Welcome to the lifespan podcast by we discussed the science of aging and how to be healthier at any stage of life.
I'm David Sinclair. I'm a professor at Harvard Medical School. I run a research lab. That studies aging why we get old and why we may not have to. I'd been there for 20 years and we've made some breakthroughs were going to talk about on this podcast.
I'm also joined by my lovely co-host. Matt Laplante, lovely, talented. Brilliant reasonably, talented good-looking. You're a great writer. We co-wrote a book called life span together. I'll take that compliment. Thank you, and we've been really excited about the reception of this book, but we thought, why don't we spread the word those of you who haven't read the book? That's fine. We're going to go into detail in this episode to give you a basis for what we're going to talk about in this series. And if you have read the book,
That's okay, too, because so much has changed in the last three years. Since the book was published, right? So a little bit about you before we get too much into the weeds. You're a writer used to be reporter. You've been a war correspondent. What am I missing? I'm a professor of Journalism at Utah State University, right? It's not Harvard University, but it's the Harvard University of the Mountain West. Anyway, you're brilliant at writing and I certainly couldn't have written this book without you but this
Cast. We actually talked, we talked a lot every week. Yeah, we're writing another book, which will be due out. We hope probably next year. Oh, dear God. Yeah, we're going as fast as we can. But so Matt and I talked a lot and we have these conversations, that pretty funny. And anyone who overhears these conversations says that should be a podcast with their funny to us. Well, we'll see, they might be funny to other people. But the point is you bring out the best in me, you act like the Caveman with the questions that.
I need to ask myself and that's what gave rise to life span. It was asking the questions that I didn't even know I needed to answer. Well. I'm for me that experience is like and whenever I work with anybody on a book, but especially, I mean, for whatever reason, the way we've hit it off, like I feel coming away from these conversations that I've just gone through like a graduate course of study in this thing that I don't have any personal expertise and I didn't go to school to do what you do, but I come away from these conversations.
Stations. And I feel like I've been in class and in really good way. Is I'm a lifelong learner. I love this, right? I'm a student right now. And that's something that we can share with everyone. Well, it sounds corny but it really is a match made in heaven. You before I met you had written a book about epigenetics. We're going to get into that. That's key to understanding aging, you'd written a book about extreme animals, your book. You want to plug it or superlative.
The biology of extremes. Yes, stem-cell quite as many copies as lifespan. Well, so yeah, we should plug that. It's a great book. It's about you animals that teach us how we can optimize our biology something that's going to be a topic of this series. Yeah. In fact, we're going to talk about that a little bit today as well. Well, we are the point of this series. Let's talk about why we can while we're doing this, besides entertaining, ourselves and others is that we are at a turning point in medical history. We finally as a species, understand how?
Control our biology, how to optimize our bodies during early life midlife and certainly late life to lead lives that can be decades longer and healthier, and we want to share that information. It's very hard for the average person to understand. Let alone digest thousands of scientific papers. That's what I do. I have a team of researchers. In fact, today was supported by a team of researchers who have helped us gather information from around the scientific literature my job and and yours is too.
Present that as a lesson to people who want to listen and learn beyond what they hear and can read on the internet which is actually rather untoward trustworthy information. We want to be I promise to be a source of facts and information when we give a study people can look it up. If I don't know something, we will make sure that we find the original source to that information so that you can trust. If we say something is a fact, it is definitely a fact. And we have
No, we're not selling anything. I'm not selling any supplement. So when I talk about supplements later, it's based on facts. And we also, we promise to say whether it's a study in a worm or a yeast cell, or a mouse or a human. Because that's very important because, otherwise people conflate a study in a mouse with a human study. And there's a big difference between a mouse and a human, of course. Okay. So we're going to do this for Eight Episodes. Today's episode is why we age, we're going to dive into that in a second here, but let's
Give a real brief overview of where we're going from here. Well, the reason for doing this podcast really is that we are living in a really important moment in medical history. I think as big as antibiotics and vaccines, we are going to be able to live decades longer with science. That's coming out every week. That's making my head spin. I want to bring that to the public and provide actionable information, what people can do in their daily lives starting today to ensure that they live well now and
Fades into the future, not just living longer, but living much better as well. And this includes for low and no cost at all. These are things people can actually Implement in their lives right now, right? So future episodes include, not just what to eat. But when to eat and actually packing meals into shorter periods of time, will ultimately, save money. It's not expensive at all. And some of the supplements will talk about and treatments and even medicines are relatively cheap. So this isn't
From billionaires though. There are plenty of billionaires. We can talk about that are into this. This is these are things that we can Implement right now. And that's the exciting part. I want to talk about the science behind that because right now, people confuse. What should I eat? What should I eat? Should I eat meat? Should I eat vegetables? We're going to go through all that in coming episodes were even going to talk about. But not just eating. It's where how we should exercise. When we should exercise. Of course, we're gonna have an episode on on that about how we should stress our bodies.
Is important. So a little bit of stress on the body, puts it into this defensive mode. We can talk about this concept of hormesis in future episodes. We're going to dive in in detail and say. All right. There's this study that shows that if you exercise this amount, you get this much Longevity. If you eat this, you get this much longevity. There's also some more exotic things. There's cold therapy. There's heat therapy. There's peptides there's things called exosomes. We're going to go right to The Cutting Edge of Science and maybe a little bit beyond to see what's into the coming, in the future, including age reversal.
A New Concept in this field as well. This episode though, our deep dive today is aging why aging happens. It is we want to provide the fundamental understanding of what the biology is. That tells us why we age and ultimately why we don't have to before we get into that David. I know you want to talk about our sponsors because that's what actually makes this possible makes it so that anybody can access this at any time that I have to pay for it. Well, exactly.
