REVERSE AGING: What To Eat & When To Eat For LONGEVITY | David Sinclair

1. 0:00 – 1:41

   Hormesis and why modern comfort speeds aging

   1. DSDavid Sinclair0:00

      This is probably the most effective diet that's ever been promoted on the planet. This protects our body against decay, disease, and the root causes of aging. It's not only good for you, but will make you live longer. [upbeat music]

   2. RCDr. Rangan Chatterjee0:16

      A central theme when I, when I think about your work and your research, for me, it's this idea of hormesis and the survival signals we put on the body. And I wonder if at the start of this conversation, you could outline what hormesis is a- and why it's so important when we come to think about aging.

   3. DSDavid Sinclair0:38

      Well, the, the problem is we've built a world that's, that's very comfortable, and we were not, we did not evolve in these conditions. We are meant to be typically, uh, cold and hungry. And in response to those adversities, our bodies fight back. And so what ... The pr- the problem is that we now sit in chairs, we eat as much food as we want, we don't have to walk anywhere or lift anything heavy, and our bodies become complacent. Now, what was discovered is you need hormesis. What's that? That basically means the, what doesn't kill you makes you stronger. Um, and so what we do when we exercise and when, if we skip a meal, what we're doing is inducing this very ancient, very, very ancient, billions of years ancient mechanism that protects our body against decay, disease, uh, and the root causes of aging in an effort to survive. Uh, and so you really wanna do the opposite of what modern life gives you.

   4. RCDr. Rangan Chatterjee1:40

      Yeah.

2. 1:41 – 3:56

   Why eating less activates longevity genes

   1. RCDr. Rangan Chatterjee1:41

      One of the things that you recommend, I guess one of the most easy to understand and simplest interventions you recommend for people is to eat less, and I think that fits quite peacefully into this, uh, idea of hormesis, doesn't it, in terms of what eating less signals to the body and then what it causes the body to do afterwards. So I wonder if we could just sort of dive in there into why is eating less important, what signal does it give us, and then how does that impact the way in which we age?

   2. DSDavid Sinclair2:17

      Well, there, there are three main longevity mechanisms that we know of. Um, they have certain names. One's called sirtuins. There's seven of those genes in our body, and we've been working on them for 25 years. Another one's called mTOR. The other one's called AMPK. The names don't matter as much as the fact that they're activated by, by a bit of hunger. Um, to give you an example, in 2005, we, we published a science paper that showed, um... Which at the time was revolutionary, now it's just considered obvious. But one of these sirtuin genes called SIRT1 was activated by caloric restrictions. So we found that animals that had been eating less and had low levels in, of insulin and another factor that's related called IGF-1 insulin-related growth factor, um, that boosted the levels dramatically of this SIRT1 protective longevity gene. Uh, and then we showed that protects against DNA damage. Uh, and so what we do when we're hungry, uh, skip a meal or two, which is what I do every day, uh, it boosts up our longevity genes, and they take care of us. Uh, we know that if we boost the longevity genes in animals, they live longer, they're healthier, they stay fitter for longer, and they die much quicker at the end of life. And, you know, I think everybody would know that in, in human history, fasting is considered one of the healthiest things you can do. Um, and so there, there's so much evidence that it's really incontrovertible that skipping meals is not only good for you, but will make you live longer.

3. 3:56 – 12:58

   Practical fasting: when to eat and how to start

   1. RCDr. Rangan Chatterjee3:56

      There's many ways, of course, to skip meals. Uh, you know, how do you view fasting? Because there's, you know, all different types of intermittent fasting, uh, protocols out there. Uh, there is time restricted eating, which I know, uh, Satchin Panda has done a lot of the research on at the Salk Institute. And, you know, I think it's quite a confusing area for people coming to it fresh. Specifically through your lens of looking at longevity and how to delay or even prevent aging or, well, we'll come to it later, even reverse aging, you know, how do you look at foods, um, and how we can practically, you know, do this in our own lives?

   2. DSDavid Sinclair4:42

      Yeah. Well, there, there was an incredible study that, um, was out of the NIH, uh, in Bethesda. A, a good friend of mine, Rafael de Cabo, in his lab had over 10,000 mice. They put them on different diets, different carbs, protein, fat. And they, they then divided those diets into two groups. Some mice got food all the time, and they nibbled on it during the day. And then the others got the meal once, I think it was for an hour only, and those mice gorged themselves and, and ate almost as much as the ones that were grazing. And it didn't matter what the food was, it was the ones that ate in that window that lived dramatically longer. So if you can extrapolate, and there's always caveats, but I think the principle still holds in ourselves, which is it's not as much about what you're eating, but when you're eating. And it is confusing because first of all, we're all different. We have different levels of willpower. We have different jobs. Some of us are hungry in the morning, some are hungry at night. Um, some of us can go for three days. I can't, but some people can. Some can go for just a f- you know, a morning. Plus we're all genetically different. We all have different microbiomes and food preferences. So it is complicated, but I, I found it relatively simple to explain it this way If you are not starving at breakfast and you prefer dinner, skip breakfast. And if you can do without dinner, skip dinner. But skip one of those two because then you have a whole period of sleep that, uh, means you're fasting and your body will protect itself and repair itself better. Now, you can take it one step further if you're game, uh, and that's what I did over the last, um, 18 months during the pandemic, was to also, as best I can, skip lunch as well. So I go all day without eating, with a tiny little bit of yogurt in the morning to dissolve a supplement. But essentially I'm just... Here I'm holding a glass of water. I'll have tea, I'll have coffee, that'll keep me full. Um, and I go till dinner, and at dinner I have a, a reasonable meal. I'll, I'll go out to a restaurant and I'll eat something and try not to be full. I don't stuff myself 'cause I'll actually sleep poorly. Um, but I, I l- I really enjoy that. And first of all, it saves money. Second of all, it makes you enjoy food a lot more. And third, there's a misconception that you'll feel tired. It's totally wrong. If you can get through three to four weeks of that with some willpower and, uh, and a bit of, uh, hot beverage, a few hot beverages, you'll actually get-- Your body will get accustomed to it to the point where eating lunch feels weird, and you definitely don't need it and you definitely don't feel tired. And I don't get that afternoon slump, which I know is caused by, uh, a, a decrease in insulin after a lunchtime meal. And I've never felt better, I've never looked better, I've never had so much energy physically and mentally.

   3. RCDr. Rangan Chatterjee7:43

      It, it's fascinating when we think about this through an evolutionary lens that, you know, of course, why, why would we be struggling mentally when we were hungry? Because of course, if we really were hungry in the past, we would need our, uh, you know, our mental acuity right as, as good as it could be to go and actually fix that problem, get out there, find some food, hunt. So it, it really makes sense. But it also, it also makes me think of what you said right at the start of our conversation about modern life being too comfortable because, you know, I'm in my early 40s. I remember from a young age, you know, even though I'm from an Indian family, I saw my mum practice various forms of fasting once or twice a week, but we never did. You know, for us it was, "Get up as soon as you're up, eat your breakfast." You know, eat, eat, eat, was the message I got as a kid. And I think that's the message a lot of society gets. So when you talk about eating less or reducing how often you eat could potentially give you short-term health benefits, but also long-term health benefits and delay aging, I think it's quite revolutionary for a lot of people to hear these days.

   4. DSDavid Sinclair8:57

      Well, intermittent fasting now is the most popular diet in the world, and it, uh... Hopefully it's not a fad because this is probably the most effective diet that's ever been promoted in the, on the planet. Um, even for children. I'm not suggesting malnutrition or starvation by any means. But having three meals a day plus snacks, uh, is a calorie overload for, even for children in most cases. And you can tell just by the amount of fat a kid is carrying as to whether you're overfeeding your kid. And if you're, if you have an obese child, and I know it's very difficult because in my family we struggle with this as well, but the effects o- on that child will echo for decades. Perhaps even towards the end of life, they will still have the memory, the epigenetic memory we call it, of having been obese as a child. And so one area that I'm researching and going to be communicating about is the effects of our lifestyle, not just on adults and the elderly, but even on children.

   5. RCDr. Rangan Chatterjee10:03

      Yeah. I wanna come back to that shortly. Um, b- before we leave the topic of eating less, you said intermittent fasting is the most popular diet or way of eating in the world now, and, you know, there's brand new blog posts, podcasts, YouTube videos every day coming out on this. Um, do you think of intermittent fasting as different to time-restricted eating? And, and the reason I'm sort of diving in here is, you know, when I see patients, I have to be very clear with what I'm asking them to do, you know, very specific so they really understand what I'm recommending. And I think for some people, intermittent fasting is one meal a day, for some people it's, you know, 16 hours without eating and 8 hours a day where I'm consuming food. Then you also have time-restricted eating, where it's eat all your food within an 8-hour window or a 10-hour window or a 12-hour window. And I think there is a little bit of confusion out there as to what these terms actually mean. So how do you put that together for people, uh, if they're asking?

   6. DSDavid Sinclair11:10

      Oh, I, I, I don't think that it's helpful to have these, all these different names. It's essentially just eat less often. That's how simple it is. Skip a meal, skip the snacks. Um, so intermittent fasting, time-restricted eating, uh, to me it's all the same thing. It's just, uh, don't keep your body filled with food. That's pretty simple. Um, the amount of hours, the more you can spread it out, so 18 for me is, is a good, good number. Um, 16's okay. Um, you know, I, I eat within two hours so I, I get basically 22 hours, which works for me. Um, but here's the, the, the really important point. Um, it's not complicated. You do what you can. You start skipping meals. Start with one, dinner or breakfast. And then if you can do that, then try to go longer. Um, it's not... The, the other really important thing is if you try to do what I do- From a standing start, you will fail. There's no question. It's too hard. Your body will freak out. It'll feel tired. Your brain will be distracted, uh, and you'll go straight to the fridge. You need to give yourself time. Y- it can take a month to get there, and one of the adaptations is your liver needs to learn to put out glucose to maintain steady levels so it's not like this through the day. And, and that takes a, takes a while. Uh, but once you're at the state that I'm in and your microbiome is optimized and your liver is very happy with its existence, then you, you will find it very hard to go back to eating the old way. Um, and you also generally look a lot better as well, which is a nice side effect.

4. 12:58 – 18:05

   Why survival genes exist and the three longevity pathways

   1. RCDr. Rangan Chatterjee12:58

      You've mentioned the term longevity gene a couple times so far, and it's quite an interesting concept to think about because why would we, on an evolutionary basis, needed a longevity gene? You know, it seems to be slightly at odds with how many of us look at the past. Um, so I'm, I'm just interested as to, you know, what's going on there. What, why does nature, why has nature put within us these genes that potentially promote longevity when that really wasn't the goal of evolution, certainly from my understanding?

   2. DSDavid Sinclair13:35

      Yeah, that's right. Um, evolution doesn't care about the elderly. Once you've raised your kids, you're pretty much expendable, with the exception of, uh, my grandmother. But the, uh, the, the real point is that these are really survival genes. These are adversity genes that have kept life forms alive ever since there was life on this planet. And the sirtuins that I work on are found in everything, even a yeast cell and bacteria. Uh, and so the... Think of them as survival, but if you keep your survival genes on for most of your life, the side effect is you don't get sick and you don't get aging as fast, and then you live longer.

   3. RCDr. Rangan Chatterjee14:16

      There are these three pathways that you have sort of briefly touched on so far, sirtuins, mTOR, and AMPK, that we are, I think, trying to influence with various things, whether it be drugs, whether it be lifestyle practices. Could you explain sort of bit by bit what they each are, a bit of the history of how you came to discover them, and then I guess where that sort of fits in as to the recommendations you make?

