The DAILY HACKS To Look Younger, Live Longer & REVERSE YOUR AGE | Dr. David Sinclair

So, we're reversing aging of the eye. That's not hard at all. But, we can reverse the age of the liver or the skin. Other labs are doing the spleen, thymus Jesus. through this method. What are the things that we can do today to slow aging uh so that we don't end up needing this or so that we can live long enough that this goes through all the safety and all that and it becomes an actual actual just like uh standard of care procedure. Well, before we get into what we can do today, just because it's a continuum of this resetting what my lab and many others now are doing is is racing to find easier ways to reset the age of the body. Gene therapy it's here, but it's not going to be, you know, mainstream soon. It's always going to be expensive. Mhm. Hundreds of thousands of dollars a treatment. What happens when you can take a pill that will reset your age by a year? All right. Happy birthday, Dad. Take this pill. Incredible. And if you reset your age by a year every year that's pretty interesting. Uh and yeah. And there are experiments now where people have reversed their DNA methylation age, which we can now measure uh by a couple of years. And that only takes a year. So, now people are going back, at least their bloodstream is going back, younger than that year took them forward. Wow. So, we are on the verge of something super interesting in humanity. It opens up all sorts of questions about what's the world going to look like for maybe us, certainly for our kids. Mhm. Um but getting back to what we can do every day the main concept that I think we all need to remember um is that our bodies respond well to perceived adversity. All right. Those of us who you know, like to struggle in life. I know you're that kind of guy. It's don't give up. Just keep going. Our bodies respond well to that. As long as you're not doing long-lasting harm an adversity mimetic which can be don't eat so much, don't eat so often, exercise, be cold, be hot. There are some other tweaks to that. Um high pressure oxygen therapy is another theme. These put the body in a state of adversity mimicry. Mhm. And what that does to the body is it says, "Oh my goodness, I could be dead next week. I could run out of food. I could be you know, chased down by that tribe over the hill or saber-toothed tiger. I got to hunker down and become more robust. And don't put so much energy into these other things. You know, maybe wound healing would be one thing that you could take away from for a little bit and put it into long-term survival. Um those are the the roles of the sirtuins. Remember the sirtuins do two things. They slow down aging on the DNA, but they also go and repair things. Mhm. And if you don't have enough sirtuin activity or enough sirtuin proteins in your body, so in other words, you don't make enough of these little machines or the ones that you have are pretty inactive and lazy or don't have enough of the fuel that they need to work, then you're going to age more rapidly. Um and when the crap hits the fan and you get a broken chromosome, then you're not going to have as much ability to repair that and you might get cancer. And so what my role or or my goal in in my lab and in my experiments with my body is to make those processes that respond to adversity super active every day so that it's slowing down the aging process until we have the technology to reset the body and reverse it. So I have a guess hypothesis on why that would work. Um cuz you've talked about like as we get into mTOR and some of your diet recommendations. So basically there there are things like getting into mTOR which is growth. If you want to add muscle, you going to have to get into mTOR. You're going to have to give your body the signal to grow which times are good, there isn't these, you know, adverse things. Um and great if you're young, great if you're trying to put on muscle, but it may have these long-term consequences. Versus putting your body into this, actually things are hard, now's not the time, let's dial back, let's make sure that we stay strong. And my gut instinct is that from an evolutionary standpoint, that would be a mechanism designed to make sure that you live long enough for times to return to good so that you can procreate. And that you're sort of going into like a semi-hibernation to like last outlast whatever environmental problem there is, so that you can uh still be around when the environment changes. Does that ring true for why this mechanism works? It does, except hibernation gives the impression that you don't have as much energy. Right. I knew that wasn't going to be the right word, yeah. Not true. Uh people who do what I do have way more energy than someone who sits around and doesn't exercise and and eats too much. Um and our bodies rev up and make more energy so that we can repair the body. We need that energy to fix the DNA and get rid of the old proteins and survive. So, think of it as hunkering down, but but also having more energy to be able to survive anything that comes at you. Mhm. Um and so the converse to adversity mimetics, which is what I try to do, are the abundance mimetics. So, you mentioned mTOR. mTOR will sense if you're