What we're doing today is separate from, I work at Harvard, of course. And what's exciting about it is we can also mention sponsors who I truly believe in. Our first sponsor is athletic greens. Athletic greens is an all-in-one Daily Greens. Drink that supports Better Health and Peak Performance. It's developed from a complex blend of 75 vitamins, minerals, and Whole Food, sourced ingredients. It's filled with adaptogens for Recovery, probiotics, prebiotics, and digestive enzymes for gut health, as well as
Ben, C and Zinc for immune support. I've been drinking athletic greens, every morning, pretty much for the last few years. And this is a way that I can cover all my nutritional basis. I'm often traveling. Sometimes, my diet isn't the best and so by drinking athletic greens. I know I'm getting the vitamins and minerals that I need to stay healthy. If you'd like to try athletic greens. You should go to athletic greens.com / Sinclair, and you can claim a special offer. They giving five free travel packs, plus a year's supply of vitamin.
III from un support. Plus vitamin K2 K2 is really important to make sure the calcium in your body. Doesn't go into your arteries, where it doesn't belong and put it into your bones where it does again go to athletic greens.com, / Sinclair to claim this special offer. Today's podcast is also brought To Us by inside tracker, inside tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body. And
CH your health goals. I've been using inside tracker for over a decade and I'm the chair of the scientific Advisory Board. The reason I have long used inside tracker is because they provide the best blood and DNA analysis that I know of that, make it easier to get your blood drawn. You can either go to a local clinic or have someone come to your home. Like I have done it only takes 15 minutes and from there inside track represents your blood analysis, in a really easy to understand way there are graphs and they give you diet and lifestyle recommendations and these improvements.
Blood biomarkers. Another feature that inside tracker has that I really like is there are inner age test actually help develop it This Test shows you what your biological age is how it compares to your chronological age and what you can do to improve it. So if you'd like to try inside tracker, you should visit them at inside track, a.com slash Sinclair and you'll get 25% off any of their inside track of plans, use the code Sinclair. My last name at the checkout. Today's episode is also brought to
Ooh, Us by levels levels is an app that syncs with A continuous glucose monitor, which they provide and interprets your glucose data for you. I've been so impressed by levels that I recently joined the company as an advisor by monitoring your blood glucose levels. Allows you to see how different foods impact you. I've had a lot of fun. Running tests of my own seeing how different foods impact, my blood glucose levels. For example, I've learned that white rice and grapes really spiked my blood sugar or as potatoes. Don't as we've discussed on this podcast.
Stable. Blood glucose is very important, not only for daily, mental and physical energy, but also for long-term health. So if you would like to try levels, you can skip the 150,000 person, waitlist and jump the line to join today. By going to levels dot link / Sinclair, that's levels. Dot link / Sinclair. David, the research in this space is moving really fast right now, it's hard.
To keep up with it's hard, even for you to keep up with sometimes, right? Well, it is, I write scientific papers even before I get out of bed. So I'm here to collate that and present it, but it is so many Publications that come out every week that it's making my head spin and the technology that's being developed. We can do a million experiments that used to take each one. Used to take a year when I started in this field as though that's just allowing Publications to just flourish right now in this area. It's allowing researchers.
To do a lot more work in a shorter amount of time. The result is that there's a lot to go through. Well, there is and it's coming out every week. And so the goal here is to keep everybody up to speed on what the latest discoveries technology and what they can apply to their lives. As we're learning this almost on a daily basis and this is the lifespan podcast, but if you haven't read lifespan,
It's okay, right. We're going to we're going to go at this. Be you should if you haven't read lifespan, you should realize ban. You don't have to pause the video right now though, right? We're going to give everybody a primer on what's in lifespan. And if you've read the book, great, we're going to go over the major topics so that everybody is with us as we go forward with these these other seven episodes and even if you've read the book, there's more information. I mean, it's been a couple of years since the book was published. Oh, yeah, we're a light years ahead of where we were in.
Spend this lot to talk about including things that you can apply in your daily lives that we didn't know when lifespan was written. One of the misconceptions. I think a lot of people have about the book. A lot of people have about your research is they think that you're trying to prevent old age? Well we are but that's not the only thing because what we're talking about really is preventing aging and that doesn't just happen when we are old, of course not. In fact, it happens over your entire life span, even before you're born, and we're going to, we're going to get
Get into exactly how we know that. But this is fascinating, is a fascinating area of research. There's been recent studies on this which can actually measure in utero, an infant age. Yeah. In fact, when we're young were aging faster than when we rolled but we'll talk about that clock later. But what's important here is that we can improve our health and our long-term survival at any age. And we're going to talk about those lessons and what people can do at any age to improve their chances of being healthy later in life, as well as look good.
Function. Optimally now. All right, there's a lot of misconceptions about what aging is, I think in no small part that comes from the conflation of Aging, with ears lived that makes sense for most of our human history because people got old when they were older or at least as we conceptualize it older. But
The other thing that people have long assumed is that aging is inevitable. It's just going to happen. All of us. You have argued to me. And I think I believe you this is not the case right in my lab. Now we can control aging very precisely at will we can speed it up as fast as we want in an animal and even reverse it. So aging is now controllable. It's in we have the technology to control how fast we age. We can measure that slow it down and even reverse it. This is never
And in human history before. And one of the reasons that we're doing this today is to make sure everybody knows that this is coming because it's going to fundamentally change the course of human history. This is something that perhaps shouldn't have come as such a shock to us because in fact if you look across the animal kingdom, there are all kinds of animals that age at different speeds at different rates, even though the it will get into
The root source of Aging is the same for everything we age at different rates, what we do in it and sometimes I'm criticized, because I've been on record. I am on record saying the first person to make it to 150 years of age has already been born and people said, how can you say that? What gives you confidence that we can even live five years longer. Well, there are if we look at the animal kingdom, first of all, there are plenty of species that live that long. There is no reason why we can't do what they do. And if we learn how they do it, we can apply that to ourselves.
