https://www.youtube.com/watch?v=QuBo2zMLZ8A
David Sinclair: We are here today to talk about aging, a topic that hopefully is on everybody's mind, because this is the one medical condition as I call it that we're all going to suffer from if we're not already. So one thing I'd like to do with you all is to start with the question and the reason for that is, well, Adam and I are going to chat and I'm going to present a few little slides to share what we work on. While we're doing all that, there's something for you to think about if you get bored with me. So I'm going to pose a question and you can type on the chat room what you think is the right answer. Now there isn't a wrong or right answer. And then when Adam and I come back, we'll talk about some of the most interesting comments that have been made by you all.
David Sinclair: So here's the question, so if we had medicines that could slow down or even reverse the aging process and prevent diseases of aging, cancer, heart disease, Alzheimer's, do you think aging should be regarded as a treatable medical condition? Or should we just let it occur naturally the way we do these days? So that's the question. Is aging a disease or a medical condition? And should doctors be able to help you with that? So that's the question. So shall we get started Susan on my little intro, is that what we want to do? All right. Good. Thanks. So I've got just a few slides to talk about with you today. Now the take home message is that we have a really advanced understanding of what aging is now. Going back to 30 years ago, when I was just a student at UNSW in Australia, we really had no idea what aging was.
David Sinclair: We talked about free radicals, DNA damage. We didn't really know what was driving it. But what I'm going to tell you today, and we can discuss later is that we think we found a very upstream root cause of aging, not just all the downstream terrible things that happen. Can we measure aging? I'm going to tell you how we actually now have a clock that we can measure. I could take your blood or even a swab of your mouth and tell you very accurately how old you are, not just based on birthday candles, but based on your biological age. And that allows me to predict when you're actually likely to die. But there's no point in measuring aging if you can't do something about it. And so that's why I've been spending my whole career really since I left Australia to work at MIT originally. I didn't know I was going to spend most of my life in the US, that's just what happened. (2:45)
David Sinclair: But I came to the US to study aging in little yeast cells. And what we discovered is that you can slow down aging pretty easily. It's not that difficult. There were a few genes that we've discovered that control the aging process. But what I think is most important and most exciting and if you've read my book you'll know, is that I think we finally have a grip on how to actually reverse the aging process. And I know that's bold. And I think this is one of the reasons why Susie was so complimentary. For a scientist at Harvard to say that it's possible to reverse aging, that's pretty hard to say. Even a few years ago, that would have been considered insanity. But as I'll show you today, it's no longer considered crazy. In fact, it's really at the forefront of Biology now. So Susie as let's go to the next slide, what we've got is a description of how the cell controls its genes.
David Sinclair: Now this is obviously not DNA, but they'll nylon thread, that white little thread there is meant to represent the DNA in ourselves, each cell having six feet of DNA. And of course it's not flailing around tangled up. It's actually bundled up very neatly in what you would probably call spool. We call these things histones and they're made up of protein and that's here represented on the screen by the black objects. So this is really what makes up a chromosome and the DNA is bundled up. And if it's tightly bundled, those genes in those bundles are switched off often for life. But sometimes when you need them, they come on. But that pattern of bundles and then loops determines what we call the gene expression, genes that are off, and then genes that come on. So why is that important to have the right pattern of gene expression? (4:30)
David Sinclair: Well, it's essential for life because pretty much all of our cells have the same genes. So what makes a brain cell different from a skin cell, different from a liver cell? It's this packaging that you see on the screen. This is what tells a nerve cell to be a nerve cell, and importantly, to stay a functional nerve cell for up to 110, or maybe even longer years in some people. But what we think is going wrong, as I'll explain is that this packaging gets disrupted as though... When you, sometimes you go fishing and you cast the line, it just explodes and you end up with a real mess. We think that's what's happening to our genome. So in the next slide, what I'm going to show you is what this kind of looks like. This is more of a realistic representation. So now we've zoomed down in through the nucleus, we've swarmed down to the chromosome and we can actually see the DNA molecule now.
David Sinclair: And that's the double helix in blue. And so there are about a couple of loops that go around these packaging proteins called histones shown in green. And what you notice or should notice is that there are these little tags, these little worms that are on these proteins that bundle the DNA. Those tags are really important. They tell the cell whether to bundle up the DNA or to loop it out and turn the genes on. And so the that's how the cell controls, whether a cell is going to be a nerve cell or a liver cell or something else. And it turns out that these tags that are attached either to these green proteins, histones or literally to the DNA itself, these are called methyls that attach to the DNA. We can measure those and use those as a biological clock because they occur very often predictably as we get older. (6:15)
David Sinclair: And so in the next slide, what you'll see is that there is what's called the Horvath Clock. So I have a really good friend at UCLA, University of California in Los Angeles. And Steve, professor Steve Horvath has discovered along with his colleagues, that if you measure those chemical tags that attach to the DNA, these methyls, the so-called methyls, you can read them all and then you can build a clock. And that's how I can tell how old you are. Biologically I could take your cells, measure those little tags that are accumulating and see how unraveled your DNA is over time. And it turns out people who live healthy, eat well, exercise are younger than their biological or their chronological age, the normal age and those that smoke become obese. Don't exercise tend to have an older biological age.
David Sinclair: Now there are exceptions, of course, you can be lucky and be born with exceptional longevity genes, which I'll tell you about in a minute. But even if you've got great longevity genes, that's not the only thing that matters. It turns out that our longevity is only 20% determined by your parents. The rest is how you live your life, which is actually great news. It means that we all have a chance to basically level the playing field and live into our nineties and a hundred and beyond in a healthy state. But it does take discipline of course. And we'll talk a bit about the kinds of things that we can do to try and keep our biological age younger. And then eventually at the end of this talk, what I'll tell you about is if you've been unlucky enough to have an accelerated biological clock, you're already an advanced age, I think we can get those crosses there to come down and actually reverse your biological age. (8:05)
David Sinclair: So let's skip to the next slide, and what this slide is going to show you is a representation of what's happening to your DNA as you get older. We think, in my lab and a few others around the world, that this is what drives the aging process. And there are a lot of other things that happen when your DNA becomes unraveled like this, you have shorter telomeres, the ends of chromosomes get shorter. You lose stem cells, you have what are called senescent cells accumulating in your body. These are zombie-like cells that cause havoc and create inflammation and even cancer. I mean there are a lot of other things that go wrong. But what I think is going on is fundamentally this loss of the packaging of the DNA. And you can actually think of this in terms of information, right? We live in the information age.
David Sinclair: So it's really not that difficult to understand that when we're born, we have this beautiful set of information, and there are actually two types of information. One is in the DNA, in the white strands on the screen, but the other information that's just as important as like explained are the black packaging proteins in this picture or those green histones. Together, those two types of information keep us young. And what I'm saying in my theory, which is called The Information Theory of Aging is that yes, we get mutations. Our DNA gets disrupted as we get older, but I don't believe that's the main cause of aging. It's the loss of the packaging of the DNA, this other type of information we call that the epigenome. So think of the epigenome disruption as a main driver of aging. But the question really is, what causes this to happen?