eating a steak, lots of amino acids, great, build new muscle, that's going to work. But an an um abundance mimetic is not going to make you live longer. We know that. You can manipulate this mTOR uh enzyme complex, we call it let's call it a gene the mTOR gene, you can manipulate that in a mouse and give it less or more of the mTOR activity. And when you do that, their lifespan changes. And the more you have of it, let's say you've now made it like the mouse is full of abundance, it'll live short and vice versa. It'll live longer if you turn down the activity of that gene. And you can do that. I mean, we can't genetically engineer ourselves easily these days. And I say easily, you can, but not easily. Um but what you can do is by eating things that are right, you can make mTOR believe that there's adversity and turn on the repair systems. All right. So, what does this adversity mimetic look like from a lifestyle perspective? So, you rattled off a few things really fast, yeah, but I imagine diet and exercise are probably going to be two of our most important things. And then knowing some of your views on supplements, I think we should get into that as well. Right. Well, I do I do talk a lot about the tweaks on exercise and diet, but but in a very scientific and detailed way. Sometimes I feel a bit silly saying, "Oh, diet and exercise." Why is this guy who studies the the process of aging and the molecular basis of it talking about these diet and exercise? We we've known that for decades, but what we haven't known is how they work. We just discovered that just by looking at thousands of people who live longer and who don't. And okay, eat that diet, fast that time, do that kind of exercise. We know those people live longer, but we didn't know why. So, now we do. So, we can tweak it. We can maximize the benefit of those lifestyle changes. But it's worth pointing this out because I I I think it's it's empowering. So, point one is we can measure our biological age. We can look at the DNA methylation. We can look at our bloodstream. I do that. And some people don't do that cuz they're scared of learning their biological age. What if it's too high? What am I going to do? But information, knowledge is power. And important point number two is that 80% of your longevity and your health in old age is controllable. And only 20% dictated by your genes. The The genome The rest is the epigenome that responds to how we live. So, that's why I'm all gung ho for for changing your lifestyle, because it's going to it could give you two more decades of life. And I'm not kidding. If you just do the five things that doctors recommend typically, don't smoke, don't over drink, get enough sleep, get a bit of exercise, and don't be overweight, if you do that versus someone who doesn't, you live on average 14 years longer. And that's just the stuff we know of. But there gets to be some really interesting stuff that is just now at least making my level of awareness. And I think that some of this speaks to this idea of the um adversity mimetic. So, when you pointed out that a type two diabetic, so diet-induced, lifestyle-induced diabetes, is going to live longer than somebody without diabetes if they're taking Metformin. That's insane to me. Here's my hypothesis, Neil, tell us whether this makes any sense. So, insulin seems like the problem child here. And so, by elevating my glucose levels, I have to pump all this insulin into the system. The insulin is potentially damaging things somehow, some way. I don't understand the mechanism, but it's overabundant presence causes damage to the cells in some way, shape, or form. By taking Metformin, it's keeping my blood glucose levels down, which means that it's going to keep my insulin levels down, and therefore I wouldn't be doing the damage to the system. So, even though I may be intaking the things that turn into glucose, because of the use of Metformin, I'm actually keeping my insulin response down. So, therefore I never get that thing that ends up damaging the system. And therefore, even though I started as a type 2 diabetic, and that's why I'm on the Metformin, because of its impact on insulin, I never get the damage isn't occurring at the level that it would even for somebody who is not a diabetic. Does that sound about right? Kind of. Kind of. But let's go back to what is Metformin. Metformin is a derivative of a plant molecule that inhibits the cells' ability slightly to make energy. And in response So it's the Metformin acting on the mitochondria? Yes. So mitochondria, in high school we were taught they're the power packs of the cell. They do a lot more. They make amino acids, they make fat, they do all this stuff. But we need them for energy. Without mitochondria, we're dead again in 30 seconds. Um and the way and so I'm I'm drawing this cuz they're like little bacteria in our cells. They float around and they make energy for us. In fact, like 4 billion years ago, uh actually only 1 billion years ago, uh mitochondria were free-floating bacteria that were subsumed by us. That's crazy. So we have little pets in our body, and they have their own DNA, uh which does get mutated over time. The reason um Metformin seems to work, one of them, is that it inhibits the ability of mitochondria