#60: How to Reverse Ageing (Part 4 of 4). The Future of Longevity Research

15th Jul 2020

David A. Sinclair, Ph.D, a tenured Professor of Genetics at Harvard Medical School, is best known for his work on genes and small molecules that delay ageing, including the Sirtuins, NAD precursors, Resveratrol and other epigenetic modifiers.

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He has received many honours including a feature on TIME magazine’s list of the “100 most influential people in the world” and this podcast episode about how to treat and reverse ageing will give you a glimpse into why he is so deserving.

On the show we talk about:

  • The hallmarks of ageing and why to distinguish it as a disease
  • Instead of trying to tackle each one of the 8 central tenants of ageing, how Prof is looking at the epigenome
  • Sirtuins and their role in ageing, DNA repair and gene expression
  • AMPK, MTor, Sirtuins as regulators of lifespan and defence pathways
  • Methods of fighting ageing and activating the body’s natural defence systems
  • Energy restriction, aerobic exercise, sauna and cold shock therapy
  • energy restriction, exercise triggering hypoxia, sauna, cold shock therapy,
  • NAD and NAD precursors, Metformin, rapamycin and resveratrol as molecules that can improve ageing
  • Why we need to treat ageing like a disease, which forms the foundation of multiple diseases. If we cure ageing, we cure a lot.
  • The ethical considerations of increasing lifespan

Do check out David’s work and his latest book - Lifespan - Why We Age and Why We Don’t Have To.

Episode guests

Professor David Sinclair

David A. Sinclair, Ph.D. is a tenured Professor of Genetics at Harvard Medical School, co-Director of the Paul F. Glenn Center for the Biology of Aging Research at Harvard Medical School, and Con-joint Professor, at the University of New South Wales, Sydney. He is best known for his work on genes and small molecules that delay aging, including the Sirtuins, NAD precursors, and other epigenetic modifiers. He serves as co-chief editor of the scientific journal Aging and has received 35 honors including being one of Australia's leading scientists under 45, the Australian Medical Research Medal, the NIH Director’s Pioneer award, TIME magazine’s list of the “100 most influential people in the world” (2014) and the “Top 50 people in Healthcare” (2018). He was elected an Officer of the Order of Australia in 2018.

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Podcast transcript

Professor David Sinclair: And then the question you can ask yourself is if you were not to age, would you get sick? Would you get diseases? And I'm arguing that you wouldn't. Now, bad stuff can still happen, we can have mutations that cause disease and cancer is one of those. But I think it's important to realise that our bodies are capable of great healing, they're capable of killing cancer cells on their own through the immune system, and that the breakdown of those processes in large part is the reason why we get sick.

Dr Rupy: Welcome to the Doctor's Kitchen podcast, the show about food, lifestyle, medicine and how to improve your health today. My name is Dr Rupy. I'm a medical doctor, I also study nutrition and I'm a firm believer in the power of food and lifestyle as medicine. Join me on this podcast where we explore multiple determinants of what allows you to live your best life. And remember you can sign up to the doctorskitchen.com for the newsletter where we give weekly recipes plus tips and hacks on how to improve your lifestyle today. This is the final episode of our four-part series on how to reverse aging. And today's episode is treating aging as a disease with Professor David Sinclair. My guest today is a world-renowned professor. He's named one of Time magazine's most influential people on the planet. He's a tenured professor of genetics at Harvard Medical School. He's co-director of the Paul F. Glenn Center for the Biology of Aging Research at Harvard Medical School and is best known for his work on genes and small molecules that delay aging, including the sirtuins, NAD precursors and other epigenetic modifiers. Now, this is going to be a little bit more of a technical podcast, so bear with me. I'll try my best to explain the technical nomenclature as much as possible as we go on, but I think you're going to find the insights from David Sinclair exceptionally useful and applicable to your daily life. Now, it's well known that diseases associated with aging have a common ground in their mechanism and what we can do with lifestyle to delay death and increase healthspan is actually quite incredible. David has written an amazing book. It's questioning whether aging is a disease and if that disease is treatable. It's called Lifespan, it's out now. The links for all which are on my podcast show notes on the doctorskitchen.com and also on the podcast notes as well. There's a few things I think everyone needs to understand before we get into this. So, the information theory of aging, what are the the hallmarks of aging? Well, there's epigenetic changes, so changes to the expression of our genes, not the genes themselves. There's changes in the cell communication, there's inflammation, a topic that we talked about on a previous podcast, protein misfolding, there's telomere loss, there's little bits of genetic material at the end of our chromosomes that protect them, metabolic changes, and and all sorts of other things as well. Rather than individually trying to tackle all those hallmarks of aging, what Professor Sinclair is trying to get us to understand is what's the root cause of that? What is the unifying theory? And his theory is that instead of looking at those in isolation, it's the reading of our DNA, our genetic material that has gone awry. It's the the way we express our genes rather than the genetic material ourselves. Our genetic material is very, very robust and actually he talks about in the book about how one of the first things he did when he was a scientist is try and boil the the DNA. But the the way that DNA is read is what unfortunately goes wrong. Once you understand what's going wrong with aging, there are a three main ways to fight aging. So, there's activating your body's innate defence mechanisms. The main two ways that we know scientifically to do that is by calorie restriction, so it's actually reducing the amount you eat in terms of its energy content, and exercise. And we've known that for a number of years, you can expand the extend the lifespan of of mice and other animal models by just doing those two things. There's another way of doing it, which is by deleting cells that cause problems. So these are called senescent cells, the sorts of cells that hang around, they're not really doing much, but they emit a lot of inflammation and can lead to a lot of issues with aging. There's a new class of molecules called senolytics that David talks about in his book as well. The other thing is partial cellular reprogramming. Now, this is the scientific method that's currently being researched in David's lab, which is how you actually reverse the age of cells. It's essentially the term for a true resetting of how we read that genetic material rather than the genetic material itself. I will sum up essentially what we talk about at the end of the podcast. Um, so you'll get an overview of everything. So listen right to the end. I'll explain all the sort of ins and outs of what we discussed and just break it down into some actual principles and why I'm actually so excited about this field because I think it really has the power to revolutionise medicine as we see it today, uh from one that's reactive to one that is proactive. Without further ado, here is my conversation with Professor David Sinclair.