   4. DSDavid Sinclair14:44

      Right. Well, there are nine known causes of aging. There's a, there's a lot of them. I won't list them all. What controls those processes are these three main longevity pathways. So sirtuins do a lot of things. They protect the cell from damage. They repair things. They reduce inflammation, um, even boost memory. So they're, they're very, very important for long-term health, and they are, they are boosted by a molecule called NAD. And so we've been, uh, adding an- NMN, which is a precursor to NAD, to the water supply of mice for many years, uh, and they're healthier and they live longer. The other s- let's call another central pathway is called mTOR, little M, capital T-O-R. And it has, uh, evolved to sense protein intake primarily, amino acids. And so w- when you eat a lot of meat and a lot of, uh, particularly branched-chain amino acids they're called, that are in meat, you, uh, will stimulate this mTOR. Now, the problem is mTOR is a signal for growth rather than survival. And so that's why if you eat a lot, a lot of meat, you're not actually going, in my view, to stimulate your longevity. The other way around when you're fasting and you don't have a lot of amino acids coming into your stomach, then mTOR will be shut down, and that's a hunker down survival mechanism. Uh, and there's a drug called rapamycin that currently is used for immunosuppression, but in low doses it inhibits mTOR and extends the lifespan of just about every organism that it's been fed to, and there are some people taking it for longevity. Then the third pillar is called AMPK, and AMPK registers the amount of energy in the body, uh, sugar for example. And when its l- sugar levels are low and insulin levels are low, then AMPK will be boosted in, into, uh, activity, boosted activity, and then the result is more mitochondria and less inflammation. So you want more sirtuins, less mTOR, and more MP- AMPK. Now, the AMPK is interesting. You can take a drug called metformin, which will boost AMPK. Now, metformin in the West is, uh, UK and in, um, America is, uh, prescription only. It's not true for most of the world. Uh, but there are people who are taking it instead of for type 2 diabetes, which is what it's normally prescribed for, to lower blood sugar, just to take it as a preventative measure. But what's interesting is that there are tens of thousands of people that have been looked at, and they also have lower risk of other diseases when they take metformin: cancer, heart disease, Alzheimer's, frailty. And it's a fact that people that take metformin daily have longer lives than those that don't even take the drug or have type 2 diabetes. Um, and so together we've got those three levers that we can pull, um, along with exercise and, and intermittent fasting, um, that we think will greatly lengthen our lives by fifteen, twenty years or even more.

5. 18:05 – 24:43

   Aging as the root cause and the future of medicine

   1. RCDr. Rangan Chatterjee18:05

      As I was reading your book and as I, as I study your work, um, I, I saw a parallel in thinking in terms of What I found in my own career as a medical doctor, so you know, I've been seeing patients now for just over 20 years, and I can't remember when, but somewhere along the line, I remember thinking, "Why are we looking at all these things as separate diseases?" There's hypertension, heart disease, you know, uh, cerebrovascular disease, and we- we're very much trained to see them differently with potentially different protocols for treatment. And then the more I sort of studied as to what is going on upstream from these things, the more you think, well, actually, you know, chronic unresolved inflammation is playing a big role in all of these, uh, different conditions. Uh, insulin resistance is playing a big role in all of these conditions. And I found more and more that when I tackle these root causes with my patients, let's say inflammation and, um, insulin resistance and help them become more insulin sensitive, actually they all start to get better, right? And, and I find that instead of seeing them differently, actually I could focus on the root cause. And I, I know in your... Early on in the book, you write about these different hallmarks of aging, whether, as you've already mentioned, mitochondria not working so well or telomeres shortening, um, or DNA being damaged. But then you went one step further, go, "Well, what's upstream from these?" And is it... Uh, as I hear you talk about sirtuins, mTOR, AP- AMPK and the benefits, forget longevity for a minute, just the benefits in energy or memory and focus, I think, well, presumably... Well, is it fair to say there's a, you know, that sort of way of thinking is similar? Do you think that's accurate? And then the natural extension for me is if we are going this far upstream to delay and prevent aging, then presumably as well as doing that, we are going to improve people's vitality and their quality of life 'cause all kinds of other things are gonna get better as well.

   2. DSDavid Sinclair20:25

      Yeah. Well, so modern medicine, as we call it, uh, it needs an overhaul. It's very, uh, 19th century, where we've been classifying diseases based on how they look at the end of the process.

   3. RCDr. Rangan Chatterjee20:37

      Yeah.

   4. DSDavid Sinclair20:37

      The, the real underlying process is aging for most diseases that, that kill people in, uh, in, in fact, most of the world, and we've been ignoring the root cause of these diseases. It's, it, it's like in physics when you've got the periodic table and then in the early 20th century, it was figured out that the same particles are within each of those atoms, and so they're all made up of the same stuff, and that's a huge breakthrough. And the same with medicine and, and disease. We've realized that there's one unifying underlying cause for most disease and disability on the planet that we've literally been ignoring for hundreds of years. And I wrote the book Lifespan to wake people up to realize that it's not good enough to stick Band-Aids on a disease after it's occurred because it's often too late. We need to get ahead of it and address the root causes of aging itself. And the... One of the, the things that I like to say because I believe it, uh, and it's also important that we move towards this as a society, and that is that aging is a medical condition. Admittedly, it's, it's common, but just because something's common doesn't mean it shouldn't be a medical condition. And if that definition was made formal or formalized by the governments around the world, then doctors like yourself could more freely prescribe very cheap and relatively safe medicines that could extend someone's life and make them healthier for five or even 10 years longer. But we still have to-- We're still at an early stage where most doctors have not even conceived that aging is something worth talking to their patients about or that it's even malleable.

   5. RCDr. Rangan Chatterjee22:27

      Yeah. It's very powerful. Um, I, I would like to think of myself as a quite a modern progressive doctor who stays on top of things, uh, trying to look for the root cause of a lot of my patients' problems rather than putting Band-Aids on. But I've got to be honest, you know, when was the last time I spoke to one of my patients about aging, specifically about aging? You know, I'm not, I'm not sure. I, I'm not sure I can remember in the, in the recent past when, when that would have been. I may have said something like, "We know that strength training, uh, some research has shown that that can help reverse the aging process," but the focus wasn't really on aging. So yeah, w- w- I think that just speaks to how groundbreaking the work you're, you know, talking about and presenting to the world, I think it really just speaks to how important and how cutting edge this work is.

   6. DSDavid Sinclair23:25

      Well, let... Yeah. I, I agree and, and let me paint a picture of what the, the world should, should be like in my view. That you go to your d... Well, first of all, a week before you go to your doctor, you have a stick-on patch that's disposable and it will monitor you a thousand times a second for, uh, all sorts of measures, movement, speech, heart, EKG for your heart, uh, temperature, uh, motion, depression. Uh, and that data will be fed into the doctor's, uh, computers and by the time you get there a week later, there will be a body of data that the doctor can look at and see if there's anything potentially wrong. You'll also be given a mouth swab at home to send in, and by the time you get to the doctor's office you will be told your biological age, and some people are 10 years older than their actual age and some are 10 years younger. And those that are 10 years older, I would hope that the doctor could sit the person down or- Give them a chat and say, "You know, you haven't led a very good lifestyle. We need to fix this. Here are the things that the computer and my, my knowledge are saying. But we also have these medicines that can help you to slow down the ticking of your clock. Um, and we even have this new therapy that will reverse your age by 10 years."

6. 24:43 – 32:48

   Measuring biological age and the epigenome

   1. RCDr. Rangan Chatterjee24:43

      Yeah. It's quite an exciting thought for me as a doctor that that's might be available at some point in the foreseeable future. I'm, I'm sure it's not as far away as we might think. Um, but, but as you were, as you were describing that, um, David, I, I was, I, I was taken back to 2015, and in 2015 I had the opportunity to make a series of BBC One documentaries called Doctor in the House, where I would go and stay with families, uh, who had chronic health problems. For four to six weeks I'd live alongside them and try and help them, and it was, you know, one of the most incredible experiences of my life 'cause I, I got to help lots of families, you know, reverse or significantly improve their conditions without using pharmaceuticals just by making small and multiple changes to their lifestyle. And there was one guy in particular that came to mind who had, uh, well, his wife had type II diabetes. He was, you know, overweight, really struggling, you know, pre-diabetic I think, and there was a machine there. Now, I don't know how accurate it was, but it would a- it would take certain metrics and give him his biological age. Now, I, I, I can't tell you what that, what, what that machine was, so it, maybe it wasn't very accurate, but I can tell you what it was incredible is when we showed it to him and said chronologically I think he was sort of 35, but biologically he was something like 47 or 48, what that did to him and his mindset and his willingness to engage, I was like, "That is incredible." Suddenly he was all in, in terms of, "Right, tell me what to do, Doc. What do I need to do?" So I actually think there's another element to this. Yes, there's the biology, but there's also the motivational factor as to when someone is struggling. I think, I think there's nothing like telling someone they're older than their actual age to get them to actually start making changes.

   2. DSDavid Sinclair26:44

      Well, that's absolutely right. Uh, in the, in my book I give the analogy of a dashboard on a car. You wouldn't dare drive a car without a dashboard, so why do we do that with our bodies? And the idea of going to a doctor for an annual checkup, uh, already seems medieval when we can monitor our bodies 1,000 times a second and know if something is going to go wrong, when you're going to have a heart attack, not trying to save lives after it's actually happened. And so this measurement and this feedback from monitors, blood tests, uh, your phone can listen to you, uh, see how you're feeling, um, as well as your doctor monitoring that and, and being alerted if there's a problem, uh, we're gonna soon, within the next five years, be in a world that really will make current healthcare look, look really pathetic. Um, but you're right about human psychology. If you don't have feedback it's easy to give up. And so I've been doing, uh, a test called InsideTracker for the last 12 years, and I've been watching my blood biomarkers get better and better over those 10 years, and my calculated biological age go down, uh, over this decade. So I'm potentially 10 years younger than I was, uh, 10 years ago. So that's pretty astounding, right? The... And, and that's helped me, looking at those numbers is motivation for me to do the right things. Uh, and so I, I, actually I, I developed a test in my lab where we can look at someone's biological age from a mouth swab for just a few dollars. Uh, the cost is coming down, uh, thanks to this tech by at least 100-fold, hopefully 1,000-fold. So people can easily monitor their biological age. Um, I have a sign-up if, I don't know if you would mind me mentioning it if people would like-

   3. RCDr. Rangan Chatterjee28:31

      Not at all, please. I, I, I think I'll be first on the list to sign up. [laughs]

   4. DSDavid Sinclair28:35

      Uh, y- yeah, you can sign up at doctorsinclair.com, D-O-C-T-O-R-S-I-N-C-L-A-I-R.com, uh, and get on the list. We're just going, we're just putting the final touches on this, this test, and the test also comes with, uh, AI behind it that'll tell you the best ways to slow down and even reverse aspects of your age and get that number to come down over time.

   5. RCDr. Rangan Chatterjee29:02

      I heard you say in a, a previous interview you've done that you could take my blood right now and tell me my biological age. What sort of things are you looking for in one's blood to help make that determination?

   6. DSDavid Sinclair29:20

      Yeah. Uh, well, there's a couple of things. We can measure your biomarkers that track with age, and we know people who have certain signatures will live shorter than others. Um, that's one signature. That's what I've been doing for 12 years. I measure about 43 different things, uh, every three to six months. Uh, and I work with people who, who want my advice. The second, which is more, which is coming, is this, this test that was once a blood test but now is a cheek swab in the mail. And out of a cheek swab we can tell you very accurately your biological age based on your, the chemicals that are on your DNA. It turns out that chemicals on the DNA called methyls will have characteristic changes over time, and we can plot where you are relative to an average human. Uh, and that will change depending on how you've lived, how you're living, um, and how you will live in the future. And I think that number you could think of as your credit score for your body. Um, and maybe eventually it will be a score that could be used to get discounts off life insurance and that kind of thing. But for now, we want people to have an insight into their body and to focus on one number, which is their actual age, not the number of birthday candles.

   7. RCDr. Rangan Chatterjee30:39

      When thinking about those methyl groups, um, is that related to the genome and the epigenome? And you have this beautiful analog digital analogy for people which perhaps it would be great to go into now. And i- and, you know, is that relevant to the, the, the markers that you are measuring?

   8. DSDavid Sinclair30:59

      Yeah, it is. It, it was such a novel idea, uh, when it, it was first, when I first came up with it. Now I'm, I'm amazed that it's probably one of the hottest areas of biology right now. Um, it's funny to think it, you know, going back to how radical it was. The idea is that we have two types of information in the body that we get from our parents. There's the genome, our DNA, and then there are chemicals and proteins that stick to the DNA that control how the DNA is turned on and off. And we need to turn DNA on and off because a skin cell needs to be different than a brain cell, and this pattern is laid down when we're developing. But it's al- this pattern also changes in response to how we live. So when you exercise and when you fast, this, these chemicals that control the genes change in a, in a semi-permanent way. We call this the epigenome. Um, an analogy would be that the digital information on a compact disc in the music is the genome, and the reader that, that reads the different songs is the epigenome. Um, and every cell will have a different number of songs and patterns. Now what I s- have proposed is that aging is the equivalent of scratches on that CD so that the music skips. And the reprogramming, as we call it, the age reversal, is polishing those scratches off so that the music can be read again. And in between, there's the slowing of the scratches. So there are things like exercise, eating less, and some supplements that I take that I believe slow down that scratching process, um, and hopefully give me enough time for the age reversal technologies to catch up.