to make the energy. So mitochondria are like a hydroelectric dam. Uh there's water, but in this case it's hydrogen atoms, not water, that gets pumped into a reservoir, which is between two membranes on the outside of the of the the bubble of the bacterium thing. So now hydrogen atoms are really acidic. That's what acid is, lots of hydrogen protons. And when you get a lot of something, it likes to equilibrate. Remember, they you go from a lot to little. It flows. But there's a membrane in between from the high level to the low level. In so internal is low, high is outside. And the cell puts this little uh generator in between that outside space and the inner space. Uh it's the outer membrane space and inner membrane space. That's what we call it. And this little little power generator sits there and those protons shoot through a pore in that protein. And at the bottom is a is a generator. It spins. Literally, it the protein is spinning at thousands of times per second. Whoa. And as it's spinning, it's doing a chemical reaction to make what's called ATP. Uh adenosine triphosphate. Doesn't matter its name. That ATP is chemical energy that we use to to live, to make things, to grow. Uh and so what metformin does is that it reduces the the ability of cells to uh make that uh those proton gradients it's called. And so you don't build up as much power and you don't make as much ATP initially. to do with glucose? Why do you give that to a diabetic? What is that, my friends? 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And I want to meet you inside of Project Kaizen and help you have fun with these ideas of always getting better. All right, click the link and join me in Discord and until then my friends, be legendary. Take care. Peace. Well, what happens is that there's a process called mitohormesis. Mhm. Hormesis is adversity. What doesn't kill you makes you stronger. And mito is the mitochondria are experiencing adversity or perceived adversity. So, mitochondria are freaking out. I can't make enough energy. I don't have enough enough ATP. Okay? And what gets activated is a protein called AMPK. AMPK is a regulator of energy in our bodies that senses when we don't make enough energy. And what metformin does is it comes in and it activates that AMPK step. And now the cells are freaking out that they're not making enough energy and in response they'll make more. And so you have a little drop in energy temporarily when you take the pill, but then the cell rebounds and starts making a lot more energy. And you you actually mitochondria will multiply. You get more of these little bacteria in your cells. So, taking metformin causes replication of your mitochondria. Yeah. Okay. AMPK starts, but I still don't know how this ties into glucose. Well, when you when you activate AMPK, you don't just make more mitochondria, but cells start to put out a a new protein that we haven't talked about, new to this chat. I'll call it GLUT4. And that's stands for glucose transporter number four and it goes to the outside of the cell right on the very what we call plasma membrane. And it sits there and now its job is to suck the glucose out from the liquid around it. no longer waiting for insulin to come around to push the glucose into the cell. It's like, "Yo, I need glucose to help with this energy creation." It does and it so it makes more of this protein, but it also becomes what we call insulin sensitive. So, the little bit of insulin that you have around, if you're a type 2 diabetic, um works better. Okay, you get more insulin receptor, which is the protein that senses insulin. So, all in all, what happens to that cell, just to summarize, cuz it's getting complicated, is that by tricking the cell into thinking it doesn't have enough energy, it panics, adversity, hormesis, and it'll go now and put the protein on the surface to grab the glucose and be more sensitive to the hormone insulin that tells the cell to suck it in. Why is that good? Cuz then your glucose levels in your bloodstream will come down, and you're no longer type 2 diabetic. There are two reasons, I believe, why being type 2 diabetic accelerates aging, why you don't want to have high levels of glucose, and why I try to keep my levels down. is is irrelevant in this chain? I do. It's a signaling molecule. Um I mean, over time, your pancreas will suffer cuz it has to make more and more of it, but that's not what's aging your brain and your muscle and all these other things. What's going on is two things. One is that that glucose will attach to proteins uh all the time. It just sticks to it. And in fact, the diagnosis of type 2 diabetes is to look at an abundant protein in your body in your blood that you can access at your doctor's office and figure out what percentage of that protein is stuck to glucose. Um and that's hemoglobin. All right, in your red blood cells. And if you've got 5% or less hemoglobin attached uh to the glucose, you're healthy. And then you get 6.5, you're a pre-diabetic, and higher than that, you're heading towards type 2 diabetes. And that's just all about glucose attaching to proteins. And glucose attaching to proteins messes things up. Um and they can really not work well, but that's really not the root cause of aging, as I've