Dr Rupy: How are you at cooking vegetarian?

Professor David Sinclair: Uh, very, very well versed. So, uh, most of the meals that I create are plant-based, um, uh, because I'm of the opinion that we need to focus on fibre rather than animal proteins. And I think, um, it's something actually you talk about in your book, isn't it? Uh, regarding, um, mTOR activation through, uh, animal proteins and how actually, you know, we probably want to dampen down the amount of total protein that we have, uh, in choice of of more plants and variety.

Dr Rupy: Yeah, well, actually, what I wrote in my book is is also being augmented by new publications coming out. And, uh, one of the things that just came out this morning, uh, that I read was, uh, this is a mouse study, but what they found was that if they gave, uh, mice some, um, a variety of different types of foods, uh, with more or less branch chain amino acids, and branch chain amino acids are found in more abundance in meats and dairy. Um, that those mice that ate a lot of those branch chain amino acids, uh, ate more food, became obese and lived shorter.

Professor David Sinclair: Oh, wow.

Dr Rupy: Yeah, and so I'm I'm not dead against meat in my own life. I I do try to avoid it as much as I can, but I also like to live a little. Uh, but this is another explanation for why, um, eating meat constantly is probably not a good thing. Yeah. One is it's inhibiting, uh, sorry, it's activating mTOR, which will not allow your body to to fight against diseases and aging. This is one of these longevity pathways that we study in my lab. But also, if this work is correct, it also means it'll make you hungrier if you have this type of food. Yeah. And together that's a terrible combination.

Professor David Sinclair: Absolutely, yeah, particularly in the modern world where there's food on every single corner. Um, great. So, I wanted to start with, uh, how you started the book with, uh, the anecdote about your grandmother, Vera. Um, was, and she sounds like she had the most incredible life, you know, being one of the first people to be kicked off Bondi Beach for wearing a bikini and, um, you know, it was her unfortunate decline that sort of put, uh, a lens on what aging really is. And I think a lot of people, myself included, can resonate with that with their own family members. Was that sort of the inspiration you had behind the the career that you ultimately chose?

Dr Rupy: Yes, I mean, for sure, she was a huge influence on me. And to take on something as complicated as aging and, uh, and actually as crazy and controversial as aging, uh, I needed to have a rebellious nature. And, uh, I think genetically I'm rebellious. Um, having seen my children. And, uh, but also epigenetically, I was taught by my grandmother to not accept the world the way it is, but look towards the way it should be and create that future. And she was also pretty upset with humanity and the way they conducted themselves in the 20th century, having lived through World War II and the aftermath. And she taught me that, uh, humans can do a lot better and I should make it my life's purpose to, uh, make humanity the best it can be.

Professor David Sinclair: That's immense. And I I it sounds like that sort of thinking is now been passed on to your daughter because I I know you there's an anecdote about how you have a discussion about whether your area of research is something that could, um, improve humanity's chances of longevity and, uh, a healthy planet. But we'll get on to that in a in a second. Um, before we we go into your research, I reckon, um, perhaps we could talk a little bit about the hallmarks of aging and the central tenets of aging and how you are really targeting aging as a disease rather than a collection of these different pathways that lead to what we see as, um, the degradation of our our muscles, our cells, our eyesight, and, uh, a propensity towards cardiovascular disease and and cancer.

Dr Rupy: Right. Well, actually, there are a number of things that we know cause aging. There are eight or nine hallmarks of aging, as we call them. And researchers, hundreds of them around the world have worked on these hallmarks. Uh, we're a little scared to call them causes of aging because that's a little out there, but they really are causes of aging. That's how we should refer to them. But in my book and and my research for for the last 25 years, I've never been satisfied with just making a list. You know, physicists aren't happy unless they can boil it down to an equation. And, uh, that's what I've been trying to do with aging. Is aging fundamental or is it just that bad stuff happens? And I I truly believe that that though a lot of bad stuff happens during aging and eventually manifests in diseases of old age and eventually death, that there's there's got to be something that is very simple at its very core. And the way to get to the core of something is to keep asking the question, why? Right? So, why does aging occur? Well, bad things happen into the to the happen in the cells. Why does that happen? Well, genes change and, uh, things go wrong. But why? And if you keep going down, usually it only takes five levels to get to the very core of it. And if you end up at the end of those questions saying, I don't know, that's just the way it is, that's not good enough. And that's the problem you want to work on. And that's how I ended up with the information theory of aging.

Professor David Sinclair: And this information of theory of theory of aging is where you make a distinction between, um, what we call the genome and the epigenome, and it's that sort of reading of that information that appears to go awry that may lead to some of the the tenets of aging that we've we've described. Um, how did you come up with that?

Dr Rupy: Uh, yeah, good question. Um, it really stemmed from 25 years of research and thinking about this as a problem. Uh, but it began in 1997 when I was trying to figure out why yeast cells age. And at the time, nobody had ever come up with a reliable theory, even why a yeast cell gets old. And one of the things that we discovered in the lab, and I'm not taking credit for this, um, there was a group of us, about seven of us rebellious scientists in the lab of Lenny Guarente at MIT. And the first thing that was discovered in that lab was that there are proteins that seem to regulate aging, and they're called sirtuins. And the sir part of that name is an acronym for silent information regulator. And these silent information regulators are information regulators. It's in the name, right? And so I started to think, what does that tell us about aging? And to cut a long story short, uh, I think that there that was key to understanding why we age, that aging is due to a loss of not the genetic information, but what we call the epigenetic information of the cell.