So, one of these animals that I know you're, you're sort of fascinated by right now, in fact, there's a picture of them on your computer screen right now. You're one of your children works on these. Yeah. More Alex. Our oldest child. Yeah, these naked mole rats. They're fascinating. They they're weird-looking. They got sharp teeth. And the rest of the body is long. Looks like a condom filled with walnuts. Actually. Yeah, that they're really weird. But what's exciting to work on them and we were going over is the
Acer that Alex works with. They found that these animals have particular traits, biologically molecular lie, that allow them to live decades longer than a typical rodent, which, on my sleeve bit over two years rats over four years, but the other similar animals and one lives for how long does the more outlive over 30 years over 30 years and then normal rodents or other rodents most rodents live a few. Right? Right. And what's important to realize is that there's a, there's a reason why that is and
Those that don't have a lot of predation Wales mollusks sharks mole, rats underground. They don't get eaten so they can put their energy into building a long-lasting body and actually as a consequence, they reproduce slowly as well. But what's important is that you can build a longer live body and we can do that too. We can engineer ourselves. We can learn from these animals by studying what makes them live so long. Well, you just named some of the pretty well-known sort of like longevity.
She's can we get into that? Can we talk about what makes each of these animals survive for so long? Right? We can learn a lot. In fact, we, we should also talk about the Bristlecone Pine, which was a species. You are going to look at when I first met you. Before we wrote the book. I was, I was in the White Mountains. Actually, the first time you called me ever. I was up on my way to go, see the Bristlecone Pines in the White Mountains, right? And so these, how long do they live like, five thousand years? It's absolutely, that's incredible. That they were old when Jesus.
I was born. They were, yeah. Yeah. So what we can learn from those species is that you don't have to get old for little girls, a big, big difference between a Bristlecone Pine and a human being, or a naked mole rat for that matter. I mean, like, it's really no, no, we're all built from the same stuff. We've got DNA, proteins RNA. We can engineer ourselves to be that long-lived if we didn't have predation for the next 10 million years, we would live for centuries. We just don't have time to wait for
on to take hold we can injure ourselves. The way Evolution would make us live longer. One of the interesting things about Bristlecone Pines. Are you see this? If you go anywhere where these amazing like gnarly trees are and they really are, I mean like they don't even actually don't really Leavin look like they're living a lot of times and they live in these incredibly adverse environment and that's that's characteristic of a lot of long-lived species. Is that, is that is there a clue there? Well, they species that don't have a lot of predation live.
Time. But also in these extreme environments, they're turning on their body's defenses against aging and we can do that to ourselves. It's a concept called hormesis and organic. We'll get to that in other episodes, but adversity, as long as it doesn't hurt, your body will make you healthy and live long. Okay. That I do take your point. That, I mean, there's vast similarities across all living organisms, but I do think also. It's hard to make the argument that a tree is, you know, something that we can learn from but we don't need to even
Make that argument because there are these other organisms, right? Going. I mean, from sort of like, a Bristlecone Pine, which is a plant to a sponge, which is an animal to a mollusc, which is an animal to a whale, which is a mammal. And we're getting closer and closer to humans and across all of these categories. We've got organisms that have learned how to live a lot longer than we do. Right? Well, we're essentially up right whales, that sounds crazy. But at the molecular
Level. If you look at the biochemistry, we're only separated by 40 million years, which is a blink of an eye. In geological time. We actually could live as long as well. There's not that much difference between us and a whale lives. We do bowhead whales can live for hundreds of years, but more than 200 years, right? Well, yeah. And they know that how they know that because, well, for a number of reasons, there's actually been some really cool studies on this, but one of the reasons is that they dated a harp.
Moon that was stuck in a bowhead whale for 200 years and the whale was still living when they pulled it out of the whale. Well, I think they wailed it. But yeah, well that what's interesting is you can we now have the Genome of these animals. We can see that they have multiple copies of what we call Longevity genes. Some of which we discovered when I was in my 20s. These are genes that protect the body longevity genes. Actually get turned on by adversity and there are ways we can tweak them, but wails -
Actually have multiple copies and higher levels of these longevity, protective mechanisms. And the Bristlecone Pine has just whopping amounts the problem and that, that connection that you're making there. You're like, oh look, we see this in a Bristlecone Pine. We see this in a will and oh, by the way, this Gene also exists in humans. Yeah. We're not that different from a banana or actually genomes of 40 percents are not that different from banana. Well, I'm not going to go there, Matt, but the important thing is that when you study other organisms, whether
It's a banana or a yeast cell, or a worm or fly. We can learn lessons about biology. And especially about aging, we can learn more about aging from a yeast cell, then we can about Alzheimer's or cancer. This is why your dismissive about people's dismissiveness about like, only in mice. When people say, oh, we discovered this, and people go only in my eyes. There's a lot we can learn from life. Well, we can and aging is one of these Universal things and what really is remarkable that we've learned in my lab over the last
What he is is that the same genes that control Aging in yeast, work in worms and flies mice and even humans. That's a big deal. We didn't know that a 30 years ago. Now we know that there's a fundamental set of genes that controls how fast we live and then we can also exploit that to slow down our own aging now and as we'll get to later we can use that knowledge. Even reverse the aging process. We will talk about these jeans. Let's, let's name some of these jeans, right? Well, it's the
So there are various categories. There are hundreds of longevity genes that are known, but they fall into three main buckets. The first one it's called mtor. It's a little M4 mammal and tour Target of rapamycin. So mtor is a longevity Gene that makes a protein that senses amino acid. So when you eat a big steak, mtor activity, actually is activated and mtor. Now, says, okay. I got lots of protein. I'm going to make Muscle. I'm going to burn energy.
That's why when you eat a steak you actually you build up muscle more than if you don't eat a lot of protein. This is that a good thing. No, it's actually not what you want is to have mtor levels low to inhibit the mtor and when you have low mtor activity, that's when you get the longest lifespan mice that are given a drug called rapamycin, which is used to suppress the immune system in patients, but you can take low doses as a human or give a low doses to Emmaus. Those mice live dramatically longer, even if you give them a rapper -
Listen, when they're 20 months of age, which is really old mouse that it'd be like a 75 year old human. They still live longer solo. Activity of mtor, is a signal that times are tough. You don't have enough food hunker down build a stronger, body survive, and the outcome of that is longer life for these mice. But it turns out it's not just for mice. You give rapamycin to a yeast cell or a fly or worm. They also live longer so you can tap in with these drugs into this Universal longevity.