told you. What's also going on is that the high levels of glucose are are your cells complacent. Tons of energy. Got lots of this stuff going around. The hormones, your brain thinks that it's good. You're swimming in treacle. Um and so your adversity and repair systems, the sirtuins, they don't work as hard. And so your clock is ticking faster. That's why type 2 diabetics have other diseases. as hard or they're lumbering under the weight of glucose that's stuck to them. Oh, interestingly, both. Sirtuins will get attached to sugar. Uh but they also they don't turn on. Like they should. to sugar or sugar gets attached to them? Sugar gets attached to them. Okay. Yeah. Um but what's also a real problem is that that adversity system is complacent. And so by keeping your glucose levels down, even at a young age, well, I'm not young, but even at a young age, um your your body will be in this adversity state versus abundance. And that can explain why type 2 diabetics are older when you measure it, and also are susceptible to heart disease, um um dementia, and even certain types of cancer, and why metformin, the drug that keeps your glucose levels down and activates this mitohormesis defense, doesn't just protect you against type 2 diabetes. It By looking at tens of thousands of patients who have that have taken metformin, they also have lower levels of heart disease, dementia, frailty, and cancer. It's bananas. It is bananas. Do you take metformin? I do. So, I'm going to walk through what I think is your ideal protocol minus the supplementation. I don't want to speak to that. I'll let you add any of that other than metformin if you think there's something else people should do, but um Okay, so a primarily vegetable diet. And a big part of the reason that I think that you recommend a primarily vegetable diet is because of this um adversity memetic versus abundance memetic and that because red meat is so rich in amino acids, it gives a signal to the body that we have an abundance, we can grow, and so we were rapid growth, but we're also aging ourselves. Um so, we want to create this um that little bit of a stressor by or I should say we don't want the signal that we have abundance. We obviously have to eat well for protein. We're going to need to make sure that we're getting all the protein that we need and all of that. And that you advise intaking vegetables that have gone through a hormetic trial themselves. So, like with the wine grapes that are highest in resveratrol, they're often dehydrated and ones that have fungus on them, I guess really do well cuz the resveratrol I would imagine is part of their defense mechanism. It is, yeah. Uh and then so, any vegetables that have had sort of a hormetic push is going to be a good idea and you give a bunch of examples that I've heard before like oranges, I guess if you drive a nail into the bark of the tree like before harvest that that helps. So interesting. Um Olives and olive oil, oleic acid. Oleic acid will activate sirtuins, resveratrol. It's not a coincidence that we figured out these kind of foods are good for us separately, but now we understand probably how they're working, too. So yes, you're right so far with my lifestyle. Utterly fascinating. Uh heat exposure. Cold exposure. Um fasting. That's one that we should probably go into a bit of detail about. So, intermittent fasting being a big one. I know that you're doing OMAD, one meal a day. I'd ask what that meant the first time I heard it. Um and you're doing that, you're still intaking a fair amount of calories. I mean, you're in good shape, um but you're not withering away. So, I imagine that you're roughly um taking in enough calories to hit maintenance levels. Right. But only in a single meal a day. Do you eat like cuz I I think you eat in a 2-hour window? I'm not strict about it. I have dinner. Um and occasionally I I break down, I have a little bit of a a snack in the afternoon. Um and occasionally As needed kind of thing. I have lunch with friends. Occasionally I have breakfast, but my my best days, I would say probably at least five, six days a week are not eating maybe more than an a nut, a few nuts, or a nibble of chocolate uh until dinner. And then dinner is great. But dinner is a big meal for me. How many calories in your dinner? Roughly? I don't I don't know, but I go to a restaurant and I'm eating multiple dishes. I just don't eat dessert. I steal little bits, but that's it. I avoid sugar like it's the plague for for the reason we just uh mentioned. Mhm. Okay, so uh you advise people to do prolonged fasting if they can. You don't personally just because it sucks and it isn't fun and you live your life at a very high level and so it gets difficult and I will second that. Uh 24-hour fast for me is pretty easy. Anything beyond that, my performance begins to decline. Certainly, my levels of enjoyment begin to decline rapidly. I've done a 5-day fast and after day three, it's like being sick for me at least as I've done it and I'm sure I could optimize and do it better, but I have found that trying to perform at the level that I perform at just has not been possible. Even at three days, halfway through day two, I'm like, I'm not as good as I would normally be. I don't have the patience for