7. 32:48 – 40:18

   Reversing aging and when aging begins

   1. RCDr. Rangan Chatterjee32:48

      Age reversal. I- i- it's a very interesting concept. And as a doctor, I think we've been quite familiar with the idea that we can perhaps delay aging, but nonetheless in the backgrounds, I guess this truth, something we've always considered truth, all humans have considered truth, is that age- aging is inevitable. But as I said at the start, what, what's so powerful about your work is you are saying, or you are offering us a thought process that actually maybe it's not just about delaying aging, maybe it's not just about stopping aging, maybe we can actually reverse aging. And that's an incredible thought.

   2. DSDavid Sinclair33:33

      Well, we can reverse aging. It... That is a, an incredible fact. Um, it's been done in my lab. We published a Nature paper on this, um, a little under a year ago. It got the cover of Nature Magazine. This is not just some theory. Uh, we know that you can reprogram epigenetically, uh, a mouse. We, we cured blindness. We've cured a variety of ailments in mice, including dementia. Now we can control aging forwards and backwards quite easily in a mouse's brain and give it its memory back. Now that I think we understand what's going on in aging, it's really easy to control it, and it's, it's not that long before we're gonna have the ability to really dramatically reverse aging. There's already some accounts in the scientific literature of people turning their age back about two years with one treatment. The fascinating thing about that is that I know of people that have been doing that treatment multiple times in clinical trials, and it's additive. You go back two years. You do that four times, you've gone back eight years. Now think about this. If you can truly reverse your age by just one year every year, then things get really, really interesting.

   3. RCDr. Rangan Chatterjee34:54

      I mean, it's such a, it's such an incredible thought, like you never change your age. You stay where you are, right?

   4. DSDavid Sinclair35:02

      Right. Now, I'm not talking immortality. I, I'm, I'm not crazy enough to think that that's gonna happen. Um, but I agree with you that we need to completely change our view of what our life's trajectories can be. And there are a lot of people who are on the cutting edge of this field where, and, and myself included, we're running clinical trials and seeing age, aspects of age reversal, cardiovascular systems, the ability to have new blood flow in the body, uh, improved memory, uh, joints healing again, not to mention the bio tracking that will predict diseases ahead of time and the ability to see cancer many years before it would ever show up as an illness. We are truly talking about a convergence of technologies that should extend lifespan by decades, and if, if it doesn't, we've failed.

   5. RCDr. Rangan Chatterjee35:54

      W- what does this mean in, in, in practical terms? I'm just trying to get my head around this. So we know that, let's say, Alzheimer's starts in the brain 20, 30 years at least before we actually get clinical symptoms, so a lot of people in their 40s, there are signs of Alzheimer's already in the body. I've read that when it comes to heart disease, uh, there's sign of coronary artery disease and calcification, et cetera, I don't know, in your 20s, maybe in your teenage years. I think maybe I read as kids you can see early signs of that. So clearly what we're saying is that before we get symptoms, before we get to that end stage state, there are markers. There are, there are Things are going on in our body before we even actually raise our hand and go to the doctor or complain of symptoms. When it comes to aging, when does that start? Is that as a kid? Is it in the womb? I mean, when, when does aging actually start? And then I guess the follow-up from that is, let's say someone wants to implement this age reversal therapy, when do you even start it? Do you do it in your 40s to bring you sort of back to 40? Or can you do it when you're 10 years old? I mean, they, they seem like crazy questions to me, but I, I, I'm sure you've thought about them already.

   6. DSDavid Sinclair37:11

      Yeah. Th- these are not crazy questions at all. Uh, so the first thing to know is that what we're finding is if you rejuvenate the body, you make it younger. I'm, I'm talking about animals 'cause that's what we've done mostly, though human trials are, are about to begin in the next year or so. But when you make the body younger, diseases of old age go away. All right? We can have a mouse with dementia, and we're giving them Alzheimer's disease. If we make the brain young, the disease goes away. That should be true, I'm predicting, for all age-related diseases. We tend to think that aging doesn't ever change, and diseases, once you've got them, are very hard to stop. That is wrong, in my view. We are going to be in a world where just by turning the body back a couple of decades, diseases that were once incurable will go away. Just take examp- for example our Nature paper. We took mice that were blind, blind from glaucoma, blind from old age. It took four weeks. We reprogrammed their eyes to be very young again, and it's a permanent reset. They could see like young mice again because their eyes were young again. Now, we just chose the eye because we thought it would be interesting. We didn't choose it because it would be easy. In fact, we chose it because it would be hard, and it worked. So that's the future, is don't treat the disease. Treat the cause, and make the body repair itself like it was 20 years old again. Now, when does aging begin? Well, if you measure the biological clock based on the epigenome, those scratches, uh, the chemicals that are on our DNA, the same one we use in our mouth swab, that process begins the moment we are conceived. So nine months before our first birthday, second, uh, zero birthday, the literal birthday, we actually are aging, and it goes very quickly when we're young and slows down as we're older. So aging is always with us even if we don't feel it. So when should we start? Well, I would say pay attention to physical and mental health even in toddlers. If you have an obese toddler or, or a child, the effects on the epigenome will last a lifetime. We know this from studies of, of children l- um, who were under adverse conditions when they were young. Do I recommend intermittent fasting for children? Of course not. No, they need adequate nutrition. The last thing you wanna do is slow their growth. But what about someone in their late 20s and 30s? I think absolutely that the lifestyle changes should be adopted, um, and even some of these very safe supplements could be looked at. I started on my program, which I've modified over the years, but I started when I was 34. Um, and I wish that I had that knowledge when I was 24. Um, you know, I'm now 52. I've got no gray hair. I haven't lost any hair. I don't have that many wrinkle. Um, I attribute that largely to what I've been doing for the last 20 years.

8. 40:18 – 44:59

   Why people would want longer, healthier lives

   1. RCDr. Rangan Chatterjee40:18

      Do, do you ever stop and go, to a lot of the global population, this stuff seems like science fiction. Do you meet people or do ... You know, when you go around and give talks, I mean, do you get pushback? D- are you surprised with how this is brand-new information for so many people, or are you sort of used to that, and do you, do you still have that passion? 'Cause you strike me as someone who always ... Like, I've watched a lot of your interviews. You have this incredible passion to teach people and get this message out there. Where does that come from? And you know, I don't know. Talk to me about that a little bit.

   2. DSDavid Sinclair40:57

      Yeah. It's, it's something that I have a skill for that I didn't know. Um, but I do like storytelling. I really like educating. I get joy out of filling people's minds with wonder. You know, I'm still a 12-year-old, maybe even younger. And you know, when, when a, a 12-year-old or younger goes home and says, "Mommy, Mommy," or, "Dad, you wouldn't believe what happened today. I saw this insect on a tree, and it laid eggs, and then a spider came," that's, that's what I am doing now. I love telling these stories because I wanna share them. They're super exciting. Um, and I, I do find that I have an ability to explain things at a level that most people can get and find entertaining, and that probably is because I'm still this 12-year-old inside my head.

   3. RCDr. Rangan Chatterjee41:47

      A lot of people, when you ask them, uh, how long you'd like to live for, you know, there's, there's a variety of different answers, aren't there? So I actually, uh, spoke to one of my friends about this a few weeks ago. We were in the car together, and he said, "80, man. I'm, I'm, I'm, by 80 I'll be done." I was quite shocked actually 'cause I thought, man, 80? You're kidding me. Like, I have a different viewpoint of what I would like for my own life. Um, I know I've seen some of your, your talks online, and you often ask this question at talks. How much of our view of w- at what age we think we'd like to die do you think is shaped by this kind of prevailing view that old age is hard, and when we get old, we can't move, and we can't see, and we need help? Because that's the big thing, right? I think- Many people would like to live a lot longer if they felt they'd have that vitality whilst they were aging as well

   4. DSDavid Sinclair42:49

      That's exactly right. I, I asked the question twice. The first question is, how long do you wanna live? And I would say a third of the people say 80, another third say 100, and then there's the other third that would say 150 and beyond. But then I ask the question again after I say, "But what if you could stay healthy till the end?" And then just about everybody's hands go up. So it's clearly a misconception of what I'm talking about. What I'm saying is that we are preventing getting old, preventing diseases, preventing cancer, heart disease, Alzheimer's. Who would not want that? And when we extend lifespan, it's not keeping people in nursing homes for longer. Who would want that? It's allowing people to be 85 and 90, even 100, to play tennis and hang out with their families and start a new career. The best example I can give you is my father, who's, stars in the book. Um, he was-- he retired at 67 and was not looking forward to being 80. He was thinking he'd be in a wheelchair like most 80-year-old men, if not in the ground. He's now 82. He's fitter than me, stronger than me, more excited about life than me, seriously. He's got a great social life, and he has no diseases, no aches or pains, mentally extremely sharp, and has started a new career. This is what 82 should look like. And if people change their lifestyles the way that I describe in the book, they have a, a great chance of reaching that point and beyond. And then the last point I wanna make is anyone who says they wanna die at 80, uh, is misguided in my view. Because if at 80 you've got friends, you've got family, you're doing something with purpose, whether it's community work or a job, no one says, "I wanna die." No one wants to die if they've got a health- healthy life with family. And, you know, if, if I-- if there's someone out there who says, "I'm, I'm happy and healthy, but kill me now," I'm yet to meet them.

9. 44:59 – 53:01

   Level one: eating, olive oil, polyphenols and xenohormesis

   1. RCDr. Rangan Chatterjee44:59

      Yeah. It's, it's so powerful. It really is. It gets-- I mean, I, I like your work anyway, but it's getting me even more excited to put in some proper anti-aging practices. And one way, there's quite a lot I wanna talk about around that in terms of what it means to, to live to an older age. But you mentioned you know people who've gone through this, uh, treatment where they've actually reversed their age by two years. Um, now, I know there are these kind of three levels you talk about of treatment. Is that level three? Is that the kinda deep level that, uh, you talk about? 'Cause I'd, I'd sort of like to sequentially go through them, though I, I presume that eating less is that sort of level one, is it? So, uh, or level one and level two. Perhaps you could explain what those three levels are, and then we could go through what we can do at the moment at each of those levels.

   2. DSDavid Sinclair45:50

      Yeah. Yeah. Well, the first level is prevention. So skipping meals, eating healthy, which I would say is roughly a, a Mediterranean diet, and, uh, and keeping exerc- keeping your body in good shape. So exercise, run for 10 minutes every few days at a minimum, uh, lose your breath, at least go for a walk, and build up muscle strength in your main muscles. That'll help hormones as well as the ability to survive a fall, which, uh, in the US happens every 19 seconds and is worse than cancer, uh, for, for, uh, longevity. So those-- that's the top level. That's easy, uh, in my view, um, and obvious, even though most people don't do it.

   3. RCDr. Rangan Chatterjee46:29

      You've mentioned eating less. You mentioned the Mediterranean diets, which I think we should just expand upon a little bit there to find out what you mean when you say that. And then I wanna come to exercise. Can we just start with the Mediterranean diet? Um, what do you mean when you say that, and what is that based upon?

   4. DSDavid Sinclair46:47

      Yeah. Well, y- your food should look more like a, a, a rabbit's dinner than a, than a, a lion's meal, put it that way. Um, vegetarianism is great. I can't do that. I like meat. But when I eat meat, it's small portions and it's usually fish, uh, or shellfish, uh, sometimes chicken and r- very rarely red meat, and not a lot of it. Um, there are carnivores who are p- promoting a, a carnivorous diet, mostly meat, keto. Now, I, I'm a scientist. I just go by the data. I don't care. In fact, I'd love it if meat was healthy, but it's-- according to the science, it's not. There's no evidence that people who eat a lot of meat around the world are the ones that live a long time. It's the smaller, thinner, typically women, who eat plant-based diets, perhaps with a bit of red wine, olive oil, that live the longest. That's undeniable. I mean, just go into a nursing home and have a look. It's not a secret. Um, so that, to me, says that we want to eat less, eat fresh, eat vegetables, less meat. Um-

   5. RCDr. Rangan Chatterjee47:56

      Is that because of mTOR? Is that-- or is that one of the reasons where you want us to keep mTOR down to promote that sort of survival signal and meat, I guess, and other high protein foods are gonna keep it up? Is that the rationale there?

