The Science of Aging: Resetting the Biological Clock

The main subject is David Sinclair's groundbreaking work on human longevity, focusing on the information theory of aging and resetting the biological clock.

### David Sinclair: The Three Levels of Aging and How to Reset the Biological Clock
* 🧬 David Sinclair introduces the concept of the three levels of aging, with the first level being the **proteins that quickly turn genes on and off**, the second level involving the **silencing of genes for a long time**, and the third level being a **DNA clock that tells our biological age**.
* 💊 Metformin, a drug prescribed to diabetics, is an AMPK activator that makes the body think it's hungry and helps **boost the energy supply**. It also increases the number of mitochondria as a response to slight poisoning and makes cells **more sensitive to insulin**.
* 🏃 Exercise is a key lifestyle factor that can help **reset aging**. It activates sirtuins, promotes the formation of new mitochondria, and creates a biological stress that can be **beneficial**.
* 🍽 Caloric restriction and intermittent fasting are effective ways to **slow down aging**. They activate **sirtuins**, reduce the levels of amino acids that activate the **mTOR pathway**, and promote the body's **ability to repair itself**.
* 🧠 "The only thing across every known living organism that **extends lifespan** is to **eat less**."
* 🐋 Evolutionary theory suggests that humans, like whales, could potentially evolve to **live much longer lifespans** if given the right conditions.
* 🕰 The DNA clock that determines biological age is based on **methylation patterns on the genome**. Machine learning models trained on thousands of people's methylation data and lifespan can predict **how fast a person is aging**.
* 🔄 Resetting the biological clock at the third level of aging is considered a **truly permanent way to reverse aging**. It is achieved through a combination of lifestyle factors, such as **exercise, diet, and periodic fasting**.

### David Sinclair on Anti-Aging, Health, and Longevity
* David Sinclair advocates for cold exposure, as it helps build brown fat, **revs up metabolism**, and may play a role in **preventing diseases like diabetes**.
* ⏰ Sinclair's research has shown that it is possible to **reverse the epigenetic clock in cells**, effectively making them **younger**.
* 💊 Sinclair recommends taking an NAD booster like NMN or NR, as it can **raise energy levels** and potentially **extend lifespan**.
* 👴 Sinclair's father has been taking **resveratrol, metformin, and NMN**, and has experienced **significant health improvements**.
* To monitor the effects of your lifestyle and supplements, Sinclair suggests getting regular blood tests and potentially having your **genome sequenced**.
* 🍽 The simplest change with the biggest impact on health, according to Sinclair, is to "**be a little bit hungry**" and **skip a meal**.
* 📚 For more information on David Sinclair's work and research, you can visit **lifespanbook.com** and follow him on **social media**.
* 🎯 Sinclair's ultimate goal is to "**figure out why we die so fast**" and make a **significant impact on human health and longevity**.

what gets really interesting, and this is something most scientists don't even know about yet, is level three: the deep layer of aging. There's actually a DNA clock that tells our bodies how old we are. I could take your blood and read it, and I could tell you roughly when you're going to die. Everyone, welcome to Health Theory. Today's guest is David Sinclair. He's an acclaimed Harvard professor who's doing some of the world's most groundbreaking work on human longevity. He was named by Time magazine as one of the most influential people on the planet, and his new book, Lifespan: The Revolutionary Science of Why We Age and Why We Don't Have To, is set to permanently shift how we think about the inevitability of aging and possibly even death. That is exactly where I want to start. So this is my favorite topic. I want to live forever. I make no bones about it. I know that right now, though, I'm on a collision course with death. So you have a really interesting theory about what makes us age that if I'm not

mistaken. You call the information theory of aging. So, what exactly is the information theory of aging, and how do we take advantage of it? So, aging actually has been worked on for about 5,000 years or more, and just in the last 20 years, we've come up with a set of hallmarks of aging. There are about eight of them, and I think many of your viewers will know that there's telomere attrition, the ends of chromosomes get shorter, mitochondria, the power packs, will run out of energy as we get older. There's a long laundry list, and most of the people in my field have said, Okay, we've figured out aging, we've got this list, we put in a nice pie chart, and that's it. But what I'm saying is that why does all that stuff happen? It's not enough just to tick off what happens. You have to understand, is there an upstream cause of all of that? And so, in my book and in scientific papers we are now putting out for the scientific community.

to read as well what we think is going on is that our bodies are losing essential information as we get older that drives many if not all of those hallmarks that we know exist so what in what way is the epigenome involved in this how are we losing the information give people a quick little diatribe about the difference between genetics which i think they get and then the epigenome and epigenetics and and how that plays out yeah yeah for sure it's not that complicated there's really just two main types of information in our body that we get from our parents the first is genetic we all know about dna and the four letters atcg it's a long molecule in cell and it's a string of letters that's digital that's like the music that's on on a dvd those things we used to use uh to store movies but there's another level of information that's above that in the cells which is the reader of the information that's called the epigenome and that really is different because

it's analog information. In the same way that records and cassette tapes, they sucked. They were terrible at storing information. But the problem is, we have an analog version of information, the epigenome, which controls which genes in the string of DNA are turned on and off. And that's why are you considering that analog. I don't think I understand how it actually works. Like, I can imagine DNA sequences as just sort of repeating the ATCG code. But what is analog about the epigenome? This reading about it in your book is the first time that I began to imagine it in a different way. Well, it's very clear that if you just have four letters, that's digital. So we understand that. But the epigenome is the structure of how the DNA is organized. So DNA isn't just flailing around like a string. It's actually packaged up around proteins we call histones. And it's like if you spool your hose in the garden, you loop it around, and then you can put those loops into bigger structures. Then you get a

chromosome which you can see any high school student can see under a microscope. That's that chromatin structure as we call it. Is the epigenome and so when when the hose is looped tightly and spooled up. That's stopping genes from being red so genes are off when they're compacted. But also if the cell needs to read certain genes and a nerve cell needs to read the nerve cell genes and the liver cell needs to read specifically the liver cell genes. And so they open those ones up and now the cell can get access and read those. That's an analog system because it it's varying all the time it changes when you wake up what you eat. So it is literally the amount that the um the dna is unspooled and the place in which it is unspooled so that it can be read right. And that's what determines the cell's function and identity which we you know when we're born where 26 billion cells each one of those cells knows what it is and what it has to be.