certain meetings that I might otherwise have. Uh so, I have a very similar response to fasting, but I I'm my average when you take it over a week cuz I'm slightly shorter on the weekends, my average is about 17 and 1/2 hours a day, 365 days a year. Um some days it's 14 and other days it's 22. So, it just depends on uh the day. But it ends up because I tracked it really religiously for a long time. It ends up on average, all things taken into consideration, 17 and 1/2 hours a day. Um is there a sweet spot? I'm similar. I think that's the sweet spot for for you and me. There are sweet spots that are different for everybody. Some people like breakfast and don't care for dinner. But you want to be able to I'm actually more like that. My last meal is at 1:15 p.m. Oh, wow. Okay. But what what you've got now is after after lunch you go all through the night. You've got that extended period. You want to use the night as a period of fasting cuz you're not thinking about food when you're sleeping anyway. But but also I'm wondering if you see this too or feel this. For a few weeks when I I started doing this in more intensely and actually skipping lunch, it was tough. It's tough for everybody, I think, cuz we we've got ghrelin coming out and we we have to eat something. We're used to eating. But after 3 4 weeks, I didn't I didn't feel like eating. In fact, if I ate something, I'd get a little bit woozy or brain fog. And what I saw when I was measuring it, so I've done the Levels Health thing on my arm. Um so there's a glucose monitor continuous glucose monitor on the phone that when you start, your body doesn't know what to do. Hungry, you're losing glucose, you feel tired, you're hungry. But what happens over time after 3 weeks is you steady out and your liver wakes up and learns that it needs to do a job its job, which is in part making sugar for your body, glucose. But our livers are much smarter than our eyes and our mouths, much. And and continuous. Your liver my liver, if you measure it during the day, I showed you a graph earlier when when we were talking, the the line through the day is really steady in this zone. And that's why I can power through the day. I don't feel over energetic. I don't feel lethargic. I don't even feel hungry. But there's a really important point, which is it's individual. The other important point is that you just you need to get through the hard part in the beginning. Yeah, I don't think people will believe you, nor will they really understand what it means to become metabolically flexible, so that you can burn glucose or ketones. And when you do it though, it changes your relationship to hunger. It's not that I don't know that I'm hungry. It's that it doesn't create any sense of urgency. I'm not distracted. I'm not like, "Oh my god, I have to eat." It's just, "Oh yeah, wow, I guess I haven't eaten in a long time." It and no one will believe you until they've done it. And I remember when I first went low carb, and this wasn't even me quite going keto, but when I first went low carb I had a headache. And I was so angry, and I remember saying to my wife, "If I had a cookie, I would feel better." And I that was true. It would have made me feel better. But, on the other side of that was you finally break your metabolic dependency on sugar, and now you can burn either glucose or ketones. Cuz I used to measure my ketones all the time. And I would I could predict with pretty high degree of accuracy when I was over 0.5, when I was around one, or if I was north of one. And because you feel differently. It's pretty crazy. Yeah, it's fun to do the the glucose monitoring because you can look on your phone and and you know how you feel. Mhm. And I could very quickly see that if I ate normally, like a a normal uh American, a big breakfast, huge spike in glucose, goes up uh now over 150, 200 Yep. mgs per deciliter, and I'm feeling wired, and I've got caffeine in my body, so okay, I've got a couple of hours of hyper. And then I'd have this crash. I'd feel terrible. I need to go to sleep. I didn't sleep well enough. I can't think. I need to get a snack to to get back to where I was. And then I look at my phone and I can see that I'm in this crash. I've gone not just you know my my levels are here. I've gone below that and now I'm feeling hungry. I'm weak and then what do I do? What does everybody do? I get I need a snack. I need a protein bar or something and then shoot straight back up. Our days if on a normal meal normal American diet it's like that and it's highs and lows and highs and lows. It's horrible. Horrible. You got to break that cycle and just do that and then you a little bit in the evening. Food is required. We're not talking about starvation or malnutrition here. Right. But Tom the the one thing that it's real things really important to tell everybody who isn't doing this is that I'm really lazy when it comes to life. I really am. It's surprising I I've gotten where I am. I know the feeling. And very well. But what I I I I am pretty stubborn and I like to do things to a point where at least I've satisfied myself that I can do something. But I like meat. I love meat. I vegetables for me were a garnish for most of my life. I love the taste of meat. I would love if meat was life