Professor David Sinclair: Gotcha. And you make this analogy between the genetic information being almost like the the DVD, and hopefully some of the listeners can remember what a DVD looks like. Um, but it's that that digital information, and then the reader, which is something that's analog, as you describe, it is what goes, um, it is what gets worn out. And if you can polish that that DVD, then that's how you can sort of hopefully help with aging.

Dr Rupy: Right. Well, so so for very young students that I teach, I have to remind them what a DVD is. Yeah. But hopefully most people know. It was a remarkable, uh, object that you could store a whole movie on. Imagine that. And, uh, but it's a really good analogy, I find that that the genome is the the little pits, the zeros and ones, the information. That's the digital part of our cells. Um, but there's also you have to remember that the cell doesn't just read every gene, it has to read the right gene at the right time for it to be the right cell. Um, and so it's similar to how a DVD gets scratched if you use it a lot. And then ultimately a a scratched DVD will not play a movie, it will skip and create havoc for the reader. And that's what I think aging is in a biological sense, is the inability of our cells to read the genetic information the way our cells did when they were young.

Professor David Sinclair: And and you've been studying these sirtuins for for a number of decades now. There's seven of them, I understand. Um, do do ones have a particular, uh, utility or are they particularly special ones or are they all just as important as each other?

Dr Rupy: Uh, uh, well, that there are just a couple of them that have been shown to extend the lifespan of mice, number one and number six. Uh, but that said, there are thousands of papers now written on all of these different seven sirtuins. And they do various things. So, and all of which seem to be good for us. Maybe not all, but almost all. You know, 99.99 of the papers, percent of the papers actually show positive benefits to cells, to mice, and hints in humans as well, based on genetic studies and, uh, people that tend to live over 100, the centenarian families. Um, and if if you're wondering that they have different roles in the cells, they're they some of them protect the DNA, some of them protect the energy supply of the cell, mitochondria. And one of them in particular, number two, controls cell division. And, uh, we find it's very important for, for example, preserving the integrity of female eggs in mammals.

Professor David Sinclair: And so when you have these sirtuins, if you're from from my understanding of it, um, if you have DNA breaks, um, the sirtuins are there to essentially halt everything else that's going on in the process of the cell, so they can focus on rebuilding and, uh, and repairing those those structures. And then, uh, then you can go on to your normal sort of cell division. And if there are multiple breaks, then your sirtuins is essentially being used up and that's what may lead to the issues that we see with aging on a macro level.

Dr Rupy: Right. So in our bodies now, 4 billion years later after sirtuins first appeared on the earth, uh, they they're much more complicated. They do lots of things besides repairing DNA. Uh, but at least three of them are doing what you just said, which is controlling genes, but also they have another role, which is repairing broken DNA. And so my hypothesis is that the sirtuins evolved to coordinate gene expression, turning genes on and off, when there's a major problem in the cell, for example, broken a broken chromosome. And what we have found actually, it's not just hypothetical, we have a lot of evidence for this, that the movement of the sirtuins from where they should be to where the break is, uh, first of all, that's beneficial because you want to turn on the whole program for repair and slow down the cell cycle. You don't want to be dividing when the cell is damaged. But what we we see is that those cells, or sorry, those proteins that have now moved away, uh, similar in the US, you might say that the the army core of engineers have gone to repair all the broken, uh, bridges that have occurred in an earthquake area. They don't all go back to where they came from. And that this mass exodus from where they should be, uh, ends up with, you know, 90% of them or even 99% probably go back to where they came from. Which, you know, if it happens once, you're not going to notice much of a difference. But if it happens every day, which it does, we our cells break their DNA at least once a day. Uh, then you're going to accumulate a lot of these these what we call epigenetic changes. And genes that should have remained off start to come on during aging and cells eventually lose their identity, their function. And I am proposing that that's the basis of the major diseases of society, heart disease, Alzheimer's, frailty, and of course, eventually we die from those things.

Professor David Sinclair: Was this the theory that you came up in the middle of a sleep-deprived state where you kind of just run out of bed and then started scribbling, you know, processes and enzymes, enzymatic reactions and on?

Dr Rupy: Yeah, actually, right here in my office, I have the notebook still where I wrote that down in the middle of the night. Really? October 1996 it was. And, uh, or maybe it was August, but in any in any case, it was a long while ago when I was a kid. Um, but yeah, I I basically sketched out my entire career and I've been working on that ever since to test the hypothesis. Um, and so people come to my lab and they say, what do you want to work on? Uh, what what can I work on? And I tell them, try to disprove this theory. And they've been trying their best for the last 20 or so years to disprove it and they haven't been able to, which is always the good sign of a hypothesis.

Professor David Sinclair: That's amazing. And if Matthew Walker's listening to this, he probably needs to add this anecdote to his next book about that sleep state and how that's where you become more creative. Um, but there's a a few, um, key sort of, uh, um, things that keep on coming up, I think in the longevity and certainly in your your book as well. There's there's the sirtuins, there's AMPK, and there's mTOR. Could you tell us a little bit more about what those individually are and and how what their relationship is to each other and how they're related to to aging?

Dr Rupy: Yeah, sure. So for the last 30 years, geneticists like myself have been mutating animals, you know, even simple things like yeast cells to see if we could find ones that lived longer. And we came up with hundreds of genes that control lifespan. But we've now settled on a system that the main three groups of genes that control lifespan in all organisms from yeast cells to little nematode worms and flies and mice and we think in our bodies as well, uh, they fall into three main camps. Of course, there's more than that, but these are the main regulators. The sirtuins, the seven genes that I've worked on for my career. The AMP kinase and mTOR. And what's what we've realised is that these regulators of lifespan are responsive to how we live our lives and in particular what we eat and when we eat. And we had a paper in 2003 that showed that the sirtuins in yeast cells respond to adversity. So when the the yeast cells are hungry, um, or they're they have not enough amino acids or they're a little bit hot, turn up the incubator, they live longer and that's because the sirtuins get activated. And without those sirtuin genes, they didn't live longer. And that as far as I know was the first real, uh, genetic pathway that said how the environment controls the longevity of a of a of any species. But we think it's similar in our bodies is that when we're hungry, we exercise, perhaps even when we're hot or cold in extreme temperatures, that it's turning on these possibly all three of these defence pathways.