80 years later, it and its descendants and over time. What I'm saying is aging is caused because cells lose their packaging and then eventually cells lose their identity. Disease ensues, cells check out, they become zombie-like, and they're now in essence, right senescence. And then our organs fail and we die. But until recently, we had no idea why that was happening. And so why is it happening? Well, so the packaging is the really important part because much like the software runs the code, the epigenome controls which genes are on and off. And if you stress the system, and by that, I mean biological stress, and the biggest stress you can cause to a cell is to break its chromosome because it's going to die if that if it doesn't fix it or worse for the body you get a tumor. So the cell has to hunker down, stop dividing, arrest just about everything it's doing, and then try to repair that broken DNA. But in doing so, it has to do two things. First of all, it has to take proteins

from somewhere else that are doing a good job keeping the cell from functioning, or making sure the cell's functioning correctly, and those proteins are used by the cell to repair the DNA that's broken. But also, what's happening at the break is that that's all opening up as well, because you remember if you break a DNA and it's spooled up, you can't fix it, you can't glue it back together unless you unpack it, stick it back together, and then you've got to repack it. So, this movement of proteins and the unpacking, repacking of the DNA, I believe leads to cells losing that original youthful, what we call a gene expression pattern, of how the genes are turned on and off. And nerve cells, as they get older, lose their ability to stay nerve cells, and liver cells lose their identity as liver cells. All right, so do proteins the way that you're talking about them sound like little creatures. I think of them, because of my background, like powder, like just sort of inert molecules, which clearly, judging by the way that you're talking about them.

they're not. I've seen them animated before as having like articulatable shapes, and they actually move. Is that accurate? That's essentially it. It's super exciting when you realize that proteins aren't just blobs or powders in the cell. They're actually little machines like Pac-Man that go around, and they can change the function of other things. They can package the DNA, and what they do is they create chemical reactions that normally would take a billion years to happen. This is what an enzyme does; it accelerates reactions. And so, we've got about 20,000 different types of enzymes in the body, and they do different things. But what we've discovered over the last 20 years is there are certain types of enzymes that help package the DNA and help with the DNA repair. These are the ones that doing the ping-pong game, and without those, we're screwed. We basically will age more rapidly. Conversely, what's really exciting is we've discovered that you can make them more active to make sure the DNA is

packaged correctly, and the repair is very efficient. And there are ways you can do that: exercise, dieting, being hungry. They allow these enzymes that control our body and make us healthier. They make those enzymes much more active. So instead of a pacman doing this, you exercise, your diet take them, take a molecule that we work on, and it'll go around and fix everything much more efficiently and keep you younger for longer. We think, why do you use the pacman analogy, which makes me think of it's eating something. Is that what's happening, is it eating cells that have a level of senescence, or is it more Bob the Builder, and it's going around tearing some things apart, putting some things back together? Yeah, it's more like Bob the Builder, but I think a good example for at least the enzymes that we work on, called sirtuins that protect the body, they're like a little tiny pair of scissors. They chip up, clip off chemicals called acetyls. And in doing so, when they clip off the acetyls off those packaging

proteins. The DNA gets more compact, and that's called gene silencing. And over time, as we get older and through this DNA damage process, the sirtuins get inactive. They're distracted by DNA repair and the packaging of that DNA. That spooling starts to loosen, and now genes that have no business being on in the brain come on. And partly, I believe that's why we have these diseases of the brain. That's so interesting. Okay, so one, I want to know from a lifestyle perspective, what are we doing that's speeding that up? And then two, what can we do from a lifestyle perspective to begin slowing that down and reversing it? Well, so I've been studying these enzymes, the sirtuins. We have seven in our bodies. I've been studying them for about 25 years. And what we've learned is that they respond to the cellular environment. There's a chemical that they require for gas. Think of them as the fuel called NAD. And there's another

molecule that is like the accelerator on the enzymes. Uh, that makes them going even faster, and that's one of them is called resveratrol, which we discovered years ago from red wine, and together they actually do really great things on these enzymes and make them keep the body younger. At least for 25 years, we've been studying mostly animals and even little fungi yi cells, and what we've learned from those studies is that these are largely involved in responding to when organisms are under threat of survival. So how do you make the body feel like it's under threat adversity, uh? So one is run a lot, or at least become out of breath, you know, a few times a week. Your body will say, Oh man, we had, we had to outpace one of those saber-toothed cats again, gotta go to build up the body. Um, the other is to be hungry, either a couple of times a week or every day, you know, skip a meal or two, and then your body will turn on these sirtuins, make more of that fuel nad for.