   6. DSDavid Sinclair48:10

      Yeah. That, that's one of the main reasons, exactly. And, uh, but also that when you have less sugar in your body, uh, AMPK and sirtuins will be activated as well. So I am very careful, not very, but I try not to eat excess sugar and, uh, and just unprocessed carbs, which are f- everywhere, including in sauces and dressings. Um, so you have to be careful. I, I've even gotten to the point as a scientist to wear a continuous glucose monitor to see what food does to me, and we don't want those spikes in sugar because they will, uh, be bad and shut down our defenses

   7. RCDr. Rangan Chatterjee48:47

      What about ol- what, what about olive oil? I've, I've read in your w- that olive oil, I think, activates sirtuins, right?

   8. DSDavid Sinclair48:54

      Yes, it does. And so the first sirtuin-

   9. RCDr. Rangan Chatterjee48:57

      And that's a good thing. That's, that's what we want.

   10. DSDavid Sinclair48:59

       Yes, correct. Now, there, there are two ways ... well, let's say three ways to activate sirtuins. One is the usual exercise and hunger will turn on those genes. Uh, but if you wanna take a supplement, uh, you can do it by e- taking resveratrol, which is a plant molecule that comes mostly from red wine, but, uh, you need it as a supplement. You don't wanna be drinking 300 glasses of red wine a day. I don't recommend that. But the, the other thing is olive oil was discovered to also activate sirtuin enzymes, um, by, uh, Doug Marcinek, uh, who was a collaborator of mine. And it's really interesting, right? That, that the components of red wine and olive oil are activating this longevity enzyme directly, just binding to it and making it work better. I find that really, really satisfying as a scientist. So I'm eating ... yeah, I guess you'd say eating not drinking, uh, more olive oil. Uh, in the morning I used to have yogurt, now I often have a little bit, a few teaspoons of olive oil. The reason that I have olive oil, uh, and/or yogurt is that resveratrol and some other plant polyphenols that we can talk about are highly insoluble. Once you pull them out of the plant and process them, they're the equivalent of trying to eat brick dust. Uh, and that's a mistake a lot of people make. They think they can just have a glass of water and take resveratrol. It won't get absorbed. So I mix those together, dissolve them, and, and then have that. And I know from clinical trials that I did in the 2000s that that works. Um, other polyphenols, quercetin, um, there's, um, there's the ... We discovered all of these extended lifespan back in the 2000s. Uh, we first showed it in yeast and in worms. Uh, it's been forgotten by, by most people, but that's where it first came from. Now, why would these plant molecules make us healthier? Well, I have a theory called xenohormesis, which is xeno means from other species, and hormesis we've discussed. What doesn't kill you makes you stronger. And I think when we eat plants that are making these molecules, particularly when they're stressed out, they don't get enough water or too much sunlight or bugs are eating them, they make these defense molecules to survive. But we ingest them and then we get that signal that our food supply might run out, and in that way we get the benefits as well.

   11. RCDr. Rangan Chatterjee51:21

       Yeah.

   12. DSDavid Sinclair51:21

       And so the combination of, uh, not eating as much, exercising, and taking plant molecules that stimulate adversity, I think that's the winning bet. That, that's stage one and stage two.

   13. RCDr. Rangan Chatterjee51:35

       That these sort of stressed out plants, you know, it's, it's, it's really ... I love that. I love that theory that that will be a signal to us that food may be going away or there may be a problem and we need to also activate this, uh, survival signal as well. Um, this presumably is why, I guess, organic food potentially which doesn't have pesticides, uh, are also gonna have to work harder to get that xenohormetic stress signal more from organic foods, do you think, than-

   14. DSDavid Sinclair52:08

       Yeah

   15. RCDr. Rangan Chatterjee52:08

       ... non-organic foods?

   16. DSDavid Sinclair52:09

       We are. We are. And, and so if, if you can afford it, it's better to eat food that's been grown outside the, uh, the typical, uh, greenhouse. So the ... If you look at a lettuce that's grown, I'll single out California, but y- you know, a lettuce that you buy that's watery and not very green, that's the worst. That's a plant that has been grown in the equivalent of a, uh, a movie theater with popcorn. You don't wanna eat those. You wanna go for the ones that are, have been picked on and full of color. Color molecules come on at the same time as these polyphenols. Um, and yeah, and, and have them picked when they're s- when they're, uh, thirsty or had a lot of sunlight. And yeah, organic is the easiest way to do that. Another way is to eat locally or even grow your own.

10. 53:01 – 56:17

    Meat, ketosis and the growth versus survival trade-off

    1. RCDr. Rangan Chatterjee53:01

       You mentioned before that you're a scientist, you like to look at the data. You don't see any long-living communities around the world having high levels of meat consumption. Of course, keto, uh, is a very popular diet, and not only is it popular, there, there's no doubt that many people feel incredible benefits in the short term, possibly even the medium term from eating that way, whether it's reversal of, you know, reversal or remission of type II diabetes, better energy, better focus, um, all kinds of benefits that, that are clearly feel good to that individual so they wanna continue eating that way. Do you feel that there is a trade-off sometimes between short-term health and how we feel and long-term longevity? Um, because it, it does seem that you're saying people s- eat less. I know you say you've got used to it, you have more energy, but someone may say, "Well, do I need to sacrifice my short-term life and vitality to have that long-term longer lifespan?"

    2. DSDavid Sinclair54:12

       Well, no. People who, who eat the way I do, uh, are known to have just as much if not more energy than people who are eating, uh, ketogenic diets. Now, the, the ketogenic diets on their own aren't, aren't horrible. Ketosis can be a great state to be in, but here's the problem. We know that there's a trade-off. Your body either wants to grow and repair or hunker down and survive. It switches depending on how much and what you're eating. We know this because if you change something that- ... is alterable in response to the environment such as growth hormone. Uh, growth hormone gives the body the signal to on this side grow and repair. Um, and then when you don't have a lot of growth hormone, you don't grow and, you know, you hunker down and you actually survive longer. This has been done ad nauseam in worms, in mice, and even in human populations that have mutations in the growth hormone receptor are a little bit shorter but apparently highly protected against diseases of aging. So this is a paradigm in our field, okay? Growth and reproduction versus hunkering down and living long. Now, if you're eating a lot of meat, taking testosterone, shooting yourself up with growth hormone, you will feel great, right? Your, your body is in the, the, the growth mode. But that's at the expense of long-term survival. Think of it as burning the candle at both ends. Instead, what I prefer is to be in the energetic mode but also have my body protect itself daily from the ravages of, of aging. Um, and so I feel just as great as I would if I was eating a lot of meat, uh, because now I'm used to it, but my body is defending itself in a way that eating a lot of meat and taking those hormones would actually suppress.

11. 56:17 – 1:05:16

    Exercise, muscle and protein

    1. RCDr. Rangan Chatterjee56:17

       Yeah. So fascinating. So interesting to think about this through, through that lens. Um, exercise. You... Well, a couple things to say on exercise. Uh, you know, I went for a walk before this conversation and I was thinking that is, is some of the way we've done research so far through the old paradigm lens. So what I mean by that is, you know, a lot of research shows us that, you know, walking 30 to 45 minutes a day seems to give us all the kind of health and longevity benefits we might want. But I'm wondering, is that through the old lens where we thought aging is inevitable and therefore walking 30 to 40 minutes a day is simply just doing the best that we can within that paradigm? Whereas if you look at it through your lens that actually aging is not inevitable, sure, you know, maybe walking is helpful, but maybe it's not enough. So what is your perspective on movement, exercise, and how that fits in to your kind of theory and philosophy on aging?

    2. DSDavid Sinclair57:21

       Yeah. Well, far be it from me to say, "Don't walk and don't, uh, move." That, that's step one. If you don't walk or move, then you're in big trouble when you get older. Um, so that's a minimum. But if we're talking about what's, what's not maximum but optimal, we don't know that for sure, and it's might be everyone's different. But in general, losing your breath is important. High intensity exercise. You don't need a lot. I just mentioned 10 minutes a few times a week. That appears to be sufficient to give you the, the longer term health benefits. And what's probably going on is, in part, is that we... Well, we discovered, uh, and we published this in 2018 in the journal Cell if anyone wants to look it up, that old muscle starts to think that it doesn't have enough oxygen even though there is enough oxygen, and it shuts itself down and doesn't make a lot of energy and the blood vessels start to be depleted and it's a just a terrible feed forward process after that. So by making your body hypoxic and giving it a stress both in the... You can actually do excess oxygen or lack of oxygen, just, you just wanna shock the system, then your body gets to reset. Um, and, and one of the, the most popular things to do in the longevity world now is, uh, what is it? High pressure bariatric, uh, oxygen therapy. And that I think is also resetting this, uh, this problem that our bodies have where they are what we call pseudo-hypoxic. Um, one of the ways that we could reset that without exercise and without high pressure oxygen chambers was using NMN, this molecule that I take. It actually boosted the, the body's ability to make new blood vessels. It restored the, the ability to measure oxygen in the muscle. Um, and when we gave it to mice, they could run 50% further without having trained. But the good news is, well, no, the important point is that the mice that were young and exercised and got the molecule in their water ran twice as far. So it's, it shouldn't be an excuse to pop a pill and not do anything. Um, but there are some little changes you can make. I lift weights. I have them around my house. I, I'm at a standing desk, which goes up and down here. These are changes that I make that, um, you know, I'm standing most of the day now and this will really help. It builds the muscles in your leg and, and your butt and your back. That's important now, especially for a male my age where I'm losing 1% muscle if I don't do something about it every year. But also the hormones. Testosterone comes, uh, from having those large muscles, uh, signal to the testes. And I've been able to correct and, and raise my testosterone levels just by keeping those large muscles in shape.

    3. RCDr. Rangan Chatterjee1:00:13

       So much to dive into there. It's incredibly fascinating that potentially to get these longevity benefits that you're talking just maybe 10 minutes of this kind of pulsed exercise where we're out of breath, so high intensity interval training several times a week, which is very achievable even for the busiest person out there. So I, I find recommendations like that really, really inspiring because, you know, eating less, exercising 10 minutes several times a week, you know, a lot of people think health and wellness is the preserve of the wealthy, the middle class, all kinds of things like that. And I, and I know there are certain things which do cost money, but it's also refreshing to know that there are lots of things that actually can be done completely free of charge. You know, eating less is actually saving you money [laughs] right, than, uh, than eating three meals a day. But, you know, th- th- there's a couple of points around exercise which I really wanna dive into. One of them is, as you say, at your age you're losing 1% muscle mass, uh, each year, uh, if you don't do something about it. I think that starts at the age of 30 for, for most of us. So what's... When I think about that and I think about mTOR and protein, I have this, like, clash in my head whereby we know that sarcopenia, this loss of muscle mass, is a problem as one gets older. Uh, risk of falling, problems after that, all kinds of things happen when we lose that muscle mass. So a lot of the recommendations around fighting sarcopenia are to do with, yes, resistance training, but also the amount of protein you are consuming to make sure you're limiting how much that happens. Yet at the same time we're sort of suggesting that to increase our aging we should l- be limiting our protein intake. Help me, help us see through that apparent contradiction.

    4. DSDavid Sinclair1:02:12

       Well, yeah, I'm not saying limit protein intake at all. I get plenty of protein, um, just mostly from plant-based sources where there's not a lot of the branched-chain amino acids. Those leucine, isoleucine, valine amino acids are the ones that activate mTOR. Um, and so, yeah, focus on plants, you'll have enough protein to build muscle. I have no, no trouble building muscle.

    5. RCDr. Rangan Chatterjee1:02:35

       [laughs]

    6. DSDavid Sinclair1:02:36

       Um, that, that... It's a fallacy that you need to be eating, you know, these protein shakes and meat to get stronger and to build muscle. Now, if you wanna professionally build muscle, by all means go for it, but for most of us who just wanna feel good, look good, live longer, um, what I'm recommending doesn't affect your ability to do those things and, and build up muscle one bit. And there's... It's also a fallacy that older people cannot build up muscle. My father, who's 82, uh, has built up a lot of muscle. He goes to the gym twice a week, he runs, he hikes, and he literally is stronger than me. Um, and he says he hasn't felt this good since he was in his 30s. Though he w- he does say that he probably felt like crap when he was 30.

    7. RCDr. Rangan Chatterjee1:03:25

       Even then, even if he did feel like crap when he was in his 30s, that's a pretty powerful thought, isn't it? That someone in their 80s can be quite confident in saying, "Doesn't matter how I felt in my 30s, I'm feeling better in my 80s than my 30s." That is... That's incredible, right? It's, it's not something to be sniffed at. That is something that is not the norm in society. It's not what people expect. People think it's an inevitability that we're gonna get slower, more tired, our memory's gonna go, and I don't buy that first of all. I've seen that there are many things we can do to mean that's not an inevitability. But I think you take it that you take it even further and, and you're showing very clearly that that does not have to happen to everyone.