Professor David Sinclair: And and the relationship with mTOR, is that, uh, in response to excess amino acids that that promotes growth in the cell?

Dr Rupy: Yeah, you're exactly right. So unlike AMP kinase and sirtuins, which as far as we know, the more the better for us, mTOR is the opposite. mTOR is is good for some things, but it's not so good for longevity. And what it does is it senses how much protein we're taking in and senses particular amino acids, such as branch chain amino acids, leucine being the main one. And so its job is to say, okay, I'm getting a lot of meat, I'm getting a lot of protein. Now's the time to grow and be fertile and build up muscle. But that's at the expense of protecting the body against the onslaughts of life and slowing down aging itself. So a lot of people have asked me, in fact every day, is it really a question of vanity versus longevity? Can you have both? Yeah. Uh, and my answer is, uh, I don't know, but my best guess would be that it's all about how you live and you you should be able to have the best of both worlds, but you need to be very careful about when and how you alternate between eating protein and being hungry and exercising.

Professor David Sinclair: Yeah, because it seems like there's a few central themes to to how to reverse aging or slow down aging in your book. There's there's ways to ways to activate your body's defence systems. So, eating less protein, uh, perhaps, um, this concept of hormesis that you refer to throughout the book. Um, deleting cells that actually, uh, cause inflammation and and can lead to aging effects, um, so the senescent cells. And then there's this theory that I haven't come across before, this partial cellular reprogramming, um, which is that resetting of the the epigenome versus the the genome. Um, what ways, if we just go in through those one by one, what ways do you can you activate the body's own sort of innate defence system to at least slow down the process of aging?

Dr Rupy: Well, the the simple ones are eat less often and, uh, and run out of breath at least a few times a week. Yeah. And we've learned this just through empirical observations of who lives longest and the people who exercise and eat less, live longer. Um, not malnutrition, not starvation, of course. That's not a path to longevity. Uh, but being hungry during the day is very likely to extend your lifespan. In mice, we do this in my lab quite often, feed them every other day and they they live about 20 to 30% longer. Um, and so this idea in my view, uh, of eating three square meals a day and snacking in between is totally misguided and that our bodies need a period of hunger, hunger to actually trigger these longevity genes that we've been discussing. Um, if if you don't, uh, do that, next best thing would be to get on a treadmill and lose your breath. Uh, you'll know that you're out of breath if you can't carry out a conversation. So you want to do that. I do it not enough. Uh, I should say, probably twice a week. I'd like to do it more often. But that hypoxia, that low oxygen state seems to be very good for triggering longevity responses. And there are other things that I'm exploring. There's some data from other labs that being in the sauna can help your cardiovascular system. Um, doing some cold shock therapy in a cold bath or in a cold pool also boosts the production of brown fat, which is very metabolically healthy. And so I'm trying all of those things. Um, those are the easy things to do. Yeah. There's a little bit more complicated things which are molecules that we've been working on and developing in my lab and in companies that I've, uh, sponsored and and helped. And then and then the epigenetic reprogramming is brand new. Uh, it's still in mice. We haven't done this in people yet. But that's essentially going to the very deep layer of aging, which is the the chemical modifications on our DNA that control the epigenome, as I mentioned earlier, the scratches on the CD or the DVD. And we're learning now how to remove those chemicals in just the right way. You don't want to take them all off, but just take the ones off that have accumulated over time and are screwing up the cell. And there we find in early experiments that we can turn the clock back on cells. And actually, if we do that to the retina of an old mouse, it regains its eyesight back to being young again, which is quite an astounding thing to see.

Professor David Sinclair: That's absolutely fascinating. That opens up a whole Pandora's box of different applications in in medicine where that could be potentially used, like spinal cord injuries, etc. Um, but I'm just before we go into that, the the, um, molecules that you were talking about, I I know of one, obviously, resveratrol, um, that's a calorie restriction mimetic. There's also rapamycin, I think, um, you you've you've been working with over the last couple of years. That is, am I right in saying that it's a similar, uh, it has a similar sort of mechanism in that it mimics calorie restriction, which which has shown to have longevity benefits?

Dr Rupy: Yes, uh, so resveratrol was the first molecule that safely mimicked calorie restriction. We had mice in 2005, 2006 that were obese, but their organs and their systems were behaving as though they were already calorie restricted. And they lived a lot longer on that molecule. Um, we also have combined resveratrol with every other day feeding and we find that they're beneficial together. We had some mice that lived over three years, which is quite a long time for a mouse. They typically die a bit over two years. Um, and so, you know, resveratrol has come in and out of fashion. There's a lot of people who jumped on the bandwagon, there's a lot of media attention. Then there were debates about how it was working. But it's fortunately it's settled down. We've got a number of studies in humans that have shown that it's protective of the cardiovascular system, um, and more recently, uh, against, uh, type two diabetes. Um, which is great because it shows that the work we did in mice is relevant to humans. Uh, but also at the other level of science, we we like to know at the molecular level how the molecule is actually working. And we proposed that it's working through the activation of a sirtuin enzyme, number one. And, uh, that looked great and then Pfizer and, uh, one other company, Amgen, put out papers that said that's wrong. Um, you can debate all you want as to what their motivations were, uh, in doing that. Uh, but nevertheless, it made us go back to the lab and work even harder to figure out whether we were right or not. And that debate, uh, is now resolved. We we do know that resveratrol is activating that gene and that's important, or that genetic pathway. But yeah, resveratrol I still continue to take it every day. Uh, I certainly don't regret it and, uh, I think the evidence points to it being beneficial. I haven't seen any downsides yet, um, and so, uh, I would think that it's one of those very simple things that people can try if they're interested.

