave you with three messages. The first message is that we have a conference in February 2026. It is the NUS Academy for Health and Longevity Intensive course and conference. What we are going to do, it's a one week of full events, three days of an intense extensive course where we are going to teach what geoscience is, what gerodiagnostics are and gerotherapeutics especially these courses are for healthcare professionals, not only physicians, but especially also for allied health, for health coaches, etc. Then on the Thursday and Friday of that last week of February we will have the conference especially focusing on the use of nutraceutical and repurposed rugs. So Nir, we are going to invite you. Of course both events are CME accredited. Then the second one I would like to highlight and focus on is the Halo white paper. As you might have heard, we are surveying around the world getting a better understanding about the perceptions on knowledge regarding health span and lifespan and the individual interest in healthy longevity medicine clinics. We now summarize the first results out of Singapore and we showcase that the interest in healthy longevity medicine is huge. It's high. Therewith we give recommendations what to do next, what the steps could do especially for Singapore to optimize the health of the public. Then the third thing I want you to remind is the webinar format. As you have seen today, the webinar format changed a little bit. We also changed the frequencies how often we have the webinars. Now it will be the first and the third Thursday of each month at again as always 7pm the next Healthy Longevity webinar will be on the 21st of August this year, 2025 and this time with Professor Michael Chi. And he, of course, will talk about sleep. Sleep, sleep, sleep, sleep, sleep. As we age, what do we know? For you, I only have one message, and that's stay young, die very old, and take care. Clinical trials are aimed at optimizing health and maximizing potential. Welcome to our new clinic. Come in,

Sam.