David Sinclair: And is it possible to tell the cell to rewind and get back these original, beautiful packaging structures? We didn't know that any of that was possible, but now we do know it's possible. In fact, for it to be possible, it means that there must be some residual information in the cell that tells the DNA how to be repackaged beautifully again. One analogy that I use is that information on a compact disc or a DVD, if there are any young people in the audience, compact discs where these funky little discs used put music on, we were pretty impressed with it at the time. But our genome as this music on a disc and aging scratches on the disc. And so now the reader of the disc cannot play the music beautifully and that's aging. Same with our genes. We don't read our genes well when we get old. But imagine if we could polish that CD and get the scratches off and get back the ability to read the genes the right way. (10:42)
David Sinclair: I actually believe this is possible. So how would we do this and what causes it to happen? Well, we did this in a mouse and I'll show you in a second, what these mice look like. What we did was we tried to look for what was disruptive in the packaging of the DNA. And what we found in yeast cells originally, but now we know in animals, mice particularly, that you can disrupt these structures by breaking the DNA. A piece of broken DNA in the cell is very disruptive and the cells struggles to try and fix it. And in doing so, those nice bundles become unraveled. And it's very hard to put them back together again. And over time, over 60, 70, 80 years, you get this complete mess. So we did this to a mouse. We broke its chromosomes. We let it heal. And we did this for three weeks when the mice were young.
David Sinclair: And what I'll show you in the next slide is the mouse that was not treated by cutting, that's the control mouse. And then the sister of that mouse is on the right. That's the mouse that we cut the chromosomes. And 10 months later, you can see that the mouse on the right definitely looks older and we can now measure its biological clock. And it is literally 50% older than its sibling. And it doesn't just look older, if we look at its organs, it has dementia, heart disease, diabetes, all of these hallmarks of aging are happening. So what that tells us is that very likely what's happening in this mouse and probably as we age, is that broken chromosomes will lead to this loss of information in the cell. So the genes are not read well. Similar to the scratches on a CD.
David Sinclair: But the real question is, if you can give something, can you now take it away? And that's what we've been working on for the last, now about six years. And what we decided to do was to do an experiment where we took very early genes in embryonic development and thought, well, if the egg and the embryo can stay young and reprogram to be young again, can we do this in an old animal? So let's go to the next slide. What I want to tell you about... And we can discuss this later, because I'm sure it's a topic of interest is how do you slow down those broken chromosomes? How do you stop your DNA from unraveling? Well, we think that there's a way to do that. And it's called hormesis. Hormesis is essentially what doesn't kill you, makes you live longer. And the reason that this works, we think is that our bodies and all life forms on earth have evolved to sense adversity. (13:26)
David Sinclair: When there's something that's threatening your survival, the body has defensive modes, repairing DNA, making sure that you process energy, fixing wounds, and this keeps you young. But you don't want to actually damage yourself to get these effects. But there are ways to trick the body into thinking that you could die. So let's go to the next slide. There are a number of ways you can do that. One of the ways is shown on the top left here. This is high intensity interval training. It just means run on a treadmill, lose your breath, you know that you're doing it correctly, if you cannot carry out a conversation. Why does high intensity interval training work? Well, it's similar to being chased by a saber-toothed tiger or having to run from your enemy. Your body thinks that it's under threat and it will fight back.
David Sinclair: There are other things you can do to trick the body, you can be hungry during the day, skip breakfast, maybe skip lunch. This is often called intermittent fasting or caloric restriction. You can expose your body to high temperatures, maybe even low temperatures, sauna and ice-baths, low amino acids, don't eat so much meat every meal, have a plant-based diet for a while. And this word on the right called Xenohormetins. I take full responsibility, I helped invent that word. It's actually a mouthful, but what it means is that you can stress your food biological. You can make it get dehydrated or get eaten by bugs or too much light. And often we see foods that are colored when they're stressed out like grapes, when you pick them at the end of their harvest, or lettuce that's been exposed to too much sun. (15:07)
David Sinclair: These plants actually make molecules that also can activate our longevity genes. So what are the longevity genes? Well, I talk a lot about them in my book. There were three main categories shown here. One is called mTOR, which primarily senses amino acids that you're eating. There's one called AMPK, which senses how much you're eating and how much energy your body's making. And then there are the sirtuins, which are the ones that I've been working on for my career. And we have seven sirtuins in all of our cells. Now we know there are a number of ways to actually chemically activate the sirtuins. And some of the ones that we've worked on, one's called NAD. NAD is a chemical that we need for life without it we'd be dead in 30 seconds. And we have a drug form of that that we are testing in rare diseases and clinical trials for actually COVID-19 patients.
David Sinclair: We think that if we can get their age to be younger, those patients will not die. So probably by end of August, September we'll know if MIB-626 is helpful there. Now, resveratrol is an old chestnut, a favorite of many people. It's found in red wine. We discovered it activates sirtuins back in 2003. Sales of red wine went up 30% and have stayed up. So if you enjoy red wine and tell everybody you do it for health reasons, you're welcome. But you have to eat a lot of resveratrol to get these effects. And then finally there's a new discovery I wanted to tell you about another lab, not mine, have discovered that MUFAs, these are monounsaturated fatty acids. These MUFAs you can find them in olive oil and avocados and nuts.
David Sinclair: Those molecules also activate the sirtuins in a very similar way, if not identical to resveratrol. And what's exciting is that we're now learning that those foods and lifestyles that other people have figured out have been healthy, now we're figuring out how they actually work. It's not that running makes your blood flow better and clean out your arteries, it's that the exercise tricks your body into turning on longevity genes. And then they give you the long-term health, fitness and longevity benefits. And we know a lot of this because many labs, hundreds of labs around the world have actually shown this in animals and now in people that this is true. And in the case of mice or yeast cells, you can get rid of these genes. And now things like low amino acids and caloric restriction, they don't work anymore. And the other thing that you can do is you can feed mice NAD or precursors to NAD, which I'll tell you about, or give them resveratrol or give them oleic acid from olive oil. (17:40)
David Sinclair: And we get very similar if not identical effects to fasting and exercise. And one of the experiments that we published couple of years ago was that if we gave a molecule called NMN to mice, they actually could run 150%. And these are old mice, they were actually running faster and longer than the young mice. And we know that this is through the sirtuins because if we deleted one of those sirtuins genes, it didn't work anymore. So in the next slide, I want to show you, how can you raise NAD levels? Well, NAD is a pretty big molecule as far as the cell is concerned. If you give it to a cell, it typically doesn't get taken inside the cell. But there are smaller versions of NAD called NAD precursors that you can eat. And we actually know from clinical trials, they do raise NAD levels in the body of humans, not just mice.
David Sinclair: And one of the classic ones is called NMN, it stands for nicotinamide mononucleotide, and you give it to people and their NAD, the body turns it into NAD and you raise those levels. And the idea is that we could give people the benefits of exercise and also fasting and maybe augment a healthy lifestyle. And as I mentioned, we're trying this in COVID-19 patients and a rare disease actually called Friedreich's ataxia. We're starting trial in Melbourne and Pennsylvania. So that's what this molecule looks like. Maybe Adam, you can probe me about my family's use of this molecule. So let's go to the next slide. I want to get onto to finally where we're really going with this.
David Sinclair: I want to show you this. These are examples of pills that are in human trials right now. We've been doing human trials for about two years in people at Harvard with some of my esteemed colleagues over there. And so far it looks very safe and we'll hopefully know in the next few months, if it's effective, at least in COVID-19 patients. Next slide, let's have a look, where are we going here? So this is the big question. Is there a memory of youth in ourselves? Can we get those messed up strands of DNA to be packaged again like they were young again? And not just make cells behave like they were young, but can we truly make them young again and reset the clock? And I believe that is possible. So what you'll see in the next slide is that there are some genes that we've... In this, basically this is showing you, of course, we want to get back to that structure, but let's go to the next slide, it's more important.