Professor David Sinclair: Yeah, no, that I I remember reading about how that might have been a turning point for you in your career, you know, when there's there's a a big organisation out there purposely trying to discredit you for whatever reason, I'm not too sure. Uh, and now you've got evidence to to demonstrate that resveratrol is doing a lot of the things that you proposed it to be doing. It's kind of like a big FU to them. So, so,

Dr Rupy: Yeah, we we had patents on the mechanism and basically were able to prevent anyone else getting into this field. Ah. Um, and so it's helpful to invalidate a patent.

Professor David Sinclair: Gotcha, right. Um, and so you take resveratrol yourself. Um, you also take a few NAD boosters. Can you tell us a little bit about NAD itself and, uh, the, uh, precursors to to NAD?

Dr Rupy: Yeah, sure. Uh, so NAD is a molecule that we all have in our bodies. It's one of the most abundant molecules. And, uh, you know, we teach it in, uh, college, we teach it in high school as a pretty boring molecule. The molecules are just, uh, the molecules used in chemical reactions in the body. And it was thought to basically be necessary for life, but nothing more than that. And what we've discovered as a field over the last 20 years is that NAD levels are also controlling our health. And if the levels go down as we age, then that's a bad thing because our defences against aging are actually weakened. And so what we've found in mice and we're testing in humans right now, um, though it's early days, is the idea that raising NAD levels, particularly in sick and elderly people, will boost their defences against disease and aging. And, uh, so though there's not a lot of evidence in humans yet, uh, any scan of the internet will show that there's a lot of people cashing in on this on on our research already. Uh, but I would like to say just for the record here that I have no connection to any supplement companies, nor do I receive anything from them.

Professor David Sinclair: Yeah, I was going to definitely put that in the intro because I know you've made a, um, made it very clear that your name is being associated with a lot of different supplements on the internet. People just need to do a quick Google search and they will see that. Um, and you you've made it very clear that you you don't have any affiliation with supplement companies. Um, you've got your own sort of n equals one experiment going on with your with your dad, right? Um, with him taking some of these supplements.

Dr Rupy: Well, I wouldn't call it an experiment. No. Uh, I would say that my dad is a scientist who has his own free will, who has looked at the data and made the calculation as he's got progressively older that the risk to his health of not doing something is worse than trying something. And, uh, so he's been steadily changing his life since he was 40 years old, um, but more recently since I've been publishing work on the subject. And, uh, he's started taking resveratrol at the same time as me about 13 years ago. Uh, does a lot of exercise, which is good for him. He's taking, uh, an NAD boosting molecule. He has for about three years. And he's also on an AMP kinase activator called metformin, which he took for his diabetes, um, and and actually has basically stopped his diabetes in its tracks. And that combination, um, among a few other tweaks that I've written on page 304 of my book, is, uh, what seems to be keeping him going. And, you know, it's remarkable to see his attitude to life change where he was not looking forward to being in his 80s, whereas now he's, he just ordered his dream car online and he's looking forward to another 10 or so years, uh, hanging out with his grandkids and maybe he'll even see his great grandkids.

Professor David Sinclair: That's amazing. And I I I want to see a lot more of that in modern day medicine as we see it today because I I think you made this, uh, this analogy of of medicine being whack-a-mole medicine right now. And there's something that I see as, you know, a general practitioner in the NHS, you know, we have specialists in individual silos, um, you know, the dermatologist is treating that, the gastroenterologist is looking after colitis, the hematologist is looking after the blood, and I was really looking at the person as a whole and actually treating the underlying root cause. And I think what you're doing by looking at the central tenets of aging and then going upstream, I think is certainly the way we need to be approaching medicine today.

Dr Rupy: Well, thanks. There's a lot of doctors who, maybe not a lot, but there's a few that I talk to that still don't understand what I'm trying to do. It's not about living for hundreds of years. It's more about trying to get us past this barrier that we've come up against with, quote unquote, modern medicine. Even if we cured cancer today, it's only going to lengthen the average lifespan by a couple of years. So we do need a a holistic approach, and I mean holistic as in the whole body, because it it's not enough to keep the heart healthy if the brain is going to age. And, uh, you know, that we've just made matters worse, uh, for people that way. And so, yeah, so I'm I'm all about now changing the course of medicine so that we appreciate aging for what it is, which is a disease, just one that's very common.

Professor David Sinclair: Yeah, I totally agree. And I think, you know, at at first people might think about what you said there, like, you know, if we just look after the heart, um, we should be devoting resources away to the bigger picture from cancer research or or, uh, heart disease research. But actually, you you're looking at lifting the entire, uh, um, sea of ships so we can actually, you know, look after all diseases at once rather than just individual silos.

Dr Rupy: Right. And and so consider that that the risk of smoking, which my mother did and died from lung cancer, that increased her chance of getting that disease by five times, fivefold. But aging will increase your chance of getting cancer by 500-fold. Uh, and by the time you're 75, about a thousand-fold. So aging is a major part of all of these diseases. Um, and then the question you can ask yourself is, if you were not to age, would you get sick? Would you get diseases? And I'm arguing that you wouldn't. Now, bad stuff can still happen. We can have mutations that cause disease and cancer is one of those. But I I think it's important to realise that our bodies are capable of great healing, they're capable of killing cancer cells on their own through the immune system, and that the breakdown of those processes in large part is the reason why we get sick.

Professor David Sinclair: Absolutely. And what I'm really interested in is can we use the learnings from your lab and your decades of research to treat the diseases of today, today? So, I'm thinking about AI disease, um, yes, cancer, but also psoriasis, dermatitis, uh, inflammatory bowel disease. Um, conditions that people wouldn't naturally think of having a, uh, a similar sort of mechanism, um, but certainly are related because they all appear past a certain age, or certainly the risk factors for them appear.