the enzymes and we think that's what's in part responsible for the health benefits of those uh lifestyle choices. All right, one thing though that you talk about that I found really interesting is this notion of what may be good for you when you're young may come back to bite you in the ass when you're older. Yeah, so it's like um the whole notion of hormesis that a little bit of bad is actually extraordinarily good, which is exactly what you're describing. Now get out of breath, do all the stuff, and so when the information started pouring out that the only thing across every known um living organism that extends lifespan is to eat less, which you talk about in your own book, it feels like you're saying to do it for that reason, just don't put as much stress on the system, but now I hear you saying no, no, what you actually want to do is stress the system. Won't that stress of I just ran from a lion a [ __ ] starving, won't that begin to stack up?

and become problematic. Well, actually, if you step on a snail, it's going to die. So there's a certain amount of stress that you don't want to do. But what you want to do is get the body to fear adversity in the future, but not enough to cause lasting damage or the unspooling of the DNA that'll lead to disease and eventually death. So you don't want to overdo it. You want to be a little bit puffed. You want to be a little bit hungry. But of course, starvation, malnutrition is not going to make you live longer. So it's a fine line. And what we've learned from many animal studies and increasing numbers of clinical trials in humans is that you want to pulse it, let the body recover, not constant. We used to make animals go hungry all their lives, and it worked. But it actually works better if you let them recover. And I think that's the secret. Then let's really dive into that. So I'm guessing you're talking about

where um animals were denied something like 20 to 30% of their caloric intake for very long periods of time is extending their life by what like 30 or something um so super interesting. But you're saying that if their caloric intake over a long period of time is roughly the same of an animal that's just allowed to eat until it's satiated that if it's done in a pulse pattern of hunger and and almost over feed they actually have the same benefits as the animal that has a chronic deficit of calories. All right well let's be clear nobody knows what the perfect diet is even when it comes to fasting. It's all largely based on rodent studies so what I can tell you about the rodent studies which I'm very familiar with is that if you take a rodent and reduce its calories by 25% for its whole life it will live longer 30% but it'll be really miserable and aggressive uh and that's true for us as well. I've tried calorie restriction for

about a week, and I gave up. I was pretty angry, but what we discovered, my colleagues, um, discovered, is that if you, it's not just what you eat, it's when you eat that's important. And what's been found is that if, as long as you have that period of hunger, um, in a mouse, so you can feed them every other day, then they can gorge themselves as much as they want, and they do. They eat about 90% of what a mouse having free access to food would eat. But they, they have the same longevity benefit as a mouse that's always been hungry. And if that's true, what that means is for us is that we can enjoy life as long as we have that period of hunger once a day or maybe twice a week. And I believe the only reason we age, you know, we could live for a thousand years otherwise, the only reason we age is that our repair systems become complacent. You mentioned that what, what is beneficial for you when you're young come back to bite you when you're old.

what we think is that these repair systems are very good. When we're young, so the idea is it's called antagonistic pleiotropy. And I think it's right, and that is that we evolved to stay healthy and alive and fit till we're 40. And then the forces of natural selection decline after that because we've essentially bred. We've often had children, but we don't need to stick around beyond that. And building a body that will last a thousand years is pointless at that, you know. So most species only live as long as they need to to reproduce, and then a little bit more. If you're a mouse that could die within two years, they only build a body that lasts two years. If you're a whale that has no predators, you can live for a couple of hundred years. That makes more sense. Why? Why does the whale live for a couple hundred years? Like, I would say it's pretty safe to say, certainly at some point in our past, we became a pretty clear apex predator. It's not that things

couldn't take us out, but I mean by and large, obviously look at how far we've come. They didn't, so why would we only live to 40? Is it that whales continue to breed and be useful in that sense? So that's really super interesting. Very few people talk about this. The reason is that we were not at the apex of the food chain until recently, but in a world where we typically would die from starvation or from war, a lot of men didn't make it to 40. Because of that, we were at the middle of the food chain. Only now we actually barely have a chance of dying before 70 or 80, unless we're unlucky. Give us another 5 million years of evolution, we could evolve 200-year life spans. That's what should happen if evolution continues. A whale has been at the apex for about 30 million years, and they've been allowed to evolve those long lifespans. We are just like them. We share most of their genes. They're warm-blooded. They

produce milk. They're conscious. They're basically us in the sea. So anyone who says we've reached our maximum limit doesn't know what they're talking about. Talk to me about this notion of resetting the biological clock. How do we do that? What's the mechanism? And so obviously going hungry occasionally exercise is going to help. But I know that you have a regiment that I'll lovingly call a regiment of drugs or precursors to things that we can take. What can we do to reset that biological clock? Well, there are different levels to resetting aging. There are three levels that we know of. The first is pretty easy to reset or to manipulate. These are the proteins that turn genes on and off very quickly. We call them transcription factors, and they basically read a gene and make a protein. That's what they do. That's level one. That's easy. Go a little bit hungry. That'll change. Level two is a little bit harder. The level two is not just changing which genes are quickly turned on and off, but actually

silencing genes for a long time, and this is where my enzymes that we work on, the sirtuins, come into play. Let's go back to the pacman. They clip off acetyls off these packing proteins. You spool up the hose, and it becomes locked in that gene gets silenced for a long time. So to do that, you can exercise, you can diet, but you also, I think, you need a little bit of help as well. What gets really interesting, and this is something most scientists don't even know about yet, is level three, the deep layer of aging. There's actually a DNA clock that tells our bodies how old we are. We could take your blood and read it, and I could tell you roughly when you're gonna die. What? Yeah, we can do that. What are you looking for? We're looking for chemical groups that get added and subtracted to our DNA, the long string in the cell. You get chemical modifications in predictable ways as you get older, starting from conception. So even in the womb, even as a kid, even as a teenager.