Program, one of which is mtor. And so, you have a colleague, a long-term colleague. He's been working on mtor for a really long time, and you really impressed with their work. I think you're referring to Matt cabling. Yeah. Yeah, so he's doing great work. These latest work that's fascinating, is he's treating dogs with rapamycin and showing that it protects their heart and he's also going to test their lifespan and we're seeing in dogs, what we saw in yeast in mice, in the rapamycin works, you know, this target of rapamycin this Gene.
Influence in a certain way works the same way across species, right? And that's why I think solving aging is going to be easier than solving cancer and heart disease. Because aging is fundamentally conserved. We can make rapid progress, extending the lifespan of Lily cells worms with chemicals and then put them into humans. And hopefully we'll see they'll work. The same way like rapamycin seems to do and other molecules that we're going to get to in later episodes. But the point here is that aging is not that complicated. Once you understand the genes that control it.
And then the fundamental causes of Aging is what you just said genes. That control is, we talked about mtor, but there are other genes that control it and we're going to see similar things in each of these genes. What do you want to talk about next after mtor? Let's do bucket to. Okay. Bucket to is ampk. It's called a MP activated kinase. So what is ampk? It sounds like the name of a punk band, that'd be a great ladies and gentlemen, its ampk. And and in this case, we don't want less of it. We want more of it, we want.
Activate ampk. So how do you do that? You actually, you eat less you fast and that'll turn on MDK. It'll do a few things. It'll make your body more sensitive to insulin suck the sugar, out of your blood stream, which can be toxic if it stays high. But it also ramps up the energy producing centers of the body. These membrane filled bags, which are actually ancient bacteria living in our bodies called mitochondria, who's doing the cool work in a, a qrst ampk, who's doing the
Cool work in the AM PK right now. How old is being studied by thousands of labs? But the the one that's most interesting. I think right now is to see if a drug that activates a k extends human lifespan slows down aging and that's near barzillai my good friend out down in New York at Albert. Einstein College of Medicine and the drug is metformin, which is most people would know as a diabetes drug him at Foreman's really interesting because it's super safe. It's one of the safest drugs ever known. It's on that the World Health organization's list of essential.
Essential medicines for Humanity in much of the world. It's it's cost pennies and you can get it over the counter, you to take it essentially. They want it in those countries. They just want you to have it like aspirin in the US and a lot of English. Speaking countries in Europe. You need a prescription for this drug and it's the front line therapy for type 2, diabetes, or high blood sugar. And there are there is an active ongoing, human trial of Metformin called Target engaging with metformin, right? The team's head.
Him study. Yeah, yeah up. So why would we think that metformin actually works? Well first is we my lab in collaboration with Rafael, De Cobo down at the National Institute on Aging showed in a mouse study that if you give the metformin, those mice are healthier and live longer. Again, doesn't prove that it works in humans, but you can take tens of thousands and people have taken tens of thousands of people who are on Metformin for type 2 diabetes and looked at their overall health and their lifespan. And this fact that I'll tell you blows my mind type 2 diabetic.
Headaches that go on Metformin on average live longer than people that don't have type 2 diabetes and the protected against diseases. So if you're susceptible to cancer or heart disease, Frailty those on Metformin, reduce their risk of those diseases, whereas those that don't take Metformin, it increases over time. Okay, why did why does is near think that this is happening like at the molecular level. What's going on? Well, ampk is a sensor of energy and low energy is a good thing for longevity. That's
Of the reasons. I first we'll get into that in a future episode but APK is Central to sensing low energy and in response. It protects the body because it's thinking we're going to run out of food. So this is another evidence of this term. Hormesis. What doesn't kill? You makes you stronger and a case. It's as a central regulator of the body's defenses. It will down-regulate mtor. It will activate other longevity genes. And that's really moving genes are working in concert with one another. That's a really important concept because
About a decade ago. Scientists like me. We were fighting over. Whose longevity Gene was more important. It was pretty pathetic and then it's very typical of scientists. Right? Everyone wants to be, you know, the smartest person in the room, but we finally realize 10 years ago is that these genes talk to each other and they're part of a network, which actually is a blessing and a curse because you can tweak one and affect the others. But now we're faced with now, what which one is best to tweak and
If you tweak 2 out of 3 or 3 out of 3, is that good or is it bad? And that will get to also in later episodes. Well, in. Okay, so then if you said three now, so I'm hearing some similar things that when I think this is really important. One of which is that in these genes are activated by
stress. Mtor, is
am gosh darnit ampk. Yep, is and the gene that you work on. The you've been working on for a really long time is as well.
Well, it's a family of genes. We have seven of these what we call sirtuins and we just we link them to aging when I was a postdoc at MIT back in the 1990s. And what we're looking at in as a group was, what can make yeast cells live longer. And there was one mutation that led us to a gene called Sir to sir2 which stands for silent information. Regulator number 2 and information is the key. We'll get to that later.
But this set of sirtuin genes is family, has been shown in yeast and worms and flies mice. And now humans to be a really important Central, regulator of longevity. We showed now going back to 2005, that fasting, activates the sirtuins and later. We showed exercise activates these genes. So a lot of the things that we're told by doctors to do to live longer. And be healthier, we think acts through the sirtuins in
Concert with these other two sets of genes. We just talked about. You know, I really, I really appreciate about this because the thinks it's a lot of like bagging on doctors right now. It's like, they never tell us the same thing. They never tell us the same thing, but they've always told us diet, and exercise, and maybe like the individualized, a vice is a little different, or maybe it's shifted a little bit. That's like, eat better workout.