Dr Rupy: Well, that that's exactly right. Uh, and so the molecules that we've developed, uh, actually, uh, they've been spun out into a few companies now. And there was one called Certus, which was bought by Glaxo Smith Klein. Uh, and they showed that that one of these activators that are much more potent than resveratrol, about a thousand times more potent in the test tube, uh, versus resveratrol, that it effectively treated psoriasis, uh, in, uh, what's called a phase two study. Now, so we know that these molecules can treat particular diseases, not just aging, but, uh, anti-aging would be their side effect. Um, though I don't like the term anti-aging, but you know what I mean. And so what I've started, in full disclosure, I I've started a number of companies, not because I want or, uh, need to get rich. That's not at all. In fact, I people are confused when they hear that, you know, I'm still trying to pay off my mortgage when I've I've made millions of dollars. And the reason is that I'd rather put the money back into research and into my lab and into employing scientists than I am paying off my mortgage. Um, but yeah, the these companies are developing drugs to treat particular diseases, and they don't have to even be diseases of aging. Uh, we're going after Friedrich's ataxia, which is a rare disease of mitochondrial dysfunction that we'll start a trial next year, early next year. So it's it's also a a misconception of my critics and those who haven't really thought about it that this is just about aging.

Professor David Sinclair: Yeah, absolutely. Uh, and I I will get crucified if I don't mention this, uh, to you. Um, I see a lot of patients as a general practitioner in the NHS with menopausal symptoms. So women after a certain age having, uh, menopause, and we currently see it as something that's part of, quote unquote, the natural process of aging. Uh, hot flushes, uh, mood disturbances, and a whole bunch of other risk factors post-menopause as well. Is there any hope for some of these molecules utility in treating menopause or at least, um, improving life for for for half the population that will eventually go through this?

Dr Rupy: Uh, we have, uh, a paper that we have posted online, uh, which, uh, I'm a co-author on. And what we're showing there is that the NAD booster, uh, that we work on mostly called NMN, not to be confused with M&M's. Um, NMN is, and I mentioned the paper because you can find it online, it's free to download. If you I think if you just search for my name and NMN and fertility, you'll probably find it. What we see is that raising the NAD levels in the ovary, uh, protects it from DNA damage and as well against aging itself. And what's surprising is how reversible it was. And that's scandalous actually. It's going to be a lot of hate mail. Yeah. People don't believe that it's possible to reverse menopause. Now, in mice, it seems to be possible. We've done a small study in old horses, uh, and it looks really promising. Um, you know, I can't promise that I'm going to reverse, uh, infertility in women, um, based on a mouse and a horse result. But scientifically, uh, it's not out of the realms of possibility. And there's a company that I co-founded called Jumpstart Fertility that's in Australia that's working on just that.

Professor David Sinclair: Fantastic. Okay, well, there's there's a lot to to hope for in the, um, in the future of aging medicine then from from menopause. I'll definitely link to that. Um, I I was really glad to to see a huge section of your book book looking at the ethics of improving lifespan as well as healthspan. So, you tell us this, uh, quite personal story of a heated discussion that you have between yourself and your daughter who didn't share the same optimism of, you know, extending the, uh, the the life of the population and essentially, uh, well, adding number of years to people who are already going to be aging. Have you managed to convince her that it's a good thing and it's beneficial for the sustainability of the planet?

Dr Rupy: Uh, I'm probably never going to find out the answer to that because my daughter wouldn't ever admit that she agrees with me about something. Uh, she's a total contrarian. If I said that the the moon is blue, she'll say that it's green. So it's, uh, that's what she's like, which is a good thing. It'll do her well in life. And, uh, so she has said that humans are the enemy and we have too many of them and that we have bigger problems. And what was important to explain to her and as I explain in my book, is to realise that the cost savings of having people healthier for longer, uh, is going to be globally in the tens of trillions of dollars for the coming decade. If we're successful, that is. And that's money that can be spent on the things that my daughter's generation, she's 16, um, that they're worried about. So they're worried about climate change, they're worried about jobs, they're worried about species extinction. And that's totally correct to worry about those things. But if we have a spare 10 trillion dollars, that's money that can be spent on those great endeavors. And I don't know where else to get 10 trillion dollars besides addressing aging. But but I'll tell you this, Rupy, we went to Africa this year and I took my whole family and my father came for his 80th birthday. And when my three kids, I should say my wife, uh, and I, our three kids, uh, we saw my father who's 80 walking up mountains with the grandkids to visit the gorillas and hang out with them. I it was certainly clear to us and I think it was pretty clear to our children that living longer in a healthy way is an incredibly good thing. Um, certainly for families and of course, I would argue for the planet.

Professor David Sinclair: Absolutely. I I love that sort of, uh, that that vision of you and and all generations being there. And hopefully a lot more people can share that as well if your if your work comes to light. Um, one of the things that struck me is that a lot of the things that we talked about today are quite complicated. You know, we're talking about the three aging factors and sirtuins and stuff. We appear to have made stepwise improvements in lifespan through very simple interventions like soap and vaccines. If you were to look with your crystal ball, what does that stepwise action look like with regards to aging? Is it something like, you know, a vaccine or, um, something that we can activate with the some of the factors, I think you you mentioned, the the Yamaka factors, um, or, yeah, what does that look like?

Dr Rupy: Well, it is it is going to be stepwise. There isn't going to be a magic pill that makes us all live another 30 years. Um, there are some molecules, drugs that are on the market already. I mentioned metformin that my father takes for his diabetes, that seems to based on studies of 100 or 100,000 or more people to slow down diseases of aging, perhaps aging itself. So tho those things will be adopted more. Um, what would speed things up at that level would be if the regulatory authorities would allow aging to be treatable. Right now, a doctor cannot prescribe any medicine for old age, um, even though the World Health Organization has just declared old age a medical condition. Yeah. Um, so these things can be done now. Um, and with lifestyle changes, if people take those on and do them in the right way, then they will live longer. It's very unlikely that they'll they'll be hurting individuals. And the more people that do that, the average age will continue to tick up. And actually the the average age of humans has been ticking up for the last 200 years and it's extremely linear. And the kind of changes that I'm talking about, um, are ways to keep continue that trend upward. Actually, a child that's born today in the United States, if the trend continues, that line extrapolates linearly, can expect to live to 104 on average, not to mention people who look after themselves. Uh, in Japan, it's 107. Uh, so other things you mentioned, uh, you asked me about that will be stepwise. I think that drugs that are in development will be very important. There are mTOR inhibitors that are in phase three. There are sirtuin activators that I work on that are in, uh, entering phase two, um, and have shown that they do work in phase two. Uh, and then there's the metformin that addresses one of those third pathways. So it's it's actually it's not that complicated. There we're going to be a variety of choices. Um, if anybody is confused by what I've said, um, my book, I hope, I think explains it very simply in diagrams as well. Very much. And there's also a list of what what I do and what my father does at towards the end of the book. Um, not that I'm prescribing that, I don't recommend anything, but I'm asked so frequently what I do and, uh, and I wanted everyone to know that I did write that down.