you're aging based on this clock that goes up linearly, and where you fit on that line, it's very accurate. That tells you your biological age. But how do you know when the person is going to die? Is that just based on straight lines? Is it actuarial tables, though the human average human lifespan is 86, and is that what you mean? Or is there, could you see something specific in my line that would say you're headed for 68? Sorry, no, it's not, not specific, but what it's based on is machine learning based on thousands of people's um code of methylation on the genome and comparing that to their health and their date of death. Oh [ __ ] that's so interesting. So if you were to take my blood right now, what would you look for exactly? We would read the methylation, the kemp. These are chemicals, hydrogen and oxygen bound to the DNA chemically physically bound, and those accumulate as you get older in very predictable ways. In fact, they're so

predictable that we can use the same clock to measure the dog's age and a human's age whoa all based on methylation right okay what causes methylation well there are two classes of enzymes the ones that add the methyl chemicals and those that subtract it okay how do i take a boatload of ones that subtract it ah that's what we're working on now here's the key level two aging reset which we can do by some of the things that i'm doing in my life yeah probably you are too those aren't permanent changes you can't just do that and expect that take take one treatment and you go on living for another 10 years okay because level 2 isn't as permanent it's somewhat permanent than level one but level three is truly permanent it you could reset yourself ten years and then go back and then wait another ten years and potentially reset the clock again if you know how to do that and we're just starting to figure out how to do that okay so level one diet exercise cool got it

level two uh metformin. You taking metformin, right? Okay, so I've talked about this on the show before, but explain what is metformin. Why is it prescribed to diabetics and now why is a seemingly rash of non-diabetic people taking it? Yeah, so there are three main pathways that regulate aging in animals and probably in ourselves. There are the sirtuins that I've talked about a lot today. There's one called mtor which responds to how much amino acids or how many amino acids are in your body. It will hunker down and protect the body the fewer amino acids it has access to. Okay, okay, then the third is called ampk, and this is the energy sensor. When your body has low levels of energy, it will allow the body to hunker down and protect itself from diseases. But why ampk is worth mentioning is this is one of the targets, as we call it, of the drug metformin. Metformin will activate this ampk pathway and make the body think that it's hungry when often

it's not and also keep your blood sugar levels more steady. Why would I, uh, hungry at a cellular level or I actually experience hunger at a certain level. Okay, but it also has an interesting side effect is from for a lot of people, myself included, it's a bit harsh on the stomach. So it also reduces my appetite. But what's great about metformin is that it's been in millions of people for a few decades. So we know the side effects. They're relatively, I'm sorry, really fast. So metformin is creating at a cellular level the sense that I'm hungry. And you're saying that from a hormesis perspective of a little bit of bad, it's like stressing the system. And that's why we think it works. It is. It's exactly doing that. And so that it actually helps the body respond in a way to boost the energy supply. So one thing it does, that's undeniable, is it boosts the level, the numbers of mitochondria. It actually creates additional mitochondria. So your

cells are getting more efficient or more able to generate energy right over the long run, but in the short run, what it does is it actually poisons part of the mitochondria. So it's a little bit of poison that leads to benefits down the line. What part is poisoned? It's called complex one. So that there are protons that are in one part of the area of the mitochondria in a membrane region, and the cell builds up protons. It becomes really acidic in that region, but the cell wants to release them. So what they do is they put little pores in between the membranes so they can leak from the high concentrated zone to the low concentration in the middle. And as they pass through that pore, it spins the pore around, and that spinning, physical spinning of that protein will generate chemical energy called ATP. That's how ATP is created, and without ATP, we're dead in about 10 seconds. Yeah, okay, that's crazy interesting. And you're saying, sorry to go back to the poison.

the poison is elevating those levels, which is causing more to go. It's actually decreasing ATP in the short run, so the cell says, Man, I haven't got enough chemical energy in ATP. So that's what forces it to create more mitochondria, right? So that's the poisoning part. It is. So the increased number of mitochondria is in response to the slight poisoning, exactly. But there are two other important points. The cells in our body also think that they need to become more sensitive to insulin, yeah, which keeps our glucose and sugar levels more steady. Okay, yeah, that's key because that's what helps the diabetes type 2 diabetics recover and you know prevents the disease from getting worse. Yes, the second is that it's just been discovered in humans that if you take metformin, a lot of it, and exercise, it can blunt the effects of exercise on building mitochondria. What we think is going on is that you don't want to always have metformin in your system or your body won't have a

chance to recover from that slight poison. I'm not going to prescribe anything. I'm not a doctor, but we think it's best better to take metformin on days that you're not exercising and recovering and pulse it again. So you've got metformin, exercise, metformin, exercise, right? I know you're not prescribing anything, but uh, how many days are you taking it? How many days are you not? How often are you exercising? How often are you not? Um, I actually spent a lot of my 30s and 40s not exercising at all. It's crazy, right? Someone like me, but I've become better at it now that I'm, you know, I was approaching 50, now I'm 50. Uh, so I spend about four hours in the gym on the weekend with my son Benjamin. Dude, like two hours a day? No, four hours straight, but it's not all exercise, okay? So it's an hour with my trainer Sean who does mostly a combination of weights and stretching, um, some free weights, some machines.