And
that's what helps activate the sirtuin to do what they do. Yeah, and it's an important concept because it most people think, oh, when you run your blood flows and clears out your arteries and
When you eat less, it's just good for you. If that's not what's happening. Well Ray, what we've discovered is that you these longevity genes, these three sets. We've just mentioned need to be either down regulated or upregulated in a certain way. How do you do that? These Lifestyles certain types of diet when you eat and exercise essentially you want to trick your body into thinking that it's under threat of survival adversity. You don't want it too much. You don't want to damage your body so that it can actually have the opposite effect, but you
To give it a little bit of fear, and it will have great results and give you pay back for decades to come. Okay, so I know we've talked about these these other two longevity genes, but I really want because you're the sirtuin guy. I wanted to dive a little deeper into what's making these things tick and this gets a little complicated. It's a little down on the wheatish, but it's important as we get to the information.
Theory of Aging. And and this idea that we're going to be driving toward minute here, which is X differentiation. So can we talk a little bit about how why the sirtuins are doing what they're doing and how that works at the genetic level, right? All right. Well, let's do a little bit of biology. Some people haven't had a biology lesson in decades been a long time. Yeah. So let's start with a cell cell is a microscopic bag of fluid packed with proteins, the proteins.
Are encoded by the DNA, which is in a part of the cell called the nucleus. So, let's become microscopic. Let's dive down into a cell and have a look what's there? So, first of all, we pierce the outer membrane. There are a lot of proteins on the surface that bring in things like sugar and amino acids that are important. Now, we're in swimming around and we can see there's a, another little structure that is surrounded by a membrane called the nucleus. So, let's go through there. That little pause we can swim through. This is what we remember from middle school. Biology is the brain of the cell.
It is the information. The genetic information of the cell and coded in a six-foot, long strand of a chemical called DNA of words. Like this is six feet of DNA in this little microscopic. You can't even see it and there's so much of it in the body, it stretches from here to the moon and back eight times, and it all has to be packed into very small space. And so you don't just the cell, doesn't just shove, this strand willy-nilly into this structure. It's not like me packing to go travel. It's actually not neatly.
A packed. And the way the soul does that is that it wraps the DNA around proteins called histones and those histones then attract each other and eventually get these structures. We call chromosomes which you can see sometimes with your eyes but usually with a microscope but it doesn't all get bundled otherwise, no genes could be read it has some of the genes have to be opened up and unraveled unspooled so that they can be turned on. It was a really good analogy for this. If you existed during the
These 1980s when cassette tapes, or a thing, you might want to describe what they were. Okay, so having existed in these times. So, for the children at home, cassette tape is a plastic cassette with a real on either side of magnetic tape, but the important thing here for this analogy is that if you turn it on its side, only a little bit of that tape, a tape includes a lot of information, but only a little
Little bit is readable at any given time and that would be a gene, and that would be a gene. And so, if your, if your cell is trying to read your code, it's accessing just that little bit at a time. It's not accessing all of it. And that's actually what helps cells know to be cells, or the kind of cells. They are. Well, it's essential when we're fertilized, is an egg. We can be anything, but we need to have certain cell types of brain cell has to know how to be a brain cell for 100 or more years. And a liver cell has to stay a liver cell.
Wake up tomorrow in your brain is Malik has consoled. You're in trouble. So what happens is that the packaging of the DNA is specific to the cell type and every time that cell divides like in a skin cell. It doesn't suddenly become a neuron because the cells inherit the information that says that Gene is for skin cells and keep that one on but don't turn on the brain cell and they know this through epigenetics. So epigenetics is the the other part of the information in a cell that controls which genes are
Each tightly or unfold unspooled, like can happen if your cassette tape gets stuck in the machine, you remember when that used to have I do and then you'd have to take the little pencil and wind it up. Yeah, exactly. That. That's part of the problem with aging we think is that that beautiful packaging of the DNA that allows us all to remain a skin cell forever or brain cell, essentially forever is lost. You start to get this unspooling of the DNA and genes. That shouldn't be on, start to come on.
Time's. It shouldn't be readable. Are now readable until you have like the all this extra information floating out there that the cells can read. And because the cells are now reading large parts of the code instead of the very specific parts of the code. They get confused. Right? And we call it X. Differentiation differentiation is the common term for cells, becoming a certain cell type. And we've coined the term X differentiation, which is essentially cellular confusion. They become a more of a generalized.
L Type rather than a specific one because genes that shouldn't be on, start to come on over time. And that we think is a root cause if not the root cause of Aging itself. Let's
unpack
that a little bit. He's the pun because I, it is kind of a pun. Um, the the thing that you've told me and that really just like, sort of completely shifted the way that I was thinking about aging even after actually,
With you for quite a bit is that this is not just the record of cause of Aging. You believe that X differentiation is the root cause of many, if not most diseases. I don't just believe it. I think it's now a fact when you look at Alzheimer's disease and unfortunately up until the last few years. We were treating it at the end, stage of the process of Aging which results in plaques and Tangles and dementia.
Shh, but the process that led to that disease was happening from birth and that's aging. So Alzheimer's at just to take one example is an age-related disease, that's not just age related. It's actually 90% of it is caused by the aging process. This unspooling the sex differentiation if we were able to slow that down you'd have Alzheimer's much later and now we're showing in my lab and we'll talk more about this, but I want to mention it because it's so profound. We can reverse the age of a
In an animal. And when we do that, we're showing, and we will continue to test this that those diseases, go away proving that those diseases are actually caused by aging. Okay. So let me see if I if I can put this into sort of some kind of a picture.
We have these brain cells neurons. Yeah, neurons. We have neurons over time because our DNA unspools it becomes less tightly packed. The code is more readable. For instance, the code that makes a liver a liver or a kidney a kidney. And so that brain cell is sort of also part kidney cell, right? And we can read all the, which Jane.
Ron, we call it gene expression patterns. It's very easy. So, you see you actually see this in Alzheimer's brain to. You can see that the cell is losing. Its identity. Losing its identity, right? Losing its mind, so to speak. And we can see that with normal aging to even if you don't have Alzheimer's during aging, I'm 50 now. So, some of my brain cells are undoubtedly. Getting confused and starting to believe that they're part skin cell part, kidney cell. And that's probably the reason why even in your 50s, you cannot function like you did in when you're 20, okay.