Professor David Sinclair: Absolutely, yeah. And in addition to those, uh, molecules that are in development and some that are already available like metformin, um, you have, uh, a couple of, uh, tracking devices that you use, uh, at this point. And I think that sort of, I think in the future, in the next 5, 10 years, a lot of my patients are going to have that as just the norm. I mean, already you have the Apple Watch that gives you heart rate variability and and ECGs and, um, the aura ring that is, uh, you know, tracking sleep and stuff. How have you found that for for you personally? Is that completely changed the way your lifestyle is?

Dr Rupy: Yeah, it has. Uh, I like the analogy of a car's dashboard. We don't think twice about adding sensors to a car. There are now more than 100 sensors in our cars that tell us all sorts of things about the car's health and how well it's doing. We don't even think about that for our bodies. We know far less about our bodies than we do about our cars, which is ridiculous. And so I've found that it's very important to get feedback on how your body is doing. Um, in part to know what's going on over time and try to correct it before it goes seriously wrong and irreversibly wrong. Things like blood sugar levels and inflammation are key to know what's going on. Uh, in addition to that, I monitor with this ring that you mentioned, the aura ring. Um, it monitors my heart rate, my sleep, heart rate variability is important, temperature, motion. And there's also a company, and in full disclosure, I I invested in this company years ago, about 12 years ago. They are do blood tests and give people feedback about their blood biomarkers. And or they have tens of thousands of of subjects or well customers, I should say. And what we find and I find by doing all of that is that first of all, it's highly motivational, right? If you don't know what's going on in your body, it's who knows if exercise is helping? Who knows if I take that pill is doing anything? So you eventually give up because it's easier just to sit around and not do anything. But if you see something work, or if you see something go wrong, then at least if you care about your future, you want to take action. And I found that extremely useful. The most late the latest thing that I do is I I've put a glucose monitor on my arm, which sounds weird and I I agree, it is weird, but you get used to it pretty quickly. And a lot of my friends are doing it. What that allows me to do is to see in real time what happens when I eat certain food. And it's particular to everybody. And so I find that eating rice and eating grapes is very bad for me, but eating potatoes doesn't seem to raise my blood sugar very sharply, which is what I'm trying to avoid. And so I think in the future, people will have a dashboard on their bodies and they won't think about flying blind or just going to a doctor once a year. That'll be like the dark ages.

Professor David Sinclair: I I actually agree, yeah. I've put CGM, uh, monitors on, um, a couple of patients and very surprised at the results when you match that with a food diary and you eat something that's considered healthy like oats, for some people, fantastic. Other people shoots their sugar right up. And if they're at risk or they're pre-diabetic, etc, um, it can be a very useful tool to to understand how their body reacts to different foods. Um, so yeah, no, and I think in an era of medicine, particularly in the NHS in the UK where we have, you know, calls for more and more doctors, longer and longer wait times for for physicians, we need to think laterally into the into the future where people will be looking after themselves and only going to the doctor when after they have all the information there. Um, so yeah, no, I welcome those thoughts and I think it would, um, be very revolutionary.

Dr Rupy: What do you think about virtual doctors?

Professor David Sinclair: Uh, so it's an interesting topic in the UK in particular. We have, I don't want to mention any names, but we have a number of different telemedicine companies here. And unfortunately, they're taking a lot of contracts away from the NHS. It's a bit of a political minefield. I do, I think on one hand, it increases accessibility to primary care physicians in the NHS, which is a a real big issue because people are waiting three, four weeks to see them. On the other hand, it takes away that sort of personal empathic approach that you have one-to-one with a with a doctor. And those private companies limit the accessibility to the NHS as well.

Dr Rupy: Um, thank you so much for your time, uh, Professor. I know it's, uh, it's stretched at the moment. Your book's doing fantastically, became a New York Times bestseller, so congratulations on that. Uh, any thoughts on, uh, future books?

Professor David Sinclair: Yeah, uh, a lot of people are asking me to write the next book, which is of course very flattering and I appreciate it. Uh, I'm putting a lot of thought into what that should be. I have some ideas. Um, I'm going to need a few months to recover because this book has been one one heck of a brain dump. Um, and I put everything into it. But I've I've enjoyed the experience and I really, uh, think that I can have an impact not just in the science world, but in education as well through this means. But yeah, I mean, keep a look out. Um, I've got to start writing the next one, uh, probably in the next few months.

Dr Rupy: Amazing. I don't know how you keep up with it. Uh, doing all the research, the spin out companies, the lab work and writing. Um, it's, uh, really, really impressive and, um, it's fantastic chatting to you as well. Uh, I'm going to be in Australia, uh, in December, so if you're around, maybe I'll say hi.

Professor David Sinclair: I might be. I'm heading down for a wedding, uh, one of my good friends. But, uh, yeah, would love to catch up in person.

Dr Rupy: Great. Yeah. And if I'm if I'm ever in Boston, I'd love to say hi as well. Um, if you're around, if you're not.