then it's another hour on my own with my son. We do some treadmill, some more stretching, and essentially just muck around doing stuff that's fun for him. And then we also, then we do some yoga downstairs in the gym, a little bit of relaxation. But the best fun part that I really love is at the end, we do a sauna, hot tub, cold bath, sauna, hot tub, cold bath for about an hour, and I feel fantastic. Talk to me about that. So in your book, you go into cold exposure. You said you moved to Boston, it sucked coming from Australia, and you bundled up, and now you wish you hadn't. Why cold exposure is cold and hot both necessary? What's the difference? Well, there are a few reasons. One is the high level view is that anything that stresses your body, puts it into a state of shock, is good in the long run. But a little bit of perceived adversity, being a little bit too hot, a little bit too cold, and especially the gradient between those two, which is why we jump from one

to the other the next point is that i've looked at the literature and at first when uh i was prompted by my publisher to look into this scientifically they said you know what about this cryotherapy what do you think and a couple of years ago i had no idea that this was real it sounded like [ ] to me but i looked into it and there were there are two important things one is cryotherapy or cold exposure we'll build up what's called brown fat we didn't know brown fat existed in humans until about five years ago typically it's across your back and in other reasons you can see with a pet scan but otherwise it's pretty invisible just looks like fat but brown fat is particularly healthy because it it has a lot of mitochondria and we think it also secretes little proteins that tell the rest of the body to be healthy in what way to be healthy we're not sure yet we're not sure it's interesting oh man i want the answer to

that question, but it certainly revs up your metabolism and will burn energy. If you're looking to stay lean, having a bit of brown fat is all good. So, my friend Ray Cronus and I have written on this, and Andrew Bremer and at the NIH. We call it the metabolic winter hypothesis, and essentially it's saying that in our lifestyles these days, we're always warm. I'm wearing this jacket, we sleep with the covers on, we turn up the heat, we never get exposed to cold unless we force ourselves to, and we think that that's possibly largely responsible, if not, you know, maybe partly, perhaps largely responsible for the diabetic problem we have. What? Okay, so if you're cold at night, you're going to burn a lot more energy staying warm. Yes, turn on your brown fat. Now, that's going to keep people lean. If we bundle up and we eat the kind of diets that we see in the supermarket, that's going to be doubly bad for our bodies. Yeah, we're warm, we're not losing energy.

and we're eating a lot more. Yeah, this is this stuff is so interesting. Okay, so what's your advisor? Whatever you're about to tell me, no, I'm going to do it. So like how frequently do I want to be doing it? Is it every day? What's that look like? Well, what I do is because I'm busy and I don't have a sauna or a cold tub at home, I subject myself to this stuff for about an hour on Sundays. And what I do is I spend about 15 minutes at 150 degrees Fahrenheit. Well, that's reasonably intense, but you get used to it. Then we go into the steam room. You know, we're sitting there chatting. It's great. Temperatures lower in the steam room because the humidity is saturated. The roof's dripping on you hot water. But that, that, I don't know if the steam helps, but I certainly love the feeling of being in there. And my skin starts to be healthier because of course it's cleaning itself out. And then the final thing I do is hot tub.

pretty hot hot water, and then, and then I go and dunk below the water a couple of times in water that's less than four degrees celsius, so that that's so cold that it takes your breath away. Yeah, yeah, but it's great. Interesting. Was there anything else on level three that we should know about? Yes. So work that we've done recently, uh, just in the last year, is finding ways to tweak the cells and the tissues of mice, at least to reset the clock. We've been working for 10 years, as I said, accelerating the clock. We can drive that hand of the clock forwards. Now we, we cut the DNA of the animal, let it heal, and in doing so, we distract those proteins from where they come from. So we're disturbing this survival circuit so much that we disrupt the spooling of the DNA, and what we got was an old mouse by every account. Based on histology, which is looking at the tissues based on their physiology, they got gray, they got arthritis, they got heart disease even.

and when we look at the molecular clock, that uh methylation clock, they were 50 percent older communications. They had more like clumps everywhere, uh those methyl groups were added to the DNA, right, right, okay. So we had given them heart disease and Alzheimer's or dementia. We'd given them all these diseases, but by measuring the clock, what we'd actually done is give them aging. But that, that was the first step that took 10 years. The last year, we've been asking, how do you get the hands to go backwards? That's a lot harder, but we were fortunate that the 2012 Nobel Prize was one for the ability to reverse that clock in cells. It's called, uh, it was the prize awarded to Shinya Yamanaka, a Japanese fellow, very smart guy, and he found at least four genes that when you put into, say, skin cells of an adult, if you gave me your skin cells, I could go back to laven, basically clone you. I could take your cells, make a stem cell pool.

and I could grow you into a new little liver or a new little kidney. That's all easy. Not easy, but it's doable. It's doable. Um, what that tells us is that those four Yamanaka genes can reset age. If I can take someone who's in like you, who's in their early 40s, and make a new you as we've done now for many species, dogs, cats, sheep, monkeys, those animals, we can reset the clock hundred percent, and those animals actually live a normal lifespan. That tells us that the instructions to be young are still in the cell somewhere, as though there's a backup hard drive that tells the epigenome those spools had to go back to be young again and get those methyl groups back to being young again, not up here, but back there, but don't strip them off too far to be a stem cell, or I'll basically turn you into the world's giant tumor. Yeah, okay. So one, why do I become a tumor because a tumor is a cell that doesn't

know to stop right so what is it that you're breaking in that process that makes it so um dysfunctional yeah so in terms of the clock let's just start with that shiny yamanaka wound the clock so far back it went back to zero back to midnight that we do not want to do because the cells lose their identity and that's the last thing we want to do. We don't want to go back to us because it's dangerous to have a pluripotent stem cell in the wrong place in the body. Of course it'll grow it won't stop growing but why doesn't why why does it become a tumor why doesn't it become a liver or a lung like i would get the problem of having a liver develop in my brain but i'm just saying like why does it become a tumor cell instead of an actual functioning liver. Well so when you go back far enough and it loses its identity it will just multiply into a mass without cellular identity so there's something else going on that