David Sinclair: All right. So this is the real important slide, that this one is in a paper that we've put online if you want to check it out, it's on our website called bioRxiv because it's a pre-print, we haven't published it yet. But we're hoping to publish it soon in international journal. But I'm going to tell you about it today because it's just too exciting to keep it a secret for now. All right, so there is a fellow, professor in Japan called Shinya Yamanaka who won the Nobel prize in 2012 for discovering that a combination of four embryonic genes, these are genes that get turned on when a cell is fertilized, that can re-rejuvenate adult cells as well. So you can take an adult cell, I could take your skin cell, for example, and I could put in these four embryonic genes, turn them on for a few weeks and turn them into Stem cells.
David Sinclair: These are called iPSC or Induced Pluripotent Stem Cells. And it was, well-worth a Nobel prize because now we can take skin cells and grow nerve cells. We can do all sorts of things with them, rebuild whole organs one day. But this is not something you want to use routinely in the body, because what you get, if you reprogram a cell using this method is a giant tumor, right? You'll get cancer if you make stem cells in your body. So this was not going to work for our purposes, but we thought maybe we could use something like this to get the cell to go back partially and reset. So I have a brilliant student in my lab actually. Now he just graduated. He's a doctor, he's a post-doc in the lab. His name is ..(inaudible 00:21:46)
David Sinclair: And what he did was he spent about three years trying combinations of these embryonic genes. And he kept turning them into cancer. And that's not going to help you live longer. But when he was about to give up, I said, "Let's try one more time. Let's try just three of these genes. Let's leave off this c-Myc gene, this one at the end, because it's known to cause cancer. Let's see if these other three are safe." And he tried it out and the cells looked very healthy. They didn't become stem cells, but they literally became younger based on the clock. So then he did a very brave experiment. One that was destined to fail. He asked, can he reprogram a complex tissue of an adult mouse? Can you reset the agent of an animal without causing it to be sick?
David Sinclair: And he decided to reprogram the eye. And the reason is that the eye is one of the first tissues to get old. We lose our eyesight, at middle age, we start to lose it. And it turns out the nerves at the back of the eye don't regenerate when you damage them. Only very young animals, very young humans will regrow their optic nerve. And we know that if you damage your spinal cord, it's not going to grow back, of course. But we thought, what if you could reverse the age of the nerve cells so much that they actually regrow. So we tried that, what we did was we delivered these three, Yamanaka genes, short we call them O, S and K. We put them into the eye of a mouse and we did three experiments. The first one we tried was we damaged the optic nerve and asked, could it regenerate, and I'll show you the results.
David Sinclair: We tested glaucoma, which is damage to the eye from pressure. And then we tested just regular aging, blind mice that were blind because of aging. So let's go to the first result. This was a result that came through about two years ago. And it was one of those results that you'll never forget. I'll never forget. This was sent to me on my iPhone. And (inaudible 00:23:50) had this is the mouse that has had its optic nerve damaged. And the eye is on the right and the brain is on the left. And you can see the optic nerve, which is colored orange has mostly disappeared because he crushed it with tweezers. And when you crush an optic nerve, it's not going to grow back. But then he did an experiment turning on the reprogramming factors, the Yamanaka factors after the crush and wondered, could we really reverse the age of those nerve cells and have them grow again?
David Sinclair: So let's look at that, at the reversal of aging, what you're looking at is increased nerve survival after the crush and the ability of the nerves to grow back all the way back to the brain. So this is the best result that anybody's ever had in growing damaged nerves in the central nervous system. Now you might ask if... Maybe Adam and I can talk about this, but we're also testing, can we reverse aging in the brain now? And we don't know what's going to happen. We don't know if the old mice will regain their memory, or if they'll lose their memory, or if their Alzheimer's will go away. We testing that. But one thing we did that I wanted to show you just to finish up here is what happens if you take an old mouse that's blind and make its eye young again.
David Sinclair: All right. So this is an old mouse. It's one year of age and these black six mice as they're called, they don't see very well. And that's because the nerves at the back of the eye, they don't turn on the genes the way they should when they were young. So we thought if we reverse the age of those optic nerves, those nerves, they don't even need to regrow, right? They're still there, but maybe they would function like they were young again. And so we did it, and this is the mouse that didn't receive the treatment. And it's not moving its head in response to those lines. Just ignore the poops. That's just because it's a little stressed out. But the important point is it's not moving its head when those lines are moving. But what we did was we took another mouse of the same age, for three weeks we turned on those genes. And now that mouse can see just as well as it did when it was young.
David Sinclair: You can see that it's following those lines. And we can actually also measure this with an electrode and see that the nerves are functioning, just like a young mouse. We could also look at the age of the eye and the eye went from a year old back to about two, three months old. And the genes that were all dysregulated and messed up, went back to being beautifully regulated like a young mouse again. So that to me is the first true evidence that we can turn back the clock in a complex tissue, like the eye and that when you do that, you actually get function back again. And we know that these little marks of the biological clock, you remember, I said, those are chemical groups, that chemicals that attached to the DNA we can read for the clock.
David Sinclair: If we didn't allow those chemicals to be taken off in the same way, like brushing your teeth to clean them, the mice, they didn't get back their vision and those nerves in the damaged eye didn't grow back. So the clock of aging, isn't just a clock. It's actually part of the reversal process. So my colleagues and I, and a few labs around the world that are now doing this work are extremely excited about the possibility of turning back the clock through what we call cellular reprogramming. And this is just a funny cartoon showing you can actually potentially turn back an entire mouse's age. Now you might say, well, that's just a mouse, David, who cares, everyone's cured cancer or so in a mouse. But we've done this in human cells. It works. We've done this in human neurons. It works. (27:33)
David Sinclair: And we're hoping to do our first clinical trial in patients that have lost their vision through glaucoma in about two years from now. So cross your fingers, that we're right, and that we will be able to reverse aging in one organ. And then we'll just eventually, hopefully be able to reprogram the entire body. Now we know that we can reverse the clock once in the mouse. We don't know how many times this might work. It might be five times, might be a hundred times. Now things get pretty interesting, right? That you can turn back the clock multiple times. And also know if you turn back the clock, it's reset. You don't need to keep the treatment. You're actually younger when those eyes are younger and they stay young. So you could imagine in the future, having a gene reset and you go back 20, 30 years, and then you wait another 20, 30 years and go back to your doctor and get another treatment that I think could happen.
David Sinclair: It's not against the laws of Biology, whether or not it happens in our lifetime, we'll see, cross your fingers. So finally, I want to thank all the people in my lab that have made this possible. This is the group of my lab. They're just wonderful people. These are... (inaudible 00:28:42) is up the back. You can see him. I guess he's got a blue thing around his neck. You can see that. Next to him on his left is Lindsay Woo. He runs our labs in Australia at UNSW. We've got this aging center. And there we are tackling things like premature infertility, or even just age induced infertility in women, as well as preventing cancer. But I really wanted to thank the group because often I get to take credit for their work, but they're the ones that are actually doing the hard work. And especially during COVID-19, it's been very difficult for them to keep things running.
Adam: Sorry. Excuse me. Sorry, professor. Just doing some research, doing some research.