That's dementia. That's all timers.
What about other diseases? There's another one. That's a good example for this type. Type 2 diabetes, right, high blood sugar, high, blood sugar. Same process. Yeah, same problem. Well, it is are two different diseases. It is the same thing, but that's a major point that we've been looking at diseases as separate things. This is how modern medicine works. We need a different drug for type 2 diabetes right now and for Alzheimer's for cancer for Frailty. Muscle-wasting bone loss. I'm saying that the same
Success is leading to all of these diseases and if we can slow down and even now we have a technology to reverse that process. Those diseases will be slow down and even go away by age reversal. Okay. I'm I'm on the cusp of this. I want you to spell it out for me though with the diabetes. And then I want you to do. Like I like things in triplicate. So I'm convinced on the Alzheimer's. Explain what's happening in the diabetes? That makes it the same process. Yeah. Well, so type 2 diabetes in part is a problem of
Bringing glucose sugar out of the bloodstream into your muscles and your brain, which are the major sources of of major requirement is glucose. And if you don't suck the sugar out of your blood stream, you're going to have basically treacle or caramelize protein in your system, which is going to cause all sorts of sounds delicious, but it's really a bad thing. No, you don't want to have glucose attached to proteins. In fact, you can measure it doctors when they do a test called hba1c that really means how much
Glucose is physically bound to your hemoglobin, which carries your oxygen and it's a percentage. So if you have over five point seven percent of your hemoglobin attached to glucose your pre-diabetic and over. Six point five, I believe in number. Is that what you're actually type 2 diabetic at that point and then you go on Metformin. The point being, is that having high levels of blood sugar. We know predisposes you to other diseases. Heart disease, Frailty dementia. You don't want her to have a lot of sugar in your blood. It's one of
The reasons for keeping my, I believe everybody should try to keep their blood sugar levels reasonably low because at the higher levels are toxic, but what's happening in terms of the aging process. One of them is that the, the cells that line, the blood vessels that suck the glucose out of your system are losing their function. Then there's a particular Gene that's required to suck, glucose through the cell from outside in. It's called glute for, it's a glucose, transporter, number 4, and over time.
With aging and particularly, if you're obese, and you don't exercise and don't all the good things, your cells lose the ability to make that glute for transporter and glucose will stay in your bloodstream for longer, which is toxic.
You just said just a couple of moments ago, you said and then you take my foreman and it occurs to me that we got this, metformin it activates ampk. So is it? Uh, next differentiating? What is it doing? Well, these defensive Jane's seem to partially reset aging. So to ins are proud of the spooling process. That with a cassette tape, they bundle the DNA. So, by activating these various longevity genes, we're slowing down, and
Reversing some aspects of that X differentiation process and getting the cells. To remember, how to behave. Okay. We did Alzheimer's type 2, diabetes heart disease, right? If this is heart, disease is cholesterol and bad food and a lifetime of bad exercise habits, write it. But the words linger about to tell me, it's not any of that. It is that but it's not that it's actually X differentiation. Yeah. Yeah.
Yeah, this is this is what we find is that we can actually now control aging forwards and backwards in my set list and we're doing experiments clinical trials in humans. Now when you do a clinical trial bike, well, I mean, they're not real well experiments in human, sounds bad, but clinical trials is that really do. Like, people are going to take that little section to tape and be like, see. He doesn't really think their clinical trials. Well, these are all double-blind placebo-controlled, clinical trials in humans, but in my that's real. Yeah, okay.
So heart disease. What we've shown in my lab is because we can drive aging forwards. By disrupting the spools. We can either reduce the amount of sirtuins which causes them to spool out, and next, differentiate, or we can create certain types of stress on the cell that that caused that problem as well, extreme stress, not the romantic type. We can accelerate Aging in a mouse and one of the effects we get is heart disease in a mouse. And so, then we have this. Now, we have this evidence that
Disrupting the epigenome, the readers of the DNA causing X differentiation is causing all of these diseases including heart disease in the mouse. Accelerating Aging in a mouse requires us to be able to measure aging. One of the ways that we can do that and probably the one that makes the most sense to people in the way that we think about aging, is you just look at Emmaus, right? It's got more gray, hair. It's becoming weaker its gets confused, right? It's not as perky and excited, and it doesn't run.
Slim treadmills long, but there are now other ways that we can measure aging and this is, this is a really important point. This lead. This is this leads to the explosion. Yeah, right. So it was 2013, a paper came out from Steve horvath's lab and there was another paper by Greg Hannum that showed that if you measure the chemicals that are controlling this bundling and spooling of the genome to
Specify soul type. There are certain sites on the on the jeans that you can measure the chemical is specifically called DNA methylation. It's very simple. It's just a carbon with three hydrogen's, this chemical cells, add to the DNA, stick to the DNA as you're developing in the womb to make a brain cell different than a liver cell different pattern. But over time, there are changes that are predictable and they change in a linear fashion. So that
If I took your skin cell or your blood and I measured the DNA methylation pattern across the genome across that six feet in one cell or in thousands of cells, which is how we do it. I can then plug that into a program and it will spit out your actual biological age. Not your birthday candles, which is based on how many times the Earth is gone around the Sun. That's irrelevant. It's how old you really are which can predict also when you're going to die.
That's terrifying. No, it's not. It's liberating because we know now how to slow that process down and even reverse it. We can get the DNA to spool less and also be repackaged to reverse the aging process, and get cells to work like they used to. So that number shouldn't be scary. It might be scary if there's nothing you can do about it, but as we will learn in this series, there are plenty of things you can do about it all. This is, well and good, if we
We can all have our biological clocks measure did any time, but this sounds really expensive and time-consuming and it's a process. And and I'm, of course, team you up here, but this is also a really important moment. Well, it used to be expensive just to read. The first human genome was more than two billion dollars and took an army of people and hold buildings. Now, we can read it a genome on a Snickers sighs bar in a day. It's going to be $100.