    8. DSDavid Sinclair1:04:08

       It's exactly right. I, I'm not gonna say my father and I are a clinical trial. Um, in fact, we were just doing this c- mainly 'cause we're scientists. We can read the literature, we're researching it. Um, but it's a fun experiment, right? We've now been doing this long enough that something weird is going on. My dad feels like and acts like he's 30, and I, I don't act or, hopefully you can judge, look like I'm 52. He's 82. So that's pretty interesting. We'll see over the next 10, 20 years what happens. But he, he's not a special person when it comes to life. He- he's an average guy. He didn't like exercise. He was not looking forward to the future. Uh, he's not obsessed with his health at all. And look at what happened. Uh, you know, he's living a life that he didn't expect at all, and we're already planning going to Africa after COVID. He's looking at life over the next 30 years. I mean, what 80-year-old does that?

    9. RCDr. Rangan Chatterjee1:05:08

       An 80-year-old whose son is David Sinclair, that's who [laughs] .

    10. DSDavid Sinclair1:05:11

        Yeah, maybe [laughs] .

    11. RCDr. Rangan Chatterjee1:05:14

        Um,

12. 1:05:16 – 1:13:34

    Marathons, NMN and the supplements Sinclair takes

    1. RCDr. Rangan Chatterjee1:05:16

       you mentioned, uh, well, the, the, the- there's this theme, isn't there, always about this hormetic stress, this pulsed stress on the body that you can then recover from. I can see how interval training does that. Um, what about other forms of training? Now, as we have this conversation, I am two and a half weeks away from doing my very first marathon, so I [laughs] I've, I'm, I'm gonna be running the London Marathon in two and a half weeks. When this conversation comes out, hopefully I will have completed it. I am not doing this for longevity, to be really clear. I'm doing it for other reasons. It's something... It was a challenge that was set to me. I'm enjoying the process of seeing if I can do it. But it's an interesting question since I have you on. You know, clearly running a marathon, and I'm not an endur- You know, typically I've not been an endurance type guy, so I've not done lots of stuff like this at all. This is well outside my comfort zone. Could this be a stressor on my body that has a powerful effect when it comes to what my body then does with respect to thinking it needs to hunker down? Of course, it's gonna be highly, uh, individual based. Or could it be that it's too much of a stress, you've gone past that hormetic sweet spot, and it's gone into the realm of actually, depending on my fitness levels and, and, and how it fits into the rest of my life, that it can actually become problematic?

    2. DSDavid Sinclair1:06:52

       Uh, I, I'm, I'm not worried about you. If you look at marathon runners, uh, there's a very clear, uh, correlation with longevity. People who bike or run long distances- Uh, do live longer. In fact, in the case of cycling, if you do, I think it was 80 miles a week, your risk of heart attack goes down, uh, 60%, a massive amount. I, I don't know about marathons, but, um, I, I think that you'll be fine based on all the evidence.

    3. RCDr. Rangan Chatterjee1:07:24

       Yeah. So, um, and then you mentioned with... We've not spoken really in detail about NMN yet, and I would like to, but you did mention when the, the, the mice took it, their endurance got better and, and that, that sort of, uh, rung a, a, a kind of... That really rung in my brain when you said it 'cause I thought, "Oh, I'm doing a marathon in a few weeks." As well as its anti-aging ability, does it also in, in your experience beyond that trial have an ability to im- improve and increase our endurance levels?

    4. DSDavid Sinclair1:07:57

       Well, we don't know in humans yet. Um, there's been very few studies, uh, with NMN and endurance. Um, in fact, uh, I'm struggling to think of one. Now, we're doing it myself, um, over at Harvard, and we'll know probably early next year if this is true. But I do have an anecdote. Um, one of my now good friends, Ken Ridout is his name, he was a middle of the road marathon runner, kind of a ho- doing it as a hobby, and I met him a few years ago and he decided to, to make it his mission to see if he could, uh, use my science to improve. And every few months he got faster and faster and faster, and he's now 50 years old and he's the world champion for his age, uh, and often just beats the 30-year-olds in marathons. Myrtle Beach was the most recent. He will be in the same marathon as you. Uh, so look out for Ken Ridout. If he wins this race, he's the official world fastest 50-year-old in marathons.

    5. RCDr. Rangan Chatterjee1:09:04

       Oh, wow. Because-

    6. DSDavid Sinclair1:09:06

       And, and he, he's, he's on NMN and resveratrol, um, mainly and, uh, you know, we don't have a twin as a negative control, which is what we should have, and it should be placebo controlled. But absent that, it's pretty interesting what we've seen happen to him.

    7. RCDr. Rangan Chatterjee1:09:23

       So let's go into these supplements. Uh, we, we have, of course, we've covered food and exercise and how we can manipulate them to increase our longevity. I do wanna talk about cold exposure later on. Um, but w- you've mentioned a few times that there are certain supplements that you take and other people are taking. Um, so I wonder if we could go through them sequentially and just sort of figure out what they are. Um, I know you've got to be careful in terms of what you are recommending or not recommending, but what does the science so far suggest from, you know, from, from what you've seen?

    8. DSDavid Sinclair1:10:00

       Well, the... It's a long conversation, um, and I, I work with clients on, on this 'cause it, it's, it'd have to be tailored to people's blood work and age and that kind of thing. But in general, what I do is listed on page 304 of my book, so that's the cheat sheet of Lifespan. Uh, but they fall into buckets. One is the plant polyphenol cocktail, resveratrol, quercetin, fisetin. Uh, I mix that in the morning. This morning I had yogurt with it mixed in.

    9. RCDr. Rangan Chatterjee1:10:28

       So you don't take them as, uh, as like a, a capsule. You wouldn't just swallow as a capsule. You want the powder mixed into something like olive oil so that it's absorbed better.

    10. DSDavid Sinclair1:10:39

        Yes.

    11. RCDr. Rangan Chatterjee1:10:39

        Yeah.

    12. DSDavid Sinclair1:10:41

        Uh, so there's that and then there's NMN, which I take a gram of every morning, uh, which is water-soluble. I just swallow that down. Uh, and then I take metformin at night, um, probably every other day and, uh, and that, those are the main things. There's, there's plenty of other things that work for me, I believe. Um, but that's a good start. And I, I would start... I'm not recommending anything, of course, I'm not a doctor, but if I was to do it I would start slowly. I would change just one or two things at a time, and I would measure baseline before and after to see how you're doing because, again, you, you don't know what's happening unless you measure it. Um, you can do InsideTracker I think. I'm not sure in the UK what the equivalent is, but you can do InsideTracker from the UK. They let you upload your data, um, for a small fee, and that would allow you to see if something's going wrong, uh, or going right. But also you can also show that data to your doctor. I, I would recommend working closely with your doctor if you're starting to take some of this stuff, even if they're just supplements. Um, I'm also working on trying to figure out how to approve or at least give education about which supplements work, don't work, might work, which ones are pure, which ones are filled with toxins. This kind of thing needs to happen in the industry because every day I get asked by dozens of people, "Tell me a brand that I can trust." And I literally cannot because how would I know? I'm not, I'm not a, a nutraceutical guy. I'm a scientist who works in a lab on mice.

    13. RCDr. Rangan Chatterjee1:12:15

        Yeah. InsideTracker, is that... What is that? Is that a, like, a company that specifically looks at various biomarkers and puts it into a context around aging or is it just sort of blood testing? I mean, what, what, what... Just what is that?

    14. DSDavid Sinclair1:12:30

        Oh, so, so I helped start this company about 12, 13 years ago, and the idea is that you measure things that give you information about wellness and health and longevity, and there are 43 things that y- we measure. Some of them your doctor would never look at. Um, and they cover things like, uh, liver health, uh, inflammation, blood, heart, muscle, uh, stress. And we put that into a, an algorithm that was built using machine learning and most of the world's scientific literature and 100,000 People's medical records. And it, it gives out recommendations on how to optimize your body, not just whether you're sick or not, but h- for you, what is optimal and then how to get that to where you need to be. There's a green zone. And so I've kept those biomarkers of mine in, in or very near to the green zone for the last 10 years. Um, and you can see the tracking. They just get better and better and better if I follow their recommendations.

13. 1:13:34 – 1:22:54

    Metformin, the microbiome and preventive medicine

    1. RCDr. Rangan Chatterjee1:13:34

       Yeah, incredible. I'm almost certain I'm gonna be looking that up straight [laughs] straight after this conversation because I'm truly fascinated, uh, with... You know, I'm, I'm very proactive with my health anyway, but this sort of thing makes me think, "Wow, what, what could... You know, what's the ceiling? Maybe there's a much bigger ceiling th- than, than we initially thought." Um, metformin. Metformin is a drug I have prescribed in the past on thousands of occasions, and it's interesting that many people in that space of longevity or the, or the wellness space online are talking about metformin. Um, you know, metformin does multiple things, I think, in the body. It makes us more sensitive to insulin. I wonder if you could explain why do you think metformin works for delaying the aging process? But also that I'm interested that a few years ago, there was a paper came out that shows that metformin, I think, increases the growth of akkermansia muciniphila in the, in the gut microbiome, what is thought to be a helpful, uh, gut bacteria, and people were speculating could some of metformin's benefits be coming through the microbiome. And so I'd love to understand a bit about metformin, but also how the gut microbiome plays into your view on aging.

    2. DSDavid Sinclair1:14:59

       Uh, yeah, well, the, the gut microbiome's r- extremely important. We know from studies of, of fish and in mice, um, that if you transplant young microbiota into older animals, they will live longer. And our microbiome changes with age. There's no question about that. Uh, and what we don't know is if you take young person's, uh, microbiome and give it to an older person, what would happen? I, I would, I would guess that it would be helpful. But there are, there are ways to optimize your microbiome. Part of the, the reason that I recommend this diet or talk about this diet is that it does change your microbiome in ways that are healthy. Um, and it also means that when I eat a giant steak, I can't, cannot digest it 'cause my body doesn't have those microbes to, to absorb it and process it. Um, so microbiome's extremely important, and metformin does alter the microbiome. The other thing that it does is it interferes with mitochondria. It slightly inhibits the energy production in the body, and as a result, the body overreacts and makes more mitochondria to make more energy. So a little bit of hormesis, right? A little bit that hurts you, gives you this protective response. And there is a, a, a s- really slight downside to metformin. Because it inhibits energy, uh, you feel a little bit weaker if you've just taken it. Um, you o- you can do maybe one or two fewer reps, repetitions of an exercise. So there are two things to do. One is just try harder, and the other is to take metformin, um, after you've worked out. Yeah. And, uh, and so that is a really s- easy thing to change.

    3. RCDr. Rangan Chatterjee1:16:52

       I- is metformin something you think within a few years, assuming you have no contraindications, that, like, it would be hard to make a case that we shouldn't all be taking? Is it... Do, do you go that far in your mind as, when you think about the future?

    4. DSDavid Sinclair1:17:09

       Well, I mean, if, if, if it was a sensible world, yeah, most people over the age of 40 would be taking it. It's very cheap. It's very safe. And if there are problems which can happen in the stomach, for example, it's reversible. You just stop taking it. Uh, and you do it under doctor supervision anyway. So I, I, I take the strong view that in a, in a... If we were a r- if we were a rational planet, uh, metformin would be given to millions of people who don't yet have type 2 diabetes. But we're not rational, and doctors and insurance companies are hesitant to give medicines to people who are not sick yet, unfortunately. My doctor, uh, wouldn't give me a, a prostate test. He said, "Do you have, uh, a family history?" "No." "Are you sick?" "No." "Can I have the test?" "No." "Why not?" "Well, you're not sick." Well, my answer to that is why, why do I have to wait until I've got prostate cancer till I come see you? It's similar the view now, which is, uh, come see me when you're sick. Um, but that has to change, and I think that having people on metformin before they get type 2 diabetes, uh, is a very sensible thing. I don't know how quickly this is going to be adopted. More likely it's gonna be the consumer that takes it into their own hands, like InsideTracker, and companies in the US are al- already, uh, with doctors involved, prescribing metformin over the internet. Um, and I think, you know, I'm not condoning it. I am just telling you a fact that that seems to be the wellness trend, is that people can't wait for their doctors to read my book and to get into it and read the papers. Straight to companies that allow them to do so.