David Sinclair: That's okay. It's late over here, you can drink.
Adam: Fascinating stuff. Let me ask you a couple of questions. They've come in from the audience on (inaudible 00:29:33) as well. People seem to agree with you on the concept of aging as a treatable condition. One listener says, if we can look at individual components, why not examine at all on (inaudible 00:29:44)? I know it's a passion of yours. Where is the scientific community on that question? Are there particular pockets or countries or ages of researchers in the field where it differs? Is there a scientific consensus or what's the range of opinion on whether aging is a treatable condition?
David Sinclair: Well, it's changing very rapidly. About 20 years ago, this was a crazy thought. And most doctors are trained to think of aging as something natural and diseases are what you treat. But my colleagues and I we've been arguing that it's not just important to understand what caused you to fall off the edge of a cliff. It's probably more important to figure out why you get to the cliff in the first place. And of course, if you can treat aging or slow it down, this would be potentially one treatment, one pill that could prevent all major diseases of society. This would be the most cost effective way to treat basically all illnesses in the advanced world or developed world. Because of that there's a real push, both at the scientific and the government level to make aging a medical condition.
David Sinclair: Countries that are doing this, so actually Australia is one of the leaders. I flew down to Canberra about 18 months ago to talk with leaders down there including a health minister about making this possible. Now, no country has actually formally put up their hand. Others are watching what others are doing, but other countries that are thinking about it and seriously considering it are Singapore, Israel, the United States and the UK. But most scientists who are PhDs in longevity research agree that aging is something we can treat. And we also realize that it's not just important what you call it, but it has real impact on the real world. If a doctor cannot prescribe a medicine for aging, first of all, their hands are basically tied. Even if we have something that works. And second of all you won't get reimbursement. So that's also an issue.
David Sinclair: And the third is that they won't be drugs developed unless there's a disease called aging. It's very difficult. Now I'm doing drug development, but I cannot convince my investors who are paying for all of this and my own money to treat aging, because that would be one of the longest clinical trials and most expensive. So we have to go, secure this route and go for rare diseases or something like COVID-19 as well. But yeah, it's a real movement. And actually the biggest thing that happened was last year, actually the World Health Organization declared that aging is actually a medical condition and they put it in their handbook of diseases. So that's a good step forward. And I think that in the next five years, one country is going to do it. And then other countries will realize that they better jump on board too, because there'll be a lot of attention on that first country that makes that step. (32:38)
Adam: You've given us a bit of an insight there to some of the challenges of working in this field. I read Stanford University scientist, Howard Chang once told The New Yorker, the longevity community is, "The most difficult field I've ever worked in." And he said he didn't want to define his scientific life with all the sort of fights he had in that field. Is it a particularly tough gig being a longevity scientist? And if so, what are the specific challenges of that field?
David Sinclair: Well, I don't want to upset my colleagues of course, because they review our work, but it has been a really tough field to be in. I've been attacked my whole career for saying things that are upsetting to people. And my science has been attacked by a couple of the largest pharmaceutical companies in the world. Are we prevailed, but it's pretty debilitating when somebody puts out a paper that's kind of vicious and says you're all wrong. So if you want to be a scientist, you're a scientist, you've got to be super resilient. And you just got to get out of bed and do the best science you can and realize it's okay to be wrong, but this profession is one where it's our job to call BS and challenge each other. But it's been particularly a nasty field. It's getting better, the new generation that... My generation is trained and now we're up to probably great grandkids in the field.
David Sinclair: They're actually really collaborative. And so the field has evolved into a much nicer field, but there were times where my mentors and even my peers were at each other's throats, arguing over whose gene is more important than other genes. And a lot of politics behind the scenes trying to destroy people's careers. I thought my career was going to be destroyed multiple times. And I think it's because the stakes are so high. People laughs, what are the stakes in science? You're not going to make a lot of money publishing papers, but there's been talk of Nobel prizes. You could argue that there'll be Nobel prizes awarded for aging, telomerase discovery of what shortens the telomeres. Yamanaka we now know is relevant to aging, protein digestion recycling won a Nobel Prize. So I think it was partly because of that. Also the founders of the field were fairly argumentative people to put it mildly.
Adam: Give us another insight into how you came to the field. And I read a lovely story about your grandmother, Vera who sounds like an amazing woman. I believe she was once thrown off Bondi Beach as a youngster for being dressed a little bit too (inaudible 00:35:22). Is it true that it was your realization that as much as you loved her, she only had a finite life that made you think about aging and tell us more about the work your own family's doing. You said they're trialing some of these molecules.
David Sinclair: Yeah, well, I come from a family of scientists, my father and my mother were scientists. My wife's a scientist, my kids, at least two of them want to be scientists. So we're that way inclined. So my grandmother, first of all she helped raise me and she was a young grandmother. She actually had my father when she was 15. So she was more like a mother. I would say if I want to be honest, and I probably, I don't think I've ever said this publicly. She thought the sun shined out of me, so to speak and told me that it was my duty to help humanity. She'd survived, World War II and the European aftermath in Hungary. And she came to Australia in 1956, and this was the land of freedom and bounty. And I came along and she just thought, wow this little kid can change the world and make the world a better place rather than what she saw in her life.
David Sinclair: And she instilled that in me, but what really got me going on aging was I was four years old. And like most kids, you are... Every kid asks their parents or their grandparents, "Are you always going to be there for me?" My grandmother is fairly brutal. She said, "No, I'm not, I'm going to die. And then your parents will die. Your pets are going to die. And then you're going to die." As a four year old that's life changing. Right. And so I wasn't worried about my own death. I'm still not worried about my own death If you've ever seen me drive a car, you'd know that that's the case. But I'm more interested in leaving a mark on society. Making my life worthwhile. I think we all want to leave an impact somehow whether it's through kids or through writing something or discovering something or just being a good person. That's what drives me. And I think that figuring out why we get sick in the first place is a really worthy goal that when I started wasn't being worked on in any rigorous way.
Adam: And what are your family doing at the moment? You said that they're using some of these molecules. What sort of results are you saying-
David Sinclair: (inaudible 00:37:42).
Adam: -Are they actual official trials or just gobbling them down occasionally what's going on?
David Sinclair: Well, consider I'm at Harvard Medical School. I get in trouble for saying stuff like this, but what I can say is I don't shy away from a question and I never tell a lie. So let me tell you the facts. So I never make recommendations, right? I'm not a doctor, a real doctor, I'm just a PhD. But my father is 81, turning 81. And he's looked at the research, he can read scientific papers and he's made a judgment call that the risk is very low. And of taking the molecules that we discovered and the risk of not taking them is really bad. Right. We know what's going to happen anyway. We're all in denial really of what's coming. And so he started taking Resveratrol probably 13, 14 years ago. He's been taking NMN daily for at least three years, four years, maybe.
David Sinclair: And a few other things that are listed in my book, page 304, if you want to jump to it. But I'm not recommending people do that, right. Everybody's different. We don't know the full safety, but they do seem to be very safe molecules. It doesn't seem to be hurting my dad, he's 81. And for his age, he's fitter than me. He's very strong. Anyone who's seen him on the internet, he's really a bright light for all of us. Now, we don't know if the molecules make a difference. It also helps that he does a lot of exercise. But it's a ray of hope, a beacon for us to follow, I think. We are doing clinical trials, right? I'm not just saying, Oh, that anecdote proves anything. Of course, we need to do rigorous placebo, double-blind controlled studies, which we're doing. But in the meantime, someone who's 81, can't wait another 10 years for the result.