stops it from figuring itself out right. So, in the lab, if we take a pluripotent stem cell and we want to make a liver cell or a neuron, a nerve cell, we give it a bunch of chemical signals in what we call the niche. And when one of these cells lands in a niche around those old cells, they'll use that stem cell to rebuild tissue. But imagine if we could reset the clock, not all the way back to a stem cell, but just partially reset the clock so that you could go back to being 20 again, right? That's what we're able to do in some tissues in the mouse right now. You do it on mass, cell by cell, DNA strand by DNA strand. Like, how the hell do you get this to take effect through a whole joint, let alone the whole body? Yeah, right now the way we do it is we inject a virus called an AAV, and this virus will target certain tissues and deliver the genes to most of the cells in that tissue. For example, we are treating aging of the

eye in mice. So we can take an old mouse, we deliver a virus, the AV into the eye, tiny little prick. It's the same virus that's used to correct genetic deficiencies in the eye right now, FDA approved drugs. So this isn't science fiction, this is out there in the world right now. We give it to the old mice, we give them an antibiotic called doxycycline, okay, same thing you might take if you got Lyme disease. And that turns on these reprogramming factors. We don't use all four of the factors, OSKM, they're called, because one of them causes cancer, the M. We leave off the M, we put OSNK into the eye, turn it on, leave it for a few weeks, measure what happens to the eye, and those mice can see again like they were young. So we've tested three different types of damage to the eye. The first one we did was a Hail Mary so that a lab near ours across the road works on

rejuvenating the spine and the optic nerve, which is crazy. Yeah, because we know as soon as you're, you know, a couple of months old, you're not going to regrow a spine. It's one of the first parts of the body that ages. In fact, but jellyfish can regrow. Axolotls can regrow an arm. We lose that ability when we're very, very young. So, the question was if we turn the clock back a lot without osk genes, will those nerve cells be young enough to regrow back to the brain if we damage them? And that was the experiment. They pinched the back of the optic nerve so that the nerves were defective and they started to die back towards the brain. Of course, the mice lost their vision. We then turned on our reprogramming factors. We now see that the nerves get young again, wind the clock back, and they regrow back to the brain. We could give ourselves the healing ability that we only had when we were embryos. And you start to think about what could

this lead to if we can do this safely. Of course, safe is the important word across the body. Imagine one day you could have every cell in your body able to be rejuvenated like that. You cut yourself, you break a bone, you lose your mind, you have a dementia, you take a course of doxycycline for a few weeks and then stop, switch it off again, and you heal. If you turn it on at high levels, there's a lab in Spain that has shown that you can get small tumors in some animals in the kidney. So we've been very careful to not just blast the cell with these factors permanently. We've titrated, or we say brought the levels down to very low levels, and switch it off when we don't need it. But we have given mice this virus throughout their body. We inject it into a vein and we turn it on. We've left it on now expecting the mice to die. A year later, they're perfectly fine. Wow, so it appears to be safe, but of course

there's a lot more work to do. I'm a scientist, and I'm developing drugs. I have to be very aware of the dangers. Sure, please, nobody go out and try this at home at all until we know more. But the eye is a good testing zone because it's protected, and if there's a problem, it's, you know, it's shielded from the rest of the body. It won't go too far. But everything we know now is that it seems to be very safe, at least in the eye. Wow, this is crazy. So that is, is there an element of getting better improvement human performance or anything that um you can tease us with? Well, we've actually uh published results that in mice. If you give them an nad booster molecule that will turn on these pac-man enzymes called the sirtuins, those mice when they're old can now run 50 further. In fact, some of our old mice ran so far that the treadmill stopped because mice are not supposed to run more than three kilometers. We haven't

talked about nad yet tell me what nad is. What are the precursors? How do I supplement for it? Uh, so there are a few on the market. I, I don't endorse or sell anything just by the way, even if you see me online, that's not me. So that said, there are there's one called NR, which is Stan, which stands for nicotinamide riboside, which is a very early precursor to making NAD in the body. There's an intermediate from that called NMN, not to be confused with M&Ms. Please don't do that. That's not healthy. And then the cell turns NMN into NAD, and you can take all three, actually, and or each one of those three and raise NAD levels in animals. And now we're doing myself and many others are doing human studies, and we've seen that NR and in my case NMN does raise the energy levels of older people and and young people alike up to levels that we think you could rarely achieve even with being a marathon runner. That's crazy.

so just to bring this home for people, talk to me about your dad and his uh n of one experimentation with nmn. Yeah, so my father has been on the same regiment as me - resveratrol - for over a decade, the red wine molecule. He's been on metformin longer than me because he had, he was a borderline diabetic, type 2 diabetic, and he's also on NMN now, and he seems to be doing great. He's now 80. When he was in his 70s, he was, he was slowing down, he was starting to say the same things twice, you know, typical 70-year-old. He's doing great now, he's 80, he's got a new lease on life. He started a new career down in Sydney, he's hiking at the world right now, he's traveling around America, driving his elderly friend, uh, around. His friend unfortunately ended up going to the hospital the last few days, so my father is taking care of his friends who he's seeing on the decline, and he's, if anything.