Professor David Sinclair: Oh, no, come by. It's it's pretty cool to see these these mice regain their vision and we didn't mention this, but now that we think we understand what's in part driving aging forward, we can actually do that. We have mice that we can accelerate their age. And we think that they'll be useful for testing potential drugs for things like Alzheimer's because it's pretty crazy testing drugs on mice that are supposed to be for old people, but the mice are only a year old. And so we think by accelerating this aging in the mice, they'll be more like human, old humans.

Dr Rupy: Yeah, that would be a really interesting model to just test stuff on, right? So if you come across Dale Bredesen's work, uh, the Buck Institute. What do you think of, uh,

Professor David Sinclair: Yeah, oh, Dale's a friend, yeah.

Dr Rupy: Um, no, I think it's it's really good. I think he has the right attitude, the right approach to Alzheimer's disease and he also, as you're probably alluding to, thinks that we need to change the way we approach treating the disease.

Professor David Sinclair: Absolutely, yeah, because, uh, he's a friend of Mark's and I I know Mark through a mutual friend of ours. I've done a few, uh, bits on his podcast and stuff. And just the way the functional medicine approach, I think is going to be very useful in the future when we look at the patient more holistically and we actually, uh, provide a number of different interventions rather than single interventions that I mean, I know from my general practice, like it just it doesn't work, unfortunately. You have to, you know, get at least the foundation of of diet and lifestyle and then add extra factors to it.

Dr Rupy: Absolutely. Um, I think it's it's important for listeners and viewers to realise that we're not talking about keeping people older for longer. This is not about extending the period in a nursing home. It's quite the opposite. If you look at my father as a role model, it's about being as fit as you were in your 20s, 30s and 40s when you're 80. Um, and I don't know anybody who would wouldn't want their parents to live a life like that.

Professor David Sinclair: Well, he's a role model. Uh, and so are you. And thank you very much for the chat.

Dr Rupy: What a guest. I absolutely love what David's doing. I think he's a a breath of fresh air in terms of the research field as well as, uh, everything he stands for with regards to looking at medicine in a different way. Uh, before I go into the tips, the basic tips that he's discussed in his book and and on this podcast, you can follow my guest, Professor Sinclair on Twitter and Instagram at David A Sinclair PhD. Buy the incredible book Lifespan and check out a bit more about the book at lifespan.com. So, overall, what things would David recommend? So, you've really got to build on the foundations of what a healthy lifestyle is, and that is diet and exercise. Diet being low animal protein, lots of colours, different types of fibres, variety, essentially all the principles of healthy eating that I've talked about in both of my books. You can check out more of those on the website thedoctorskitchen.com. Exercise is a big proponent of things like hit training, but it's also about variety. So yoga, flow, mobility, again, a lot of the things I talk about in both of my books. David, as he said, has mentioned a number of molecules, including resveratrol and something called NAD boosters, um, or precursors, uh, to NAD, the molecule that we find naturally in cells, um, that he takes. But there are no long-term clinical trials on that. Again, he's made it very clear that this is not advice, uh, but there's some interesting research around those. Um, they are available as nutraceuticals. I personally don't don't take them. Um, I prefer to use a diet and lifestyle approach, and I think that's probably the most effective. However, it is very, very interesting science at this point. Uh, there are a number of other molecules that we mentioned, uh, rapamycin and metformin. Again, those are not used, uh, in aging or reversal of aging at this point in time, but they are medications that are used in medicine. Metformin being a type two diabetic medication that I prescribe widely to people who are pre-diabetic or diabetic, I should say. And, uh, rapamycin is used in, um, immunotherapy for, uh, transplant patients. Um, a number of, uh, tracking devices were mentioned. So, aura ring, there are other sleep tracking devices and a continuous glucose monitor. Again, those are, well, the continuous glucose monitor is, uh, prescribable, so that isn't, uh, available for the general public. Um, but I do see these tracking devices as something that could be useful in the future as long as they're with the right advice and you actually have someone looking after what the results are of those as well. Sauna and cold exposure. These are things that I think are readily accessible. There's a lot of information, a lot of research coming out about sauna use in particular from looking at some Finnish studies. Um, there appears to be an association between sauna use and, uh, lower rates of Alzheimer's and cardiovascular disease. So having a sauna a couple of times a week probably wouldn't be a bad thing, uh, in addition to exercise as well. And then cold exposure. So that's actually where you you expose yourself to cold for a short period of time, not a long period of time. I think, uh, people have a tendency to overdo these things. But essentially the, um, the the science behind cold exposure is that it increases brown fat accumulation on your body. This is a metabolically active type of, uh, fat in a good way, um, that has a, uh, a high concentration of mitochondria, which are the powerhouses of our cells, uh, that, uh, diminish as we age. So mitochondria and the reduction in numbers of mitochondria is something that's been purported as one of the reasons as to why, uh, people age. And so something, uh, like cold exposure that increases the concentration of them could be useful. Uh, so short bursts of of cold exposure, as David describes in his book, it could be going to a cryotherapy chamber or simply cold water swimming, uh, which I think is a great way because you're combining the cold water exposure plus exercise benefits as well. Uh, and avoiding DNA breaks as much as possible. So psychological stress, I would say is something that everyone could be, uh, could get on board with. So meditation regimes, taking time away from our screens and getting adequate amounts of sleep is probably the easiest way to protect your genetic material and live a longer, healthier lifestyle. All this plus more are going to be on the show notes at thedoctorskitchen.com. Subscribe to the newsletter. Uh, post us anything, any comments about this episode, uh, on Twitter or Instagram. I'd love to hear your thoughts on it. And, uh, make sure you subscribe to the newsletter for weekly recipes plus much more content to help you live the healthiest, happiest life. Give us a five-star rating if you like this podcast. It really helps spread the love and message. And let us know if there's anyone else that you want to get on this podcast to talk a bit more about this because I think aging is a developing field. Um, there's a lot more research being, uh, directed towards it because I think it underpins a lot of what we see in medicine, particularly in the NHS, uh, as the problems associated with increasing lifespan pile up on top of each other. That's all for this week. Uh, thank you so much for listening and, uh, have a fantastic day. Bye-bye for now.

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