Adam: That's interesting because a lot of people would know, of course, you're doing this sort of stuff in mice. I'm sure you have been for a long time, but there are actual clinical trials taking place now on aspects of this research with humans?
David Sinclair: Dozens of them actually. There are trials on drugs that are already available from your doctor, not for aging, of course. There's one called Metformin, which is given to type 2 diabetics. When you have high blood sugar, that one looks like in tens of thousands of people actually reduces diseases of aging, not just diabetes, but cancer, heart disease. Alzheimer's. So that's one aspect. We want to do bigger studies with thousands of people, but that's coming. But also drugs in development, it may come as a surprise to hear that there is probably 50 companies that are working on aging or drugs that may help aging. I've started, I think now 13 different companies, many of them work on aging and we have clinical trials in progress such as this MIB-626, which has been in humans for the last two years. And it looks really interesting.
David Sinclair: There are other ones like senolytics, these are drugs that kill off the zombie cells that accumulate in the body. And they look promising too, some of those are public companies. So somebody is going to crack this, it's going to happen often you say in the next five years, but certainly within our lifetimes, there will be drugs that your doctor can give you legally and ethically that should be able to slow down aging and maybe even reverse it.
Adam: Austin asks a question if it does become possible to actively reverse biological aging, what are some of the limits of this? He asks, how far could you push someone's biological age back from some given point in time, he's hinting at, is it better to wait once in your life and do it when you're 80 and drive it all the way back to 20? Or when you get to 50, should you constantly back it back a few years, the numbers aren't important, but do you have any insight from the work you've done yet as to... You touched on with the mice, you're not sure how many times you can do it. Do you see the way the process would roll out in the life of someone who grew up where these medications were fully available? (41:40)
David Sinclair: We're getting some glimpses, right? These are still early days. And we've only been doing these for a couple of years, so there's not a lot. But here's what I know is that unlike the Yamanaka factors that won the Nobel Prize, that technology just rips the cells clean. It's like brushing your teeth and ripping your teeth out. It's that strong. But our method, it actually takes the cells back to a point and then they stop. There's this natural barrier to getting too young. Now, of course, we get too young, you get cancer, but we're very lucky that if we turn it on for three, four weeks the cells stop going backwards. So I think what's going to happen is, and we've actually engineered this for mice and now humans, is that the system is turned on by an antibiotic.
David Sinclair: Now we're not using an antibiotic to kill bacteria, we're using it to turn on this treatment. So what we're going to do with the people as we've done with the mice, is you put it in the eye and it just sits there, you've got the genes in your eye. And then when you want to get your vision, your doctor will give you three weeks course of doxycycline, the antibiotic, it'll turn on the genes. And when you get your vision back, then you stop taking the antibiotic. And then I think what'll happen is when your vision starts to fail again, whether it's in five or 10 years, then you just take another course of antibiotics for three weeks, then you get reset again. But we don't know how many times, we don't know if you can do it a little bit each time. We've mainly been going for three weeks. We haven't done less than that.
David Sinclair: But also the good news is we've reprogrammed an entire mouse for over a year. I think we... What did we do? 15 months of treatment, if anything, those mice had less cancer than a normal mouse. So we're pretty confident so far. Well, let's say quietly confident that we're not going to be causing harm. And actually it's remarkably safe so far. One of the reasons for going for the eye actually is that it's a contained unit and there are already drugs that use gene therapy in the eye for that reason. It's a little more... I don't know how soon we'll be able to inject it into our veins and be reprogrammed completely. We got to ways to go, but we'll take it one step at a time.
Adam: I'm about to ask a few more slightly scientific technical questions. Let me ask you one more big picture for the simple people like me in the audience question. I know there's a difference between being a life spanner and a health spanner, but in terms of just lifespan, what are your thoughts in this field? We hear some things, some people say 150 is a magic number. If you can get to that old, you can live forever. Some people say there are people born now who lived to be 150. I've read somewhere, once you get beyond about 105, the difference in aging profile is not that great. 105 compared to 110, et cetera. In terms of just the simplistic, give me some numbers, how long do you think people could realistically live healthy lives within some foreseeable time from now?
David Sinclair: Well, we know that people can live close to 120 years, the maximum. The longest lived person, extensively was 122. And the average age in most countries that are developed is 80. So that's 40 years, we know that we can get, it's not impossible. So that's a long... I'll take that if we can get everybody up to 120. The important thing to remember is if you live to 120, it means that you're a hundred still playing tennis, having a great time, multiple careers. It's not that you're extending the period of life when you're old. What we're talking about is extending the period when you're young. And actually people who live a long time die fairly quickly. It's the same for the mice we treat. And someone who lives over a hundred costs the healthcare system, a third of what everyone else does, but how far can we go?
David Sinclair: I think I was the first person in Australia to say that 150 number that the first person could be born to live that long. The prime minister actually used me and then got in trouble for that quote. I also got in trouble for that quote, my colleagues, a couple of them took me aside and said, "Can you just stop saying that number? It's not a good look." And I said, "Well, do you think it's possible?" And they said, "Yeah, but just stop saying it. It's not a good look." Right? So especially with the reprogramming work, I think it's possible that that is true. And people forget that children born today will see the 22nd century for sure. And that's a long time away and there's a lot we can do by then. You can't really just use today's technology or even the next 10 years to extrapolate. (46:17)
David Sinclair: So the other number that's interesting is every year you stay alive, you get another three months because technology is improving. And then if you get another year for every year of life, then things get pretty interesting. I don't think we're going to be there anytime soon. I think immortality, it's not even worth talking about, it'd be like asking the Wright brothers when are we going to the next solar system? That's not even worth talking about, even though it'll happen one day. But will we be able to slow down aging to get most of us to 90 or a hundred within this century? I don't see why not. I think we're already proving that the science is working. There are already drugs on the market as I mentioned that if we used widely could extend lifespan, even though they're not being used widely for that. So that's where we're at. It's hard to predict the future and you're always wrong. But I know for sure that you're going to see a large jump in lifespan based on the science that I'm seeing come out of various labs around the world.
Adam: I'm going to go into a few more, slightly more technical questions now. I'd suggest we are on the side of not getting too far down the scientific rabbit hole for fear of some people in the crowd losing us, but Sashen asks, how does it work? How does exercise and certain foods actually activate the longevity genes? What is it about these activities that turn them on? How can we tell which activities activate particular genes?
David Sinclair: Oh, well, we're right on the cusp of that. So we don't know for sure which exercise is best for every individual and everybody's different. But what we do know is that if you lose your breath and you train, you will have more NAD in your body. The body makes more NAD as you exercise, same for when you're hungry, your NAD levels go up. And the sirtuins, they use NAD as their fuel and then resveratrol and the monounsaturated fatty acids are like accelerator pedal. So you've got the fuel accelerator and that's how they work. But exercise mainly is making NAD. The other thing that's interesting is when you're hungry and you exercise, you start burning fat, right? We know that. You know one of the byproducts of burning fat is, in the body? It's oleic acid, the same monounsaturated fatty acid that you get from avocados and olive oil.