improving every year. I'd love to hear more about resveratrol, which is something that I've completely written off until I started researching you. Um, it seemed for a red hot minute like it was real, and then it seemed to completely die. And I know that you got sort of caught in the middle of some of this stuff. So where has all the forget, like what pop culture thinks of it, like what's the reality of it? Yeah, so resveratrol was a proof of concept molecule back in 2003, the first of its kind that could mimic caloric restriction, make mice healthy on a high-fat Western diet. And it was a great proof of something that we were trying to figure out, and it led to drugs that went into humans that looked really promising. I got embroiled in a scientific and a corporate war song. In the case of Pfizer, they put out a scientific paper that said essentially everything that David has said is wrong, okay. And then that was a great headline.

harvard scientists started companies is wrong okay and you know and then i spent about a week in bed saying [ __ ] the world you know why am i doing this why am i working so hard for society if they don't care but i worked my way out of bed i thought let's dig deep and see if they're right or if we're right and so for another three years we really worked hard in my lab at harvard to test whether we were right so the question was with this pac-man that spools the dna does resveratrol work on it or is it working on something else and that to scientists is really important because if it's not working on this all the drugs that we're trying to work on this are probably working um the wrong way that we thought to cut a long story short what we found and published in the journal science which is one of the top you can do and i say that because it's validated science is that we show that resveratrol does

bind to the pacman and it is responsible for this, and we now have new information that we haven't published, but I'll tell your audience about it. We've made a mouse that is resistant to activation of the pacman. We can tweak the enzyme just in one amino acid in that protein, out of about a thousand, that blocks this movement activation. It's normally chewing like this, but if we add resveratrol to a normal mouse, it'll do that to our mutant mouse. It's this, and which is better, the rapid munching? Rapid munching's better, okay, because the rapid was, we think, was responsible for the health benefits and the longevity. So what you're showing is by slowing it down, you cause real problems, and thusly if you have resveratrol on there and get it munching really fast, that you've done something positive, right, and our mutant mouse should be resistant to the benefits of resveratrol if we're right, but if Pfizer is right, then resveratrol should still provide benefits even

though this enzyme because it's working on some other some other way got it so the mouse that could not be sped up the mutant mouse does not live longer when given resveratrol on its high fat diet. Interesting so that will be the the punctuation mark the fu we will ride but but interestingly the world has moved on right well i'm left to clean up the pieces right yeah. So and when you say the world has moved on you're talking about people like me who just assumed that it was garbage and that it's not real and right okay. So um you've said that the only supplement you take is vitamin d um so how are you getting resveratrol in the system is it a drug do you have to have it prescribed uh well i'm taking resveratrol i have um and would we call that a supplement sure and it's commercially available uh it is if it's a legitimate seller and it's 98 plus percent pure it seems to be similar to what i take.

and ballpark, how much do you take? Um, I take a teaspoon into my yogurt. That's probably close to a gram every day. Every day. Yeah, okay. Uh, resveratrol, roughly a gram. Are you taking nmm or is nmn or is that just your dad? Uh, both of us. Okay. And then um, metformin, right? Those three. Anything else? Those are the main things that I think are helpful. And I've been monitoring my blood by chemistry. So I, and you said you took an MRI of your heart, right? Which I love. What are things that we should be testing? Assume for a second I'm willing to go all the way. Do any crazy test to know if what I'm doing is working. Um, what would you recommend? Well, I avoid x-rays and CT scans unless I have to, sure, right? If your doctor says go for it, please don't refuse that. But otherwise, don't do it for fun. Don't do it because you're curious, uh, because those CT scans will break your DNA. And when we break the

mouse's dna it's a its age goes up by 50 percent so whoa right so avoid dna breaks as much as possible what i do is i take a blood test from a company called inside tracker which in full disclosure i invested in years ago and they look at about 30 parameters in your blood and give you feedback it's doctor supervised so it's it's legit and it's based on a lot of science and that at least gives you some feedback about your body about what's actually happening if you change your lifestyle or you take a supplement or even a new drug for that matter so you've got to have you've got to be monitoring because you don't you don't want to fly blind you don't know if for you you're doing harm or doing good so do do a blood test at least go to your doctor and have a blood test for for a good goodness sake you could have your genome sequenced or do something that looks at the the variance in your genome for relatively

little cost. I think it's 99. Now, I gave a test of that kind to my whole family as a Christmas present. And what we've learned is that some of our members, lab members, are not lab members. Family members have variants that predict longevity. Some don't. Some have mutations in their genome that are a little bit scary. Um, down the line, you could get your DNA methylation age determined, the true what's called the Horvath clock. Some people measure their telomere lengths. Um, did you have a biopsy to do that, or can you do it from blood? Blood, blood test is fine, yeah. So interesting. All right. Where can people learn more about you? Uh, well, so the main site is lifespanbook.com. That's where you can sign up for the newsletter and buy a copy of the book if you're interested. I highly encourage it. Well, thanks. I'm also, um, now on social media. So I have a Twitter account. I try to talk about the science, about new findings, about things that I've just learned and stuff like

this that they might want to tune into. So my twitter account is David A. Sinclair, and I have Instagram where I send out some, you know, little fun to do is not to do this kind of thing, and that's David Sinclair, PhD. Okay, what's the impact that you want to have on the world? Well, that's easy. Since I was four years old, I've wanted to figure out why we die so fast, and you know, in my view, I think it's cruel to have a sentient being that knows it's going to die in such a short time frame. 80 years is nothing. It goes by in a blink of an eye. Even a thousand years will go by in a blink. It's only 20 times what I've lived. So I want to be able to leave a mark on the planet. I'm hoping to have moved the needle somewhat on the course of human history. I think we've come further than I thought we would in my whole lifetime, and this, I've still got a few years left.