Probably next year and we use that same technology to read the DNA methylation patterns. We put it through what's called a DNA sequencer. And right now it's a few hundred dollars to run your sample, which is still Beyond most people if you want to do it every week or even every month, but we've now as a student in my lab, Patrick Griffin, who is just is just put up online. Our, our pre-publication that shows that we can pull thousands of people's samples together and run them as
In these sequencing machines, that brings the cost down to about less than a dollar to run this. Why is that important? It means that one day, anybody can do a cheek swab and determine their biological age and figure out whether what they're doing in their life is working or not to slow down aging. So, theoretically, if I wanted to check my biological age every week.
I could do that for 50 bucks a year, essentially. Exactly. And eventually it'll be a little home device. You can do it every morning if you feel like and your argument is and I totally, I'm on board with this to this is, far far more important to our understanding of our general sense of health and our general state of propensity for disease, and then our chronological age ever was right. And we find that people who haven't done the right things who haven't exercised in heaven.
Maintain a good diet, have an older biological age and will die sooner because of it. We can now measure the aging process with accuracy, which is it blows my mind that we now have our biological credit score which we can. By the way, we can alter aging is malleable. That number doesn't stay the same and it doesn't have to continue to tick up every year and is in yeast in mice. Well, and in humans, now, there are there's a, there are Publications, Greg Fahy.
Who's got a company out on in California work with UCLA researchers? In fact, the guy that co-invented the clock Steve Horvath. They published last year that a triple treatment of chemicals. I'll name them. DHEA metformin and growth hormone it rebuilt the thymus which is something that happens to all of us. It gets smaller, but more importantly they measured the blood biological clock to figure out what happened to their age and they got younger by two and a half years.
After one treatment, I took a mother to treat. There is a treatment. One. Series of treatments. Yeah, but here's what's fundamental about this. You might say, two and a half years, who cares. First of all, I'll take an extra two and a half years. I'll take an extra two weeks if I can get it. But two and a half years is a big deal. For two reasons. One is Greg is now showing that you can repeat this and go back, not just two and a half years but five years, I know of people that have reversed their epigenetic clock by 20 years over a year out of
Measured pretreatment, right? They've gone through the same treatment. The same treatment that Greg used in the study or some similar treatment, some people. But let's talk about it later. At least that's how we do that. There are a number of ways. Now, that seemed to reverse the age of the body. It's a, it's an amazed, at least according to these biological clocks. Exactly. Now, we want to now figure out. Are they healthier? Do they look younger so far? Anecdotally? The answer is yes, but think about this. This is a second Point, that's important.
Point two and a half years, may not be a big deal to some people, some of our audience. But to be immortal. All you have to do is go back one year, every birthday. Oh, well, that's good. So we're Immortal now. Thank you. David. You can we go home now? Yeah, I think we're done. We have some work to do. We definitely work to do especially when it comes to. This is going to freak people out because they're going to say David Sinclair. Harvard University just said that we can be a mortal. Well, there's no reason why we cannot there's no law. That says we have to age and we now are learning.
Not just what causes aging, but how to reset the body. So that it's young again and we don't know how many times you can reset the body, but I'm betting that it's more than once. So what happens in a world where you can reset your age multiple times, maybe hundreds of times. That's when things get really interesting and I think when people look at this podcast and listened to it, a hundred years from now, they're going to say yeah, that was the moment when Humanity really changed.
Okay, so let's kind of encapsulate this all together summarize, this podcast, episode is why we age.
So, if people want to come away from this and just be able to like instead of listening to the episode again, and again and again and trying to summarize, there's a lot here. Let's hit the points. Why do we age? Well, we now have an understanding that it's not just things go wrong. There's actually a fundamental process this ticking of the clock, the unspooling, the genes that happens in everything from a tree to a yeast to a worm Mouse and ourselves. That's a fundamental cause of Aging that leads to a lot of things going wrong. There are Hallmarks of
Beijing, that lead to disease and we see these in clinics and doctors are trying to treat the end stage of that process often too late putting a Band-Aid on a problem. What I'm saying? And what we've been discussing is that there's a layer above, the all these diseases in the cause of aging and that is The Regulators. Okay. So The Regulators we've talked about, we've got em toward that Reg, that responds to meet and amino acids and PK, which is blood, sugar and energy, and so 21.
Which respond to both of those things and more. We'll talk about those other things in another episode, like, heat and cold. And what they do is that they're slowing down all those bad processes. The main one that's driving all these other bad things. In these diseases, we call diseases of old age is the X differentiation process. So what we really want to do is to get this middle layer to be super potent and slow down and even reverse the aging process. So how do we do that? So now we have this upper layer. That's
This is the environment turns out that most of what regulates this middle protective survival layer is not the genetics that you get from your parents. That's 20% of the control of Aging. We know that from a twin study of really old data from from Denmark. Yeah, there's a study by Christensen at Al 2003 that looked at Danish twins that are genetically identical but they live different, Lifestyles have different environments, some smoke, some didn't some
Exercise some didn't and so now we know that even though if you're genetically identical, 20% of that, it determines your health in later, life slows, down aging, but 80% is in your own hands, how you live your life. And that's the top layer, that controls the longevity, genes that controls the X differentiation and disease process. So now, we're going to figure out what to do in that top layer. Like, what are the things? This is in your hands. Most of this is in our hands. Well, heck of a lot 80%, and we now are starting to
To stand how to live a life to maximize your longevity and slow down that X differentiation aging process, but we didn't cover sirtuins in a way that I think we might have lost a few people that this sirtuins, which is the third group of these longevity genes. How did they work? And so three of those seven exist in the nucleus to control that spooling process? So the sex differentiation process actually is due to malfunctions in sirtuins and we can maintain
maintain their function during old age and even middle aged by exercising and dieting and being hungry sometimes. So Tunes will be activated and we'll talk about chemical ways to do that later. But then they take care of this of the packaging of the genome. Remember I said sirtuins are sort of stands for silent information regulator. So what does that mean? Silence is the bundling of the DNA silencing them. So you don't want the liver gene on in the brain information is the DNA and they regulate it.