David Sinclair: So that may be why exercise is also good. It's liberating this accelerator pedal molecule, as well as raising NAD for the sirtuins. Now, AMPK is also activated that one in the middle. That's also true. And so also if you're hungry, that mTOR one that was on the left gets turned in the right direction. So it's not an easy answer. There's a lot of things that go on that the body senses when there's a problem. But I hope I gave you a good flavor of what are the main things that happen.
Adam: Particularly on NAD. James asks, can you test your NAD levels? And if you have normal, healthy levels, does taking NMN make any difference or at that period of time in your life, is it a waste of time and money?
David Sinclair: Well there's no commercial test. We do it in my lab and at the company. And it's not a cheap or a simple test yet, though we are working on that. You can have your biological age tested if you search that on the internet, you'll see, there are some (inaudible 49:46) called Horvath Clock. So DNA methylation clocks available. But not an NAD test, unfortunately, even, I don't know my NAD levels. It's that hard and expensive. What was the question, Adam? There was a good one after that.
Adam: Yes. So if you do know your level, if you're already at a healthy level of it--Is there any point of taking NMN?
David Sinclair: Yeah, that's a really good question. So the answer is in mice, we know the answer that if you have high levels of NAD it has less benefit. So young people probably will benefit less than older people. That said we took young mice and gave them NMN. And then also exercised them. And that combination was really powerful. Then they were the super mice that ran the furthest. One, mouse ran so far, it actually broke the treadmill. And so what we think is going on is if you practice hormesis, a bit of hunger, a bit of exercise combined with NMN it possibly will work even if you're young, that's what the science says. We haven't proven that yet, but that would be my guess.
Adam: Do you know... You don't know your own NMM levels, do you know your own biological age and is it indiscreet for a gentleman to ask?
David Sinclair: I'm going to test it. We just filed a patent to bring the cost of that test down a hundred fold. So we're excited about that. But I haven't done it yet. I know it sounds crazy. I should be the first person to do it, but honestly, I'm so busy just trying to get clinical trials running for COVID and all that stuff. But what I can tell you is I took a predecessor test. There's company called InsideTracker in the US, I don't know if it's in Australia. But and in full disclosure I consult an investor in that company. InsideTracker would take a blood test and use some of those, the blood biochemistry to tell you potentially your biological age. I took that test and I actually got a big shock. I was 47 at the time, and I came out as 58, I think it was. So I panicked. I thought, Oh no. And at the time I wasn't exercising, I was eating badly. So I turned my life around. I started taking NMN, I went on this Metformin drug and I lost weight because of it, I think.
David Sinclair: That combination I could say there were various changes in my blood biochemistry eventually got my age, predicted age down to 31.4 and I've stayed that way ever since.
Adam: On that, before we get into a couple more technical questions, what's one bit of advice, lifestyle advice someone could take on right now to significantly improve or get them to where they could be with their biological age?
David Sinclair: Yeah. Well, besides giving up smoking, that's probably the main one, but if you're not a smoker, if there's one thing I could recommend that has the biggest impact we found, that's even easier than exercising is to skip a meal each day. Be a little bit hungry, let your body fast. And it's pretty easy. This is what I do. I tend to skip breakfast and not eat late at night. And then you get this whole 18 hours, if you can of not eating. Now, if you're hungry and you can't think, of course, that's not good. But you do get used to it after about a couple of weeks. Now, I don't feel the need for food and I just have coffee is okay. Even a little spoonful of yogurt, it's not going to hurt you. And I think that that's the biggest bang for the buck.
David Sinclair: We know that people who live a long time, people that are eating relatively little amounts of food, at least for part of the week, you can be more extreme, you can skip two days of eating a week. I cannot do that. And some people even skip a whole week, every few months and that's really deep cleanse. But I just don't have the willpower. I can't think when I'm that hungry.
Adam: I skipped a couple of hours, one day, about six months ago, felt very good about herself. Veronica asks a question, it's a bit more technical and feel free to take this back as simply as you want, but what determines the positioning of epigenetic tags that determining the switching on and off a gene expression, she doesn't (inaudible 00:53:55) one of the factors that lead to those tags, but what determines where they place themselves on the DNA?
David Sinclair: All right. Well, we do know that from other labs, actually, people who study development of embryos, there are protein complexes that find places on the DNA and get directed to put them on. Exactly how they find the right place, we don't know that yet. The other big question is how does the cell know which of these chemical tags to remove when you get younger, right? You don't strip them all off. There's a code and they take some off, they actually, sometimes they put them on to reverse aging. And that I think is the key question in Biology right now is how does the cell remember what those tags were 50 years ago? That's the information that's missing. We call this the observer based on... I'll get a little technical, I hope you don't mind. So Claude Shannon was the guy that invented Information Theory of Communication.
David Sinclair: That led to the internet, it led to the ability to have backup hard drives of information. And he called the backup hard drive, the observer, really the person, the thing that remembers the original signal. And we think in the cells, there's this observer, this backup hard drive, but we don't know where it is. It could be another chemical tag on the DNA, it could be a protein that sticks to our DNA when we were very young or it could be something else that we're looking for, but you can bet that about a third of the people in my lab are now actively looking to answer that question.
Adam: Got a question here from Lisa. Can you tell us a bit more about the different combinations of NMN and other drugs? Do you have an opinion on what's the most promising combination or cocktail at the moment?
David Sinclair: Not really, that the problem with aging research is that it's really slow and expensive even in mice, a mouse experiment will take you about three years and another two to publish. So I apologize that we haven't done all these combinations. What's the best I can tell you, now we've tried, well, the field has tried Metformin plus rapamycin, which is the AMPK mTOR inhibition. And that worked additively. So there was a better effect by having both of those things. But we really don't know what the right levers to flick are. Should you be taking NMN with exercise? Or should you exercise with fasting? We literally are not at that point yet. I'm still trying to figure out with my body what seems to work because I'm measuring myself all the time. I've got this biological measurement ring called the Oura Ring. (56:42)
David Sinclair: You can see that thing. I measure my blood. I measure... Well, I've got one of those wristwatches as well, that measure things. But it's hard. I wish I had a good answer for you. But I think that's also one of the cutting edge questions that we need to answer is what are the combinations? Oh, there's one thing I want to tell you that is kind of a roundabout way of saying something that isn't really the answer. Often, we wonder what should we eat, which is more important, protein, carbohydrate, fat, or is it more important when we eat? And my colleague Rafael de Cabo at the National Institutes of Health in Bethesda, he did an experiment that he got completely opposite from expectations. What he found was that it didn't matter whether he fed his mice, a lot of fat, a lot of carbohydrates or a lot of protein in different combinations. He found that if he gave it to them only for a couple of hours a day, those were the ones that always lived the longest.
David Sinclair: So it's probably more about when you ate than what you eat. To some extent you can't just go eat fatty hamburgers every day and expect to live longer either.
Adam: So let me ask you a question that sort of comes from that in some ways, I mean, the work you're doing is incredible. It's right at the edge, it's really expensive, it could affect the world in the future. But as we sit here to die, the percentage of health budgets, that is spend treating diseases that are completely avoidable with standard lifestyle reset? So I was doing an event with Ian Frazer once, and we had a health policy of give up the smokes, ease up on the (inaudible 58:26), walk to the shops now and then, the percentage of chronic disease, the amount of money in the health system that if enough money was put into prevention could now get people born today, just leading 84 year old lives that are so much healthier. Is there an argument that the sort of money that's going to your incredible research would be better spent just giving really simple messages about what we now know is an arguably true for people to live lives today?