to try and make what i'm talking about come true. I certainly hope so. If you were going to have people make one change that would have the biggest impact on their health, what change would you have them make? Well, so having read tens of thousands of papers and done this for now 30 years and talked to people, and I know what's on the cutting edge. The simplest thing you can do that would have the biggest bang for the buck is be a little bit hungry. Don't eat, but that's not to say be nourished. Don't starve yourself right. There are a lot of teenage girls, particularly, who don't eat enough. So I'm not saying that at all. You've got to have a minimum nutrition. But for those of us, myself included, who likes to eat, those of us who don't mind a bit of dessert, try to skip a meal. I skip breakfast. Besides that bit of yogurt, often I'm too busy to eat. Eat a lunch at dinner. I eat a normal meal. I don't

gorge myself because that'll trigger all these defensive pathways that'll rebuild the body, or at least keep it pristine until we have such things as the level three reversal, which we're now working on. That's amazing, David. Thank you so much for being here. That's incredible, and guys, read the book, dive in. If you're like me and you want to live forever, I'm telling you, this guy is at the tip of a very exciting sphere, so check them out if you haven't already. Be sure to subscribe, and until next time, my friends, be legendary. Take care, my man. That was [ __ ] awesome. Thank you guys so much for watching and being a part of this community. If you haven't already, be sure to subscribe. You're going to get weekly videos on building a growth mindset, cultivating grit, and unlocking your full potential.

Harvard Professor REVEALS How To SLOW & REVERSE AGING | Dr. David Sinclair

If you’re looking to thrive in uncertain times, achieve unprecedented goals, and improve the most meaningful aspects of your life, then Impact Theory is the show for you. Hosted by Tom Bilyeu, a voracious learner and hyper-successful entrepreneur, the show investigates and analyzes the most useful topics with the world’s most sought-after guests. 

Bilyeu attacks each episode with a clear desire to further evolve the holistic skillset that allowed him to co-found the billion-dollar company Quest Nutrition, generate over half a billion organic views on his content, build a thriving marriage of over 20 years, and quantifiably improve the lives of over 10,000 people through his school, Impact Theory University. 

Bilyeu’s insatiable hunger for knowledge gives the show urgency, relevance, and depth while leaving listeners with the knowledge, tools, and empowerment to take control of their lives and develop true personal power.


Tom Bilyeu

Decoding the Science of Aging with David Sinclair

David Sinclair, a renowned Harvard professor, discusses the DNA clock that determines human aging and the information theory of aging.

He explains that the epigenome, which controls gene regulation, plays a crucial role in the aging process, causing cells to lose their identity over time.

Sinclair believes that biological stress and DNA damage lead to the disruption of the youthful gene expression pattern, ultimately contributing to the loss of cell function and identity.

The Role of Enzymes in Aging and DNA Repair

Proteins like enzymes play a crucial role in accelerating chemical reactions in the body, affecting DNA packaging and repair.

Certain lifestyle choices such as exercise and fasting can make these enzymes more active, promoting efficient DNA repair and potentially slowing down the aging process.

The key lies in stressing the body just enough to activate these enzymes, but not to the extent of causing lasting damage, and pulsing the stress with periods of recovery, rather than constant exposure.

Periodic fasting has been found to have a significant impact on longevity in mice, allowing them to gorge while still experiencing the same benefits as those who are consistently hungry.

The theory of antagonistic pleiotropy suggests that humans have evolved to prioritize health and fitness until around the age of 40, after which the forces of natural selection decline.

Research also indicates that there are three levels of aging reset, with the third level involving a DNA clock that can predict biological age and potential lifespan.

The Role of Metformin in Aging and Health

Metformin is prescribed to diabetics to help regulate blood sugar levels, but it is also being taken by non-diabetics due to its potential anti-aging effects.

The drug works by activating the AMPK pathway, leading the body to believe it is hungry and helping to stabilize blood sugar levels.

Metformin also has the effect of increasing the number of mitochondria in cells, ultimately improving energy production and potentially impacting the benefits of exercise.

Cold and hot exposure, as well as the gradient between the two, can provide stress to the body, offering long-term benefits for health and aging.

The Impact of Cryotherapy on Aging and Metabolism

Cryotherapy can help build up brown fat, which is rich in mitochondria and can rev up metabolism, potentially helping to keep people lean.

Cold exposure may also play a role in resetting the aging clock in cells, with the potential to reverse the effects of aging.

The work on tweaking cells in mice has shown that it's possible to reset the age of cells, indicating that the instructions to be young are still present in the cell's epigenome.

Resetting the Biological Clock: Implications and Challenges

Scientists are exploring the process of resetting the biological clock to rejuvenate cells and tissues, potentially reversing aging and damage.

This process involves using a virus to deliver reprogramming genes to cells, effectively turning back the clock and restoring youthfulness in mice.

While the method has shown promising results in rejuvenating the eyes and improving physical performance in mice, there is a need for further research to ensure safety and understand the full potential of this biological reset.

The Role of NAD and Resveratrol in Health

NAD, or nicotinamide adenine dinucleotide, can be supplemented in the body using precursors like NR and NMN, which have been shown to increase energy levels in both older and younger individuals.

Resveratrol, known for its initial promise in mimicking caloric restriction, has been found to bind to a specific enzyme, potentially providing health benefits and longevity.

These supplements are commercially available and can be taken to boost NAD levels in the body.

David Sinclair's Advice on Health and Longevity

David Sinclair recommends monitoring blood chemistry and getting regular blood tests to track the effects of lifestyle changes and supplements.

He also suggests being mindful of DNA damage and recommends being slightly hungry as the simplest way to improve health.

Sinclair's main impact goal is to extend human lifespan and he advises his audience to read his book for more information on his research.