    5. RCDr. Rangan Chatterjee1:18:53

       Yeah, it, it speaks to the problem you touched on multiple times in this conversation of medicine in some ways still being stuck in the Dark Ages or certainly in the 19th century. We do wait until you're sick before we often do anything. Uh, take type 2 diabetes that we're talking about in the context of metformin You know, we have these blood sugar, um, ranges. Um, you know, depending on which country you're in, when your A1C gets to, you know, it can be anywhere from 4.5 or whatever it is all the way up to sort of 5.9, and it would be reported as normal. Suddenly it goes up .1 to six, now you're pre-diabetic, and 6.5 is type 2 diabetic. But I know many people who they have 5.8, 5.7, 5.9, and it's reported as normal, and the patient goes away thinking, "Oh, everything's fine." So I feel in medicine we... things have been quite black and white, and we haven't really thought about this term optimal. What is optimal? You know, what should we really be aiming for rather than just waiting until people get sick? And you're sort of saying the same thing with aging, right? You're saying let's not wait until then, let's get on top of this, identify the root causes, and tackle them early.

    6. DSDavid Sinclair1:20:08

       Well, that's exactly right. It's much easier to prevent something, um, than to treat it once it's happened. Just, uh, right now we, we look at people falling off a cliff and, and we, we... Another analogy that I'd use is Whack-a-Mole medicine, trying to, you know, just beat these things down as they pop up. Um, but, you know, going... speaking of going to the edge of a cliff, it's not just important to know why someone fell off a cliff, it's important to know why were they on the edge of a cliff in the first place. And we ignore that first process, which is really the majority of our lives. And, and that is changing though, and I think the medical community is catching up. Um, World Health Organization has declared aging a medical condition for the first time ever. Um, so there's that movement. But consumers are saying that they've had enough of this approach to medicine, and that having an annual checkup or waiting till you get sick is not what they're looking for. And there is a booming industry. InsideTracker is leading, but there are a lot of companies now with monitors of glucose and, uh, and home swabs, where people are taking their own health into their own hands. Now, physicians and maybe yourself are saying, "Well, we're all gonna die if people are diagnosing themselves." But that's really not the point. They wanna get some data on themselves. They wanna know how they're doing, which they cannot get anywhere else. And the fascinating thing is that that data is quality. InsideTracker uses the same testing companies that the doctors use here. Uh, and my doctor, for example, loves that data. I show him the graphs, and he makes better decisions because of it. But he cannot afford, or the insurance company will not pay for everybody to have that level of testing. So if you'd rather give up a cappuccino a day and rather have a look inside your body, that's the trade-off. And I choose to look inside my body and just make my own coffee at home.

    7. RCDr. Rangan Chatterjee1:22:02

       Yeah, I'm all for patients getting empowered and having more information. Um, I've, I've, I've, you know, never been worried about patients empowering themselves or even this whole idea of, um, Google searches. You know, I, I sort of talk to, you know... We, we've got a training course for doctors about lifestyle measures they can adopt with their patients, and one of the things I, I teach doctors, I, I say, "Guys, look, what... Instead of being annoyed that your patients are googling things, you've got to embrace it. You google everything in your own life. Why would you expect your patient would come to see you and not have googled something? So why not ask them, 'What have you googled about this? What, what are your concerns? What do you think this might be?'" I think it's a much more open and, uh, collaborative way actually of doing medicine. You mentioned foods. You mentioned exercise. Uh, I,

14. 1:22:54 – 1:35:23

    Sleep, stress and finding meaning

    1. RCDr. Rangan Chatterjee1:22:54

       I'd love to touch on sleep and stress, two other very, very important lifestyle factors. So let's start with sleep. When I think about your work and I think about hormesis, it strikes me that sleep is a, is a slightly oddball because you could make the case that not sleeping well and not sleeping enough is sending your body a signal that actually there's a problem, you know, I need to hunker down. Whereas most of the evidence that I've seen suggests that, you know, getting decent amounts of sleep, deep, quality sleep actually helps reduce your risk of all kinds of diseases, and I'm sure it's gonna have an impact on aging as well.

    2. DSDavid Sinclair1:23:34

       Right. So sleep is an exception. If you don't get enough sleep, then you've got cortisol levels going up, and it's, it's very clear that if you don't sleep well, you will age faster. Um, I'll, I'll give you the best example. If you take, if you take a rat and you deprive it of sleep for two weeks, after that two weeks it will have Type 2 diabetes.

    3. RCDr. Rangan Chatterjee1:23:55

       Yeah.

    4. DSDavid Sinclair1:23:55

       That's how important sleep is. Um, and so think of sleep as something that's totally connected to the, the clock of aging. So SIRT1 is the enzyme that we work on in my lab, and resveratrol and NAD activate it. We talked about resveratrol, talked about NAD and NMN. Now, SIRT1 is not just central to our health, cardiovascular disease, inflammation, longevity, but during the day this same enzyme controls the body's sleep-wake cycle. Without SIRT1, you don't sleep properly, your body doesn't, um, have a, a proper circadian rhythm, as it's called. So what does that mean? Well, if you disrupt your sleep, you're going to disrupt your body's ability to repair itself. And actually, as we get older, our lack of, uh, SIRT1, which is often due to obesity and lack of exercise, will make it harder to sleep normally as well. And, and there are plenty of people who are elderly who do not sleep well, in part because their SIRT1 and their NAD fluctuations are out of sync and not, not really high amplitude. They just waddle along. So what does this mean? It means sleep is longevity, and longevity gives you sleep

    5. RCDr. Rangan Chatterjee1:25:14

       Sorry to interrupt. If you're enjoying this conversation, there's loads more like it on my channel. Please do press Subscribe and hit that bell. Now, back to the conversation

    6. DSDavid Sinclair1:25:24

       And they're interconnected, and to mess with one and not get the right amount of sleep is just going to put you on a path of aging more quickly.

    7. RCDr. Rangan Chatterjee1:25:36

       I think I read somewhere that in your own life, uh, you- you've had to make some changes in order to sleep better, one of them being wearing blue light-blocking glasses. Uh, is that correct?

    8. DSDavid Sinclair1:25:47

       Yeah. I- I've never slept well without help. I typically, um, go to bed late. Uh, I've been going lately to sleep pretty late, uh, 1:00, 2:00, 3:00 in the morning. Um, I have friends overseas. This is my problem. But, but I've learned to be able to modifying my life so that I get better sleep and deeper sleep. Uh, there are supplements. There's one called L-theanine.

    9. RCDr. Rangan Chatterjee1:26:14

       Yeah.

    10. DSDavid Sinclair1:26:14

        Um, a bit of melatonin is, works well for me. Um, but yeah, I, I now re- relax. I don't read emails past 10:00, and I also, um, tend to wind down and not stress, uh, late at night. And the blue block- blue light-blocking glasses have been helpful, too. I try not to stare at a screen, and if I do, I turn down the blue light on my computer and on my phone.

    11. RCDr. Rangan Chatterjee1:26:41

        When you were talking about SIR-1 there, it, I also thought, well, actually reversing someone's age actually may also help improve their sleep, right? 'Cause as you get older, you don't sleep so well for a variety of reasons, including biological ones. So it, it, it seems reasonable then that reversing the clock is actually, for some people, gonna help them sleep better?

    12. DSDavid Sinclair1:27:08

        Yeah. Right. Well, exercise and, um, and a good diet really does help with sleep. We see that. Uh, what I'd like to do now i- now that we can reverse the age of the brain is test if, uh, that improves the sleep-wake cycle of these old mice. Um, we do know that if we feed them NMN or resveratrol, they do sleep better, and they have better rhythms. Um, and, uh, so that would fit with that theory.

    13. RCDr. Rangan Chatterjee1:27:33

        Yeah. Yeah. Let's talk about stress. Um-

    14. DSDavid Sinclair1:27:37

        Yeah

    15. RCDr. Rangan Chatterjee1:27:37

        ... the right dose of stress and the right intensity is a hormetic signal to the body. So it's not that all stress is bad, but many of us around the world these days live with a sort of chronic, unrelenting stress from the way our lives are currently set up. So what impact does chronic, unrelenting stress have on our biological clock? Uh, and do you have any sort of strategies as to what we might be able to do about that, specifically when it comes to aging?

    16. DSDavid Sinclair1:28:10

        Right. Well, I, I was a very stressed out kid. Um, I was always nervous, had butterflies every day of my life, and so I've been able to cope with that. I now actively reduce my stress levels even though my daily life is way more stressful than it ever has been in, in any previous decade. You know, I've, I've got a dozen companies. I've got millions of dollars to lose that I've invested. I've got a big lab to run. I'm writing another book. Th- this is a lot of stress, but I don't get stressed. Uh, I've ba- managed to cope with it. And one of the big things that I've learned with my old age, older age, uh, is that nothing's as bad as you think. And my mother died in front of me from suffocation, and at that moment, I realized that if nobody died today that I know of, uh, it's a great day. Uh, and that's how I live life. I'm happy to get up in the morning. I'm still alive. I'm excited about what I do. Um, and that's a conscious thing. I think my default would be to be mopey and depressed and lack energy. So anybody who feels that way, find a purpose. Realize that life is here to be enjoyed. Every day is a blessing. We don't get that many days. Um, and you can actively fight to be excited about life rather than pessimistic, but you have to focus on the positive. It doesn't come naturally to most of us.

    17. RCDr. Rangan Chatterjee1:29:41

        A lot of the work of yours that, that I've read is around the biological process of aging. You know, what is going on in a cell? How can we change that? How can we improve things? But there's another side to living as well, isn't there? There's the more, I guess, spiritual, uh, side to life which many people start to connect with as they get older. What is the point of life? What is the meaning of life? And you sort of touched upon a bit of that there, and I find that really interesting 'cause you're someone who is, as I said at the beginning, completely changing the way that we view the inevitability of aging. I know this s- past summer, uh, I had a l- a lot of death in my family within a few weeks, aunties, uncles, which really caused me to reflect on what does it mean to actually be alive. A- and I wonder for you, David, someone who's right at the forefront of longevity research, what has studying aging, what has studying delaying death taught you about what it actually means to be alive?

    18. DSDavid Sinclair1:30:53

        Right. Well, it's a, this is what, uh, I think everybody should try to do, and that is to consciously think about your death every day. It's, it's scary, right? But if you imagine your funeral, or even worse, imagine your last 10 minutes of life, what that's gonna be like. Will you have regrets? Will you be surrounded by family? What will people say about you when you're gone? Uh, I think about that a lot because it's in my job. I, I'm, I'm working on ways to not prevent, but slow that eventuality. And what I've ended up doing in my life is being much more cognizant of the brevity of life. When I was in my 20s, like all 20-year-olds, we think the future is so far away you don't even worry about your mortality. Um, tell you what, by the time you get to 50, you can actually see that there are fewer days potentially than you've lived already. So that, that happens to everybody. But try to, if you're young, try to live life like every day counts. One saying, I, I hear that it's a Jewish saying, but one that I think of often is, uh, I do live my life like it could be my last, but I have the optimism of someone who can live forever. Uh, and that's really the secret. It's to be excited but realistic that you may not be here tomorrow. So tell your loved ones that you love them, make the most of every day, work hard on what you find passion in, um, and just be energetic. And if you do take control of your life mentally and physically, eating the right things, doing the right things, reducing stress, you will naturally be more optimistic about the future and every day that you wake up.

    19. RCDr. Rangan Chatterjee1:32:44

        We know that having a strong sense of meaning and purpose is associated with longer, happier lives. We know that loneliness is an epidemic that was a huge problem pre-COVID and, uh, for many people has become a lot worse over the past 18, 20 months or so. Where does this all fit in to your model of aging? Because let's say you're doing all the right things with respect to these three pathways that have been identified, you know, sirtuins, mTOR, AMPK, yet at the same time, you're lonely so your body is in a state of stress because it's isolated and, you know, on an evolutionary level, that means you're prone and vulnerable to attack, so you activate the stress pathways in your body or you don't have a sense of meaning and purpose. You know, w- where does this sort of fit in with us changing and taking control of our biology, whereas I guess these are the, the kind of softer components, uh, to life, which I think are the actually the really important parts of life?