David Sinclair: Well, I don't think so. We've been spending a lot of money on the message for the last few decades and it hasn't worked. Right. And the other thing is you can't expect someone who's in a nursing home or had a heart attack or is in a wheelchair to go for a run or to restrict their food. So these are medicines that will help very sick people as well. Not just people who are middle-aged looking to live longer. So that's important, right? Every ambulance might have one of these medicines in there to save a patient or to protect the spinal cord. So I would say that the research goes way beyond just living longer. These are real medicines to treat even acute diseases, perhaps even COVID-19, we'll see. But there is a good point to making sure that people live a good life. Now, the statistic that I recall, it was just recently from Harvard, where I work.
David Sinclair: And it was that you can get another 14 years of healthy life just by doing the five standard things. I think they were don't smoke, exercise, eat the right things, get enough sleep and don't get stressed. Something like that. Those easy things, if we just do what we're told you can get 14 years. If you add on what I'm doing, the sky's the limit, I think.
Adam: Thomas asks, you've shared the research on Twitter recently from the team who proved that blood plasma of younger rats injected into older rats made older rats, genetically younger, but also cleaned up senescence cells. What's your gut feel on what causes that? Do you think that young blood plasma can reset Yamanaka factors as you described them in your book? Now, obviously I know what a Yamanaka factor is, but for anyone out there who doesn't, do you want to give us some background and address that broader question Thomas is asking?
David Sinclair: Yeah, well, Thomas, I don't know if you're a scientist, but those are the kinds of questions we ask in my lab. So the Yamanaka factors are the genes that we use to reprogram the eye, those three genes, O, S and K. It would make perfect sense that young blood is resetting the biological clock and turning on those Yamanaka genes, the same way we're doing. And we've actually designed experiments to test if that's true. It would make perfect sense that young blood is resetting the age of that mouse. What was it? 54% on average. Because right now we don't know of any other way to reset the body. Senescent cells getting rid of them, that's really interesting. It means that the body can clear out senescent cells. We know that when we're young, we can clear them out. We have immune cells that detect and kill them.
David Sinclair: But as we get older, they become immune to the immune system. And so maybe this young blood says, "Okay, wake up again, go kill those senescent cells, those zombie cells." So what that experiment... The reason I tweeted about it is that if it's true and actually Steve Horvath was the one that did the clock. So I believe him. He's the guy that invented the clock. I called him up and I said, "Steve, are you kidding me? You just took off the half the age of the mouse. Is that true?" And he said, "Yeah, it's kind of hard to believe." And I said, "Surely they just mixed up the rats." And he said, "No, no, no, really, we can tell from the DNA that they didn't mix up the rats." But that's stunning if you can take the biological age of a rat back 50%, it means that there are factors that you could one day inject into a person and possibly have the same effect.
David Sinclair: Now I'm not condoning going to bleed your younger relatives and have a transfusion or anything, that I think is kind of risky. And in fact, in the US that's been outlawed because we don't know enough of the side effects of that. But I do believe it's a proof. It is some proof that at least in rats, you can reset the age of an entire animal.
Adam: I'd suggest perhaps for your grandfather's 80th birthday or something to be one of the most thoughtful gifts you could give. But anyway James asks, are there any other theories that scientists and researchers have about aging that are different from your Information Theory? What are some of the most common criticisms you've encountered? What are your responses to those, or what are some of the criticisms you've received that you've taken on board and shaped and tweaked your research as a result?
David Sinclair: Yeah, well, there are about eight or nine, depending on who you ask, Hallmarks of Aging. These are really what we should be calling causes of aging. We just don't like to say that. But these hallmarks, I listed some of them, there's lots of stem cells, there's telomeres, the ends of the chromosome shortening, loss of nutrient sensing, loss of protein recycling, loss of energy production, mitochondria, senescent cell accumulation, epigenetic changes, which we talked about today. There are others. Clearly this is not the only theory of aging... Oh, DNA damage, that was another one. But what I'm trying to do in my theory is to say, why do all of those things occur? What's driving them all?
David Sinclair: Because I think in all science, we like to figure out, is there something that's unifying this. In physics, it's unsatisfying having 10 different equations that don't fit, right? You know this Adam, So we've got, we like to unify. And I liked the idea that aging is the loss of information that leads to these many hallmarks of aging. What are the criticisms of my work? Well, every scientist's work gets criticized. The one that was the hardest to deal with was, we published that resveratrol and some drugs that we took into humans, activated the cert enzyme directly. So you can think of the cert enzyme as an enzyme that's like a “packman”, that does good things in the cell, telling other proteins what to do. And we said that was virtual binds to that and actually does makes it chump faster. I don't know why I'm putting on American accent. I should just speak Australian. But what we were criticized by scientists at Pfizer and Amgen because they said it was wrong. (1:04:54)
David Sinclair: There was no evidence that this was true because when they tried to repeat it in their own fashion, it didn't work. It took another three years for us to figure out what was wrong. And in the end we figured out that the difference between our system and their system was telling us very interesting things about what happens fundamentally in the cell. And now, fortunately we were found to be correct. But that's pretty hard when somebody says the foundational work that you built your career on is totally wrong. And of course, I had my face published in Nature magazine. I had my university come talk to me saying what the hell was going on. That kind of makes it hard to get out of bed in the morning. And I did have days where I thought, screw humanity. Why am I working so hard?
David Sinclair: But I think I'm not that kind of person, I got out of bed, went back to the lab, found a couple of students who were willing to work on this. And three years later, we published a paper in Science Magazine that showed that we were right and it's worked out well. But it's tough. It's really tough when that kind of stuff happens. But I'm now 51. And I've learned that if you do good science and you check things and you have many people doing the same kind of experiments, so there's no impossibility of reproducibility, then you just put it out there and you be honest and you let the world judge it. And you hope that you're right. But as long as you're honest and you do the best science you can, then there's nothing to fear.
Adam: Well, if you're 51, we are actually both exactly the same age. So before this wraps up, you should get someone from your lab to take a quick screenshot of our two heads next to each other. And if that doesn't prove your theories my friend, I don't know what does. A couple of our viewers have asked some real interesting questions, moving away from the scientific, into the broader ethical realm, which of course walks hand in hand with all science. But Susan asks there are other variables to consider population growth, food production, environmental damage, @Carrie asks, where do you stand on the idea there are already too many people on the earth and this will make the situation worse. What are your thoughts on those with some first up ethical issues?
David Sinclair: Yeah. Well, Susan and Carrie you've asked the right questions because there are always implications for these scientific breakthroughs, some positive, some negative. The good news is as I've outlined in part three of my book, that if you do the numbers, it's actually not as bad as you might think. In fact, it's a huge benefit to the world's economy to have people less of a burden on healthcare. And not just less of a burden, they're actually productive. If you look at my father, who's 81, he started a new career. He's helping... It's non-profit work, but it's still work. He's helping with the grandkids. This is very different than being in a nursing home, having to be paid for and cared for. It's also better for families, right? You don't want to see your parents suffer or your grandparents.