Sirtuins, it's in the name. And in fact in the 1990s, that's why I've been working ever since I'm trying to understand. And test my information Theory of Aging which is only recently, thanks to the book become a very popular theory in biology. And in fact is now I would say the leading theory of why we age and there's a really good metaphor. We've used it before you've used it a lot, but I think it's worth repeating for this information Theory and memo again apologize.
Sighs apologies to people who didn't grow up in the 80s and 90s, but going to go now, from cassette tapes to compact, it compact discs CDs. Yeah. Yeah. Well, these were amazing amazing devices you could fit about 10 songs on them. And the way that they work is you've got digital information in ones and zeros similar to how DNA is encoded which is four bases are chemical. Actg. This digital information is read by a laser and it plays beautiful music. Let's say you've got a symphony with 10
It's to it. Each cell will play a different combination of those songs. But instead of there being 10 in a Cell, there's 20,000 different genes to play. What I'm saying with aging is that it's equivalent having scratches on the CD. So that the reader which is a laser these days are blue laser is skipping and playing the wrong songs at the wrong time. And that sounds horrible. That's a cacophony. Nobody wants to listen to that. That I'm saying is the equivalent of the aging process.
And what we've been working on for the last 20 years. In my lab at Harvard is, how do you slow down those scratches? And also, can you polish the CD so that those beautiful Symphonies are played again? And we're going to come back to this metaphor. I think probably get in again. Does it sort of a point that we can refer back to when we're talking about all of these things that we can do to get rid of those scratches to wipe away that epigenetic junk to reverse aging.
Right? And then diseases of Aging will go away. That's a big deal. This is I think a turning point in medical history that we actually understand what causes those disease fundamentally not just trying to fix the actual problem when it occurs. I liken this to getting to the edge of a cliff. And this is you wrote this in the book is that we've been far too often working on trying to understand why we falling off a cliff at the end of life without even
Seeing the question. What brings us to the edge of that cliff in the first place. Now, we finally understand how we get to that cliff and even how to prevent it. And so at some point perhaps we don't have to worry about diseases because we're going to be so healthy. So young that they're not going to push us off. They're going to make us sick. Maybe we can treat that. But well as we saw with covid-19 that if you're young you can survive. So this is really important. It's not just about disease.
Old age diseases throughout life can be prevented and treated by harnessing this middle layer of these protective survival jeans. Mtor, mpk. Also to ones and others, not just with Lifestyle Changes, which are pretty easy to implement. We can do that today, but also increasingly with nutrients with drugs and supplements, but it's a messy world out there. And what are the things that we're going to do in this podcast in later episodes is struck about what's true. What isn't
What supplements work what manufacturers you can trust? All of this is to clarify this really untrustworthy world out there and talk about that. What is known and what is not known and what soon hopefully will be known. So we're going to talk a lot about what people can do individually to mitigate aging but there's one thing that you said you think we should be doing collectively as a society to address the security.
Keep not just us individually from that, precipice. But to keep us as a, as a people to keep us as a people from that precipice. Well, there's one thing that we've been ignoring for centuries, modern medicine, doesn't even think of it. And that is that aging itself is a medical condition. Aging is a disease and as we've been talking about today and we'll talk about in later episodes. It's increasingly a treatable medical condition. So why is that important?
The main problem with the way we do, what I call whack-a-mole medicine right now is that you have you wait till you get sick. You go to the doctor, which is often too late, especially when it's cancer, but even heart disease is hard to reverse. Currently. If you go to the doctor, they'll treat that specific disease and ignoring what got you there in the first place. And you end up having a healthier heart. We have pretty good drugs for blood pressure and heart disease, but that ignores the rest of the body, our brain still gets old and this is
Worst nightmare for, for society. No wonder. We're seeing an increase in dementia is because we're not treating the whole body. But now that we understand that all parts of the body and essentially, all diseases of old age are due to this same underlying process. We can find ways to hold, certainly, slow down. Hold, and reverse this process not just in one part of the body, but in all tissues and organs, so that we can stay young not just with our cardiovascular system, but our
brains as well. And when we do that, that is true, longevity, that can get us decades longer healthier life and we can get there together. Well, that's what we're going to talk about. It's not that difficult to be able to slow down the aging process and not that difficult to measure it and we're going to learn how to do that. And this was just the primer. We're going to get into the more details in later episodes about practical things that people can do every day to be able to maximize their health, their performance, how they look and that ultimately their longevity.
Once doctors, understand that we can do this. Once, we all understand that we can do this. It becomes an imperative. Well, I say it's not just a right to live longer. It's actually your obligation, your duty to your family. It's not fair to just abuse, your body or neglect it and have them take care of you for 20 years, in a nursing home. We owe it to our families to stay as healthy as possible and is just society as productive as possible and let's say we get another 30 years. Well,
Another 30 years, buys you a chance to start a new career to visit places to educate your great grand, kids to have a good time. We are going to have the type of lives that people can only dream of right now. This is going to be fun this next seven episodes. I'm already having a lot of fun. We're also going to get into some rather interesting research about what works and for the most part, what doesn't and that's going to be? I think challenging also too.
A lot of people who want a very quick and easy solution or want to believe.
What they've?
They assume works. Well, there's a lot of, there are a lot of myths out there. Let's rattle some off telomeres antioxidants. These things we're going to get into it. But it's there were so many things that have become myths out there that do very little for you longevity, but there are some things that actually do work right now and things that are just around the corner, that will blow everybody's minds and the next episode we're going to be talking specifically about dieting and fasting and we don't want to give it that away, but that's
That's up next right? It is and so we'll see you in a week. We're going to round this out with a thanks. If you've enjoyed the show, you can subscribe either on Apple Spotify or YouTube and on Apple you can leave up to a five star rating. Another way of supporting us is to support our sponsors who I mentioned earlier in the show. And finally, another great way to support us is through patreon. We have a patreon website at patreon.com slash David Sinclair.
Thanks again for joining us. We hope to see you next
week.