    20. DSDavid Sinclair1:33:50

        They're essential. There, there's a study from Harvard that was done in the 20th century looking at people's lives, uh, war veterans, and the people that had a partner who cared for them deeply, they were the ones that lived the longest. In fact, it was more important than any other component in their lives, was having someone who cared for them emotionally and I guess at the end of life, physically. So if you're lonely, I think that it's one of the, the fastest way to age. And loneliness is an epidemic right now. Uh, it's just getting worse. So what are the solutions? Well, we have the internet at least. We can be in touch with people. We can get-- We can have pets. A lot of people have bought dogs and cats recently to overcome that. Uh, and if you have divorce, try to cope with it, uh, and then find someone new. If you have a job that you don't have a purpose in, you hate your job, most people do, if you have a long life, then you have a chance to retrain, you have a chance to do multiple careers like my father did. I call these pauses in life skill verticals. In fact, I think the governments should be paying for them. Um, so the, really what I'm talking about is try not to fall into the, the trap of, um, being isolated. Get out there, find friends, connect with people, even if it's through the internet, because loneliness, as you mentioned, is a very dangerous thing long term.

15. 1:35:23 – 1:44:44

    Critics, his daughter and how long we might live

    1. RCDr. Rangan Chatterjee1:35:23

       Are there any critics of your work, David? Are there many people saying, "We shouldn't be doing this. This is not what it means to be human"? And I'm particularly drawn to this. Um, I was rereading your book over the last couple of days, and there's a very poignant part of the book where you mention at the time of writing, I think your eldest daughter, Alex, was 16, and you wrote about how she was sort of questioning your work and questioning in a, in a world which is struggling with all kinds of problems and the climate and, you know, the environment. And, uh, it seems to have really, really struck you that your eldest was actually questioning this incredibly important work you're doing. So I'm interested as to do you ever have doubts? Do you ever think, "Man, I'm actually barking up the wrong tree here"? Um, but also how your view, and maybe if you're willing to share, how your daughter's view may have, may have evolved over the last two or three years.

    2. DSDavid Sinclair1:36:20

       Oh, that's, that's one of the best questions I've been asked in recent memory. Um, I also had, uh, my wife w- w- was telling me that what I was doing w- was unethical, so it's been tough. Um, and I've had a lot of critics on the science side and the ethics. So I've had to grow a thick skin. I wasn't born with it. So let's just focus on Alex. Alex is now 18 and went off to college a few weeks ago. Uh, Alex inherited the FU gene just like I do. I'm a rebel. I f- I always go against what people say. I'm a scientist. They're a scientist in, in training. They have changed their mind. In fact, just in the last week, Alex has started work on longevity at, at, uh, uni, at the college.

    3. RCDr. Rangan Chatterjee1:37:09

       Oh.

    4. DSDavid Sinclair1:37:10

       She's at, uh, they are at the, um, uh, University of Rochester in New York, and without me saying anything, signed up for a lab that studies the longevity, the un- re- the remarkable longevity of the naked mole rat which can live 30 years instead of a rat, which is a few years. And I just posted on Instagram a few days ago a picture of Alex with thumbs up in the lab having just, uh, fed and washed and, uh, removed the bedding of those naked mole rats. And I, I can't remember being so proud of, of one of my kids as that moment when they were fighting everything that I did, uh, and then without me doing anything said, "Okay, I give in. I'm gonna work on this too."

    5. RCDr. Rangan Chatterjee1:37:57

       Yeah. I- I- incredible. Um, I ca- I can just see the pride [laughs] and the excitement in your face as you, as, as you recount that story. Um, how do you, how do you really feel, you know, when people attack you? Um, you said you've grown a thick skin. Because I, I guess if you think about your work, on the outside it could be, you know, can this man and his team and other teams around the world help us live to 120, 130, 140, 150? I mean, I don't know if you, you know what is a reasonable human lifespan based upon the work that you've done. But, but there's also like a, an under- underlayer which, uh, for me is in some ways even more fascinating, which is if aging is the root cause of all problems that come in to see me as a doctor and afflicts humanity, well, if we can just sort of tackle that right ... you know, turn the tap off, how many lives do we improve? No matter whether their lifespan's 80, 90, 70, 100, actually the quality of all of those lives is gonna be so much better and enhanced irrespective of that final age, right?

    6. DSDavid Sinclair1:39:15

       Yeah, it is. Uh, I don't wanna get too emotional, but the way you described it is, is really what I'm living my life to, to achieve. And that is that we will be in a world where there's much less suffering and a lot more happiness, joy, and productivity. Uh, the economy will boom and families will be happier. Um, and it's just gonna be a much better world. And when we reach that world, and maybe it's only 10 years away, uh, we'll look back at today and think, "Why did we ignore this for so long?" And it, it, it warms my heart that, that you and many other doctors, uh, and the public, uh, probably close to a million people around the world now have read my book-

    7. RCDr. Rangan Chatterjee1:39:57

       Wow

    8. DSDavid Sinclair1:39:58

       ... and, you know, changed the way they think about their lives, the course of their lives, what they can do, that they can actually change the course of their lives pretty easily. Um, and when this becomes a global phenomenon, and it, it is, it's really taking off around the world, uh, that millions of lives are going to be improved just by simple things. Not, not even to mention these high-tech things that we're working on.

    9. RCDr. Rangan Chatterjee1:40:24

       W- w- what, what do you think is a reasonable age that most humans could realistically hope to live to based upon what you've seen so far?

    10. DSDavid Sinclair1:40:34

        Yeah. Um, well, what I've been allowed to say publicly has changed over time too. Um, five years ago when I stood up, up on a stage at Stanford University, uh, I said for the first time, "Age reversal," and this was talking about the mice that were on a treadmill, which clearly was age reversal. There's no question about it. But those two words, it was ... they'd never been said before in public by a scientist. Now it's all anybody talks about. It's only been five years. So that's a long way of, of me saying, um, A, I'm, I'm more comfortable saying numbers that before my colleagues would write emails telling me I'm, I'm damaging the reputation of our field. Um, I once said the first human to live to 150 has already been born, and that has been said by a lot of people now. I actually got an email from someone I respect who said, "You cannot say that. Stop it. It's embarrassing." Now they say it. And it's ... so it's funny in five years how much has changed. So what do, what do I really think? Um, I think that just an extra 15 years of life is easy. If you just don't smoke, don't drink, eat the right things, eat less, get good sleep, don't stress out, do a bit of exercise, that gets you 15 years more of life. That's ... we already know that. That's not hard. Imagine if everybody did that on the planet or at least, you know, in, in, uh, advanced countries where, you know, they have the time and money to do so. That, that's hundreds of millions of people, uh, if not billions. But then on top of that we've got drugs like metformin, rapamycin. There's others. Uh, there's one called acarbose. There's a spermidine one. There's, there's a, a long list and, um, if those are used I am quite confident that we can add more years on. Then there's the age reversal technology that we've just discovered that could change everything. So what's realistic? I think i- if you do the right things, you should be able to make it to 100 if you're lucky. You know, you ... everyone's unlucky, uh, can be unlucky. Cancer can hit you. But, um, or a bus can hit you. But I think 100 is a realistic goal. Um, I think I should be able to reach that with what I'm doing. Uh, but what about beyond? Now we know that humans can live to 120. Why couldn't we all? Just we have to level the playing field and give us those, uh, advantages that they had. And typically the people that live to 100 and 120 don't look after themselves. They don't exercise. They smoke. They, uh, they overeat. So what would've happened to their lives if they did do the right things? Why couldn't those people have lived to 125, 130? You know, so that's why with all of this, and I haven't even talked about resetting the age of the body, polishing those scratches, why 150 is not unreasonable for somebody to reach. Someone who lives to 150 or at least over 100 who's born today will live into the 22nd century. We can't even imagine what the technology's gonna be like then. It'll make the kind of things we're talking about now seem medieval the same way that the world was pre-antibiotics. Um, so I, you know, I'm optimistic. I'm often classified as someone who's overly sanguine. But, you know, so far I haven't been proven wrong in any of my predictions. I haven't been proven wrong in any of my scientific publications. You know, so we'll see, and I put them on record in my book.

    11. RCDr. Rangan Chatterjee1:44:13

        Yeah, you certainly have, and it, it's a phenomenal read. I, I really would recommend everyone have a copy to, to get through it because it's just so fascinating. The ... And you have an incredible writing style. You clearly have a, a deep love of history and storytelling, which makes it a very fun read. But that's an incredible thought that a person who is gonna live to 150 has already been born. I just want everyone to sit with that for a minute because I think that's [laughs] such a powerful statement. And let's

16. 1:44:44 – 1:58:27

    Age reversal technology, overpopulation and incentives

    1. RCDr. Rangan Chatterjee1:44:44

       talk about some of this age reversal technology. So you have touched on it. You've hinted at it a couple times in this conversation. So what is going on there, and how soon do we think this might be, I guess, more widespread than just the small research trials?

    2. DSDavid Sinclair1:45:00

       All right. Well, the, the thing to know really is that the world has shifted after the ... We published this paper in December. Uh, it's become the most downloaded paper, at least in the last 12 months, in the journal Nature. I think it's 80,000 downloads at this point, which is massive. $20 billion have been already, uh, collected to invest in this area of reprogramming and aging research. 20 billion, and it's just the beginning. This is private money and sovereign wealth. Now, I could get hit by a bus tomorrow, but the wheels are in motion that make it certain that this is not an if but a when that we can reverse the age of the body with a treatment. Now, right now the treatment is a gene therapy. Uh, in the patients that we're going to treat, it's going to be a very quick injection into the eye. We're going to introduce three embryonic genes into the retina and the optic nerve, turn them on for three to eight weeks, and if we're right, the age of the eye and those nerves will go backwards in time. They will be s- 75% or so younger, and they will be rejuvenated and work again. And people will get their vision back if everything goes to plan. And that, the first patient we're going to dose probably in 2024. Uh, we're already treating non-human primates this month after extensive safety studies in mice that look really great. We haven't seen any evidence of cancer being promoted anywhere in the mouse, which is great because that's, that's the biggest possible downside is to ... If we take the body back too far, it might get a tumor or develop cancer. But that doesn't happen. The way we do it is using three embryonic genes called OSNK for short, and using those three we found that there's a barrier to going too young, and we don't get cancer. And that's just, that's just fortunate that biology works that way. And we think we're tapping into an ancient mechanism that other species use to grow new limbs and to heal and to regenerate their brain, like a salamander would or a jellyfish, and we're finally using those advanced biologies in our own adult life. That's the plan.

    3. RCDr. Rangan Chatterjee1:47:18

       I don't really know what to say. It's so mind-blowingly incredible to hear that. And, and I guess this would ... I mean, the implications for everything like Alzheimer's, neurodegenerative disease, uh, all kinds of different conditions. It, it's just incredible, right?

    4. DSDavid Sinclair1:47:38

       Well, we o- we only chose the eye be- because, uh, it was an interesting challenge, and gene therapies al- are already approved for the eye. But we're ticking off the tissues. We've done the whole mouse. Uh, it was fine. Uh, no cancer. We've done muscle, skin. Uh, we're doing hearing. Uh, we're doing, uh, spinal cord injury. We can regrow nerves in the eye. We're gonna re- hopefully regrow them in the spine. The heart can be rejuvenated. We've already reversed the age of the brain in the mouse, and they get their ability to learn back. We haven't found a part of the body that doesn't respond to reprogramming, polishing the scratches. So yeah, I think every branch of medicine will ... This is potentially going to be useful for, um, joints I mentioned. Right now there's not much you can do for osteoarthritis except steroids. We think that we can regenerate entire, uh, joints by reversing the age of those tissues. Same for the immune system. Why not rejuvenate the body? And we wouldn't have a pandemic if that were the case.

    5. RCDr. Rangan Chatterjee1:48:42

       Do you have to do different organs separately? Because I'm, I'm just sort of tr- imagining in my head that, I don't know, let's say I was 60 years old and we reversed the age in my, I don't know, joints to, let's say, 55, but my eyes had degenerated and they were sort of the eyes of a, let's say, a 70-year-old. So I've got super great joints, but my eyes were still at my chronological age or even older. Uh, do you see what I'm getting at? Do you have to do it all separately to sort of sync up everything in the body, or can one thing actually do multiple organs at the same time?

    6. DSDavid Sinclair1:49:22

       Well, based on, uh, the, the publication that we just put out, uh, we can treat an entire mouse with this, uh, gene therapy, uh, with no downsides. Um, and- Others have shown that that rejuvenates spleen and liver. Um, so I think that if, if we got a bit of luck here, we should be able to have one treatment that can rejuvenate the body. Now, in the lab, we isolate tissues. Um, we like to study them individually 'cause we grow them, uh, in a dish as well. Uh, but I am just as interested in whole body rejuvenation as I am in individual tissues. Um, of course, the, the easiest way to make a drug, which is what I'm trying to do, is to focus on one particular part of the body and fix that first because the government regulators prefer that. You know, otherwise, they're worried about safety issues. Um, so that's why I'm doing an iterative approach. But, you know, mark my words, my goal is to rejuvenate, and, and it looks like it's gonna be possible to rejuvenate the entire body with one treatment, and it may not be a gene therapy 10 years from now. It could just be a course of, you know, some pills that you take.