David Sinclair: So that's all on the good side. What about overpopulation? Well, there will be more people, but the good news is that it's not as many as you might think. Even if we stopped aging completely today and nobody ever died, which I don't think we'll ever do, the population rate of growth is not a lot. Surprising, it's a few percent. If you do the math and actually project into the future by the end of the century, well actually not even that long, it's another 40 years, the earth population will level off and start to decline. We already see that in Europe. And even in the US. And so the rate of replacement will equal... Birth and death will equal even if we're successful here. And that's good news. I talk about the environment a lot in my book because I'm very concerned, there's no point in having people live around if there's no where to live. (1:08:39)
David Sinclair: So I talk about technologies that could actually improve the earth for people who are around to see these technologies. I'm a huge optimist. I think that if we put our minds to any problem, we can solve it. I drive a Tesla for good reason, I believe that that's a perfect example of how we can completely change what we thought the future looked like.
Adam: Meredith asks, what about the impact of these technologies on the planet, in the sense that we know that the first to access any cutting edge new technology will be the wealthy. She turns that into a question on climate change and the impact the wealthy have there, thoughts on that I'd be interested to know, but also are these the sort of therapies that when they come online, at least initially will be incredibly expensive and under the providence of a select few?
David Sinclair: It depends. Now it depends on the technology. There are some technologies being developed, such as the gene therapy that will be expensive. It could be a hundred thousand dollars a treatment to get your eyesight back initially. And the reason for that is it's going to cost probably hundred million dollars to develop those medicines. But there's good news, some of the medicines that I'm helping develop. And of course there are other companies, I'm not the only one working here. But I can speak better about my work. MIB-626 is an NAD booster that I've mentioned today. That one could be very cheap. I mentioned that if it works for helping COVID-19 patients, it could be just a few cents a pill and give it to a hundred million people around the planet. That would be a great outcome. And so there are some drugs that are not expensive to make at all.
Adam: One final question here, professor, and you've touched on this a little bit. It's the biggest issue on the world at the moment, can I have any podcast or interview or Zoom session without talking about COVID, quickly take us slowly through the link you're talking about here. Obviously we know older people seem more susceptible to COVID, so it would make sense there's possibly some overlap between treatments that understand aging and making you more resilient to COVID. But what's the specific link that you're looking for in the couple of sort of lines you've hinted at so far. Walk me through that, nice and slow. I really want to get this. (1:10:56)
David Sinclair: Okay. Well, so when, when COVID-19 hit, I think anyone who follows me on social media knows I was there trying to help the world and not talking about my work, it was really trying to get humanity through this. And so I avoided talking about NAD and COVID-19. I don't want to be the person who's running around with a hammer, looking for a nail. It looks just self-serving. And it also didn't seem to be the right thing to do. But I had people write to me and say, "Do you know there's this connection to NAD?" And there was a doctor who's published case reports of patients who've recovered remarkably being treated with NMN, an NMN cocktail out at Cedars-Sinai in LA. And all of that started me to start putting two and two together.
David Sinclair: And we actually, we've been working on this interestingly in my lab for the last five years. One of my students, Michael Schultz. And he actually showed that NAD is very important for the immune system to function. And it just turns out that COVID-19 virus, well, coronavirus, SARS-Coronavirus-2. It actually, one of the strategies it uses to overcome the body is to chew up the NAD in the cell. Right? And so what we think is going on is that there's actually a gene in the genome of CoV-2 called NPS3 that is designed to chew up NAD. And so you get this vicious cycle of the cell trying to make NAD and the virus chewing it up. So we think that by replacing that lost NAD cells will survive and immune system will recover. And the other thing that happens when you have low NAD is that you get activation of the hyper-inflammatory state.
David Sinclair: There's a protein complex called the inflammasome. And within that protein complex is a protein called NPO3, and that is controlled by NAD in the sirtuins. So the idea is if we get the NAD backup in the elderly patients, their cytokine storm would be alleviated. And that would be a way to treat those very severe patients.
Adam: Let me ask you one final question before getting a comment from you, with the COVID thing more generally moving away from your specific research, my background is I'm a Maths nerd and there's been some horrible suffering worldwide during COVID. But an interesting side issue for me has been, I've never seen millions of people day by day, obsessed with mathematical modeling, exponential growth, re-infection rates, looking at two different curves and realizing the area around the one is the same as the area under the other, but the maximum is different. Waking up each morning to see the new figures and see are we flattening the curve, et cetera. As someone who's spent his life in science and research, what have you observed more generally about... It's far more important that people have died and we need to make sure as little that happens as possible.
Adam: But what have you seen about... This is the first time I've ever seen the entire world concentrating on just one thing. It happens to be a science issue, right at the edge of what we do and don't know, it seems to have elevated certain scientists to a position of respect that maybe another debates around climate change, et cetera, experts haven't had. What have you seen play out, especially in the United States during the ups and downs, don't get political, but the incredible rod we've all been on over the last couple of months.
David Sinclair: Well, it's been heartwarming to see, there's always a backlash against whatever happens. And you've seen that in the United States, backlash against scientists and Tony Fauci, even Bill Gates. But I was really encouraged by what you're saying, Adam, that the world's never coming up against one problem together and scientists have united, scientists that would fight and argue are now working together. You should see where I work at Harvard Medical School, I've now got probably 20 collaborations trying to solve this problem and everybody's rooting for each other. Whereas before that, there was some kind of unspoken jealousy, that's gone. But also the general public I thought, and I still believe that the status of scientists was elevated. Hopefully not just temporarily. I experienced that myself personally, that people were just asking me for my opinion because I'm a fairly prominent scientist. And I'm not even a virus expert, or at least I (inaudible 01:15:31).
David Sinclair: But I was right in the middle of that. And it was in part overwhelming for everybody, including my family. But I was just like (inaudible 01:15:41) in a coal mine that, that people turned to scientists because what was happening was people didn't know who to trust. And we lived in a world where, we still live in a world where it's hard to know what's truth and what is real. And scientists seem to be one of the few professions where you can always trust what they say.
Adam: Well, this has been absolutely wonderful professor. Thank you. I know some of our viewers are going to be lucky enough to have some special one-on-one time with you soon, but in throwing to you for your final comment, this will be the final comment from any of the wonderful experts who have shared, the entire Think Inc. Outside The Box series. What's your catchy takeaway message from what you've had to say today, what's the one thing you really want people to leave with a sense of?
David Sinclair: Well, the biggest one would be that your lifespan and how you will be in your eighties and hopefully nineties, is really in your hands. We often think, well, it's in our genes. DNA is destiny. That's not true. How you live, what you eat, when you eat, when you exercise and you don't need to do a lot of it. I do a few times a week in the gym, it's not a lot. I don't run marathons. I'm not that active, but a little bit goes a long way. Skipping breakfast once in a while, maybe every day, if you can, running a little bit, lifting weights, making sure you're flexible. These will help ensure you have a really productive, healthy, enjoyable, old age. And the longer you live, the better chance you have of living longer. So yeah, please don't fear aging, it's in your hands and hopefully I've given you some things to think about to live longer. And there's a lot more, of course I wrote about in my book that if you've read it as you've done Adam, there's a lot more you can actually do. And it's not that hard.
Adam: I can't recommend the book highly enough. I want to thank you so much for your time today, David, these have been wise words to live by, cheers to you my friend. And it's been such a thrill to have you as our final presenter on Think Inc. Outside The Box. I'll see you David at your 150th birthday. We'll be celebrating the same. Well, have a combined 300th. That's what we'll do. A combined 300th for the two of us. Thank you so much.
David Sinclair: Thank you Adam, we will have an age reversal party.
Adam: I can only imagine what we would be injecting into ourselves at that little shindig.
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