    7. RCDr. Rangan Chatterjee1:50:34

       What does the world look like, David, where humans can reverse their age potentially indefinitely on multiple occasions, sort of knock the clock back? Let, let's say ... I don't know. Let's say every human could live to 150. Thought experiment. In a world where people are already saying that we have too many people to be able to sustain life in a way that we would like to, uh, is there a case to be saying that kind of we shouldn't be doing this? Or, or have you thought it through as to if we can prolong the age of multiple humans across the planet like this, you know, what, what does the world look like or what might it look like i- in your view?

    8. DSDavid Sinclair1:51:22

       The analogy that I use in my book is old London from the early 1800s where, you know, Charles Dickens kind of world where there's horse poop on the streets and kids running around that haven't had a bath for a year, child labor. And s- if you ask somebody then, "If you tripled the size of London, what would happen?" They'd say, "Oh, the cholera outbreak and the river is gonna be more polluted and horse manure up to our necks." Well, if you look at London today, that didn't happen. Why? Because we engineered our way. We scienced the crap out of it, and we've stopped cholera. We don't have horses. We have sanitation, and we stopped kids from working. Um, so that's ... But there are solutions to everything. And even if there are more people, uh, I think we can live with much less impact on the planet. We are already. We're moving to battery and solar and wind, and we're getting, getting there. But the important point ... Actually, two important points. One is that we're not gonna be overpopulated. If you do the math rather than just use your gut, uh ... And I've done the math. We're not going to be overpopulated. Um, we can't all live forever, and that's not gonna happen in our lifetimes. But even if we were to stop aging today, the population growth rate would still be 1 or 2%. Now, we're not stopping aging, of course. We're just delaying diseases, which is what all medical research is trying to do, by the way. Um, but the numbers are, are the following, that we're going to level out at 10 billion people on the planet, and it's gonna start coming down. Already developing countries, Africa, are greatly slowing their rate of growth in terms of population. Europe is a negative. America, USA, is negative. Australia's negative if, if it wasn't for immigration. So humans naturally don't replace themselves, right? So what do you do? Well, you can fill it out with people who are more productive. Now, the second point is productivity. We calculated that the value just to the US economy by extending lifespan just by one year, which we could easily do ... If everyone read my book, that would happen. That would be a value to the US economy at, of $38 trillion over the next decade. If you extend lifespan, healthy lifespan, by 10 years, which I g- again, we can do, that would be $365 trillion. Now, okay, those are big numbers, but what does that mean? That's more important than stopping military spending. These are numbers that can be put to solving most of the world's problems where, you know, if it, if it would include climate change, education. That's a lot of money saved rather than squandering it on keeping people alive in nursing homes where we basically kept their heart beating, but their brains have gotten old. That's the worst way for us to practice healthcare, and it's extremely expensive.

    9. RCDr. Rangan Chatterjee1:54:22

       Yeah. A- I mean, what you said there, I guess that's what all treatments are trying to do is delay aging, and you're absolutely [laughs] right, of course. But then also, you know, you, you said earlier that the simple things, eating less, eating healthier, moving a bit, um, you know, not smoking, these things you said could give us an extra 15 years. So to give us an extra one year, which will give all these savings, you just then think, why are governments not more aligned with this because the way diets are promoted, you know, highly processed diets that really aren't, uh, health promoting in any way. They're sort of disease promoting. Uh, it, it seems like the incentive system is all kind of skewed and messed up, and i- is that something you're trying to tackle as well by presenting this data?

    10. DSDavid Sinclair1:55:10

        Yes. I, I'm trying to overcome, uh, the human's desire for sedentary lifestyle and consumption, um, and laziness.

    11. RCDr. Rangan Chatterjee1:55:21

        Yeah.

    12. DSDavid Sinclair1:55:21

        You know, w- we, we evolved this way because it conserves energy, um, and we enjoy sitting around. We enjoy eating. That's important if you're going through feast and famine. If it's always feast- And you don't even have to exercise, and your suitcases have wheels on them. Then this is a world where that is going to kill you or accelerate your aging. But we, we love sweet things. We love being lazy. We love watching movies, eating sweet popcorn, eating fat. That's what our brain responds to. But that's just dopamine, right? That, that's not what's good for us in this, today's world. And the reason that we are in such trouble, uh, is that we are a capitalist society, and companies' goal is to sell more stuff to us. And so they know what gets us excited. They know that we will respond to dopamine on our phones, and sweet food, and salty. And they make food that, that is perfectly setting those triggers off. Um, ketchup, perfect food for making you feel comfort and stimulating your dopamine. But high-fructose corn syrup, the worst... one of the worst foods you can eat. So w- in capitalist society, we've, we've got this force, and governments find it very hard to regulate because their view, particularly in the US, is that markets will determine what's best for the customer and for the population, which clearly isn't always the case.

    13. RCDr. Rangan Chatterjee1:56:52

        You mentioned high-fructose corn syrup. Uh, earlier on, you mentioned the benefits of olive oil on sirtuins. Um, you know, one of the common things that are used to cook foods in these days are seed oils, whether it's, you know, sunflower oil, I guess rapeseed oil, corn oil. Um, have you done much research as to how these things impacts aging?

    14. DSDavid Sinclair1:57:16

        Uh, no- n- nobody has, actually. Um, I think it, it, it would be a great area to study. And, uh, clearly there, there are some oils that are particularly bad. Um, the, the saturated ones and the hydrogenated ones are, are known. But in the context of aging, um, the closest thing that people have come to is to look at the various fatty acids, um, you know, DHA, DHA, for example, from fish.

    15. RCDr. Rangan Chatterjee1:57:45

        Yeah.

    16. DSDavid Sinclair1:57:45

        Those are very healthy even for mice. But it... We really haven't looked into it as a field, and I think we should. I've actually... I switched my supplement from a fish oil to one that has more oleic acid.

    17. RCDr. Rangan Chatterjee1:57:58

        Yeah.

    18. DSDavid Sinclair1:57:58

        And oleic acid is the one that activates Sirtuin, and you find it in olive oil and avocados. Um, but again, it, it's a guess that that's optimal for me. Uh, again, we, we always need more research. This is a fact of life. But the sad thing is the government in the US spends a fraction of 1% of the research budget on aging, the biology of aging. Um, and I think that really needs to change because they're ignoring the major cause of diseases in this country.

17. 1:58:27 – 2:05:27

    Cold, heat exposure and final advice

    1. RCDr. Rangan Chatterjee1:58:27

       Just to start closing down this conversation, uh, David, I, um, I did wanna touch on cold exposure if, if possible. You... We started off this talk- talking about hormesis, and, you know, what doesn't kill you makes you stronger. How does cold or cold and heat fit into that? And what sort of recommendations do you have for people w- with respect to longevity?

    2. DSDavid Sinclair1:58:50

       Well, when I was writing my book, my editor said, "You should put this cold therapy in, and saunas." And I, I rolled my eyes. I wanted to write a really scientifically based book. But I looked into it anyway and actually found that there was decent scientific evidence that both of these approaches could work. Um, in saunas, 'cause the saunas have been around since pre-Roman times, there's a, a... there's more evidence that they're good for you. Uh, there are Finnish studies in from Finland looking mostly at men, um, for whatever reason. So the Finnish typically sauna bathe, as they call it, a few times a week. They have them at home. And it's very clear that the more times you go in the sauna per week, the less cardiovascular disease and heart attacks you have as a, as a man. I don't know about women, but pro- probably the same. And so the... I think that raising the core body temp... well, not core, but the surface and lung temperature of your body may induce hormesis. We know heat shock proteins that come on with heat can extend lifespan of animals, so that's makes sense. And on the cold side, we don't know as much about that. It's, it's more recent. But, uh, we do know that cold does induce what's called brown fat, which we have on our shoulders and back. Only discovered 15 years ago to exist in adults. Babies have it 'cause they don't shiver. They actually use their brown fat to stay warm. And brown fat is very healthy metabolically. Um, it burns energy. It's got lots of mitochondria. And it's thought that the brown fat secretes little molecules in the bloodstream that's helping the rest of the body. So there is some evidence that being cold and shocking your body that way is also inducing hormesis. Um, there's a sirtuin called sirtuin number three, Sirt 3, and that one is induced dramatically in levels by cold. Uh, and so again, just more evidence that putting your body into adverse conditions the way we used to live before we had air conditioning and heating, uh, can really be beneficial.

    3. RCDr. Rangan Chatterjee2:00:54

       Is that something you try and implement in your own life based upon what you've read now?

    4. DSDavid Sinclair2:00:58

       I used to. Uh, pre-COVID I used to go to the, the gym, and I would dunk myself in, in a cold water bath and go in the sauna and repeat that. I loved it. I haven't gone since, uh, the pandemic, but I wanna get back into it for sure.

    5. RCDr. Rangan Chatterjee2:01:11

       Yeah. It's incredible. I spoke to, uh, a doctor, uh, Roger Seheult recently on the podcast, and he was sharing other research showing how this sort of hot-cold therapy can have a remarkable effect on our immune system and, and our ability to fight off infection. So, you know, all these... I guess we've have one human body, right? If the immune system's working better, it's probably a good thing. It's probably gonna help us- ... delay aging. Uh, so I guess more evidence there to support that. David, it, it's been a, just an utter joy talking to you. Uh, I've waited a long time to speak to you. I'm, I'm really, really so grateful to have had the opportunity to pick your brain and, and share your work with my audience. Um, this podcast is called Feel Better, Live More. When we feel better in ourselves, we get more out of life. And I wonder if right at the end here of this conversation, you could m- leave my listeners or viewers with, you know, what are some of your best tips, some of your kind of practical wisdom? A lot of it you've shared already, but just to bring it together at the end. But also for anyone who's skeptical, anyone who thinks, "Come on, you know, should we be doing this? Can we really do this?" Uh, what are, what are, what are your final thoughts for my audience?

    6. DSDavid Sinclair2:02:30

       Well, I wrote in my book that w- we all have a choice, and we all have the power to live healthier for longer. And some people say, "Well, why should I?" Well, my view is that you have a f- family, I assume. Many of us have children. You don't just have a right to live longer, you have a responsibility to your children to stay healthier for longer. Otherwise, it's extremely selfish putting yourself into a nursing home and getting sick at a young age. Your kids want you around, and you don't wanna be a burden on them. So I would, I would think of it that way, which is if you don't wanna do it for yourself, do it for your kids. That's one. The second is, it's not that hard, and it, it works. Eat less often, eat the right foods, move a little bit, even if you need to walk or stand up, try to lift a few weights or do yoga or Pilates. These are the easy things. If you smoke, that is the fastest way to accelerate your epigenetic clock and scratch up that CD. So if you like listening to scratched up CDs and music that sounds like crap, by all means, you know, keep smoking. But I'm, I'm an advocate for quitting. My mother died of lung cancer, and it was a horrible death. I watched her suffocate in front of my eyes, and I got to whisper to her ear that she was the best mom I could have wished for. Please quit smoking if you smoke. Use any method that you can. Um, same with alcohol. A little bit is okay. Red wine is even better, but don't overdo that either. So that's what I'm saying, is that we have the tools right now to live years, and I would say decades longer, and that the science that's coming along is just remarkable. In the same way that we've now seen the Wright brothers fly and we're looking forward to seeing commercial air flight, the Concorde, and even space travel, that's gonna happen in our lifetimes, I'm certain of it. Um, and it's, uh, really the most exciting time to be alive that I could imagine happening, and we're way ahead of schedule in terms of technology than I thought I'd see in my lifetime.

    7. RCDr. Rangan Chatterjee2:04:51

       David, you're an incredible human being. Your work is literally transforming the world. Thank you for making time to come on the show, and, uh, I hope I get to meet you in person at some point.

    8. DSDavid Sinclair2:05:02

       That'd be great. I'll give you the Willy Wonka tour of my lab. It's been great to be on. Thank you.

    9. RCDr. Rangan Chatterjee2:05:06

       [upbeat music] If you enjoyed that conversation, I think you are really going to enjoy the one with Professor Shane O'Mara. It is right here. Give it a click, and let me know what you think. And click here to download my super practical free breathing guides. Our bodies and brains need movement. The brain changes dynamically in response to what you do to it. If you leave it, it tends to atrophy

Episode duration: 2:05:27