prolonging. I'd be the happiest guy. But I've now learned A that that that vegetable at least plant focused. You can eat some meat and fish preferably. It's not going to hurt you but a a carnivorous mainly carnivorous diet there's really no evidence that in the long run that's healthy unfortunately. So I've switched and I'm very happy with it. I I do enjoy a mostly plant based diet now. Exercise. I freaking hate exercise. I'm Joe average or worse. I do not like the feeling of being out of breath at all. I like lifting weights cuz at least I I don't lose my breath but I'm lazy. I have to force myself to go to the gym everyday when I do it which isn't everyday by the way. Um so if if I can do it anybody should be able to do this. It's just a matter of willpower and getting into the habit of doing that and letting your body adjust. 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 regimen that I'll lovingly call a regimen of drugs or precursors to things that we can take. What can we do to reset that biological clock? Mhm. 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 to manipulate. These are the proteins that turn genes on and off very quickly. We call them transcription factors and they 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 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 Pac-Man. They clip off acetyls off these packing proteins. You spool up the hose and it becomes becomes locked in. That 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. I could take your blood and read it. And I could tell you roughly when you're going to 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 is very accurate. That tells you your biological age. But how do you know when the person's going to die? Is that just based on draw a straight line. 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, "Ooh, you're headed for 68. Sorry." Uh 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 chem- These are chemicals, hydrogen and oxygen bound to the DNA, chemically, physically bound. Um 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 a 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? Uh 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. Cuz level two isn't as permanent. It's somewhat permanent than level one. But level three is truly permanent. It you could reset yourself 10 years and then go back and then wait another 10 years and potentially reset the clock again if you know how to do that. And we're just starting to figure out how to to that. Okay. So, level one, diet, exercise, cool, got it. Level two, uh Metformin. You take 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 are in 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 hungry at a cellular level or I actually experience hunger? At a cellular level. Okay. But it also has an 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 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 low. 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. Uh so, one thing it does that's 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 it's a little bit of poison that leads to benefits down the line. What part is poisoned? Uh it's called complex one. So, there there are protons that are in one part of the area of the mitochondria in in a in a membrane region. And you the cell builds up protons. It becomes really acidic in that region. But, they the cell wants to release them. So, what they do is they put little pores in between the membranes so that 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. ATP, we're dead in about 10 seconds. Yeah. Okay. That's crazy interesting. Uh and you're saying, sorry, to go back to the poison, the poison is elevating those levels, which is causing more to go through the 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 diabet- type 2 diabetics recover um and you know, prevents the disease from getting worse. Yes. And 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 uh 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. Uh-huh. 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 you're 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? Uh someone like me. Mhm. Uh but I've become better at it now that I'm, you know, I was approaching 50, now I'm 50. Uh so, I I spend uh about 4 hours in the gym on the weekend with my son, Benjamin. Do you like 2 hours a day? No, 4 hours straight, but it's not all exercise. Okay. Uh so, it's an hour with my trainer, Shawn, who does mostly a combination of 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 at doing stuff that's fun for him. Um and then we also then we do um some 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. Yeah, yeah, yeah, yeah, yeah. Sauna, hot tub, cold bath for about an hour, and I feel fantastic after that. Talk to me about that. So, in your book, you go into cold exposure, you said you moved to Boston and it sucked coming from Australia, and you bundled up, and now you wish you hadn't. Um why cold exposure? Is cold and hot both necessary? What's the difference? Yeah, well, there 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 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 really sounded like [ __ ] to me. Uh but, I looked into it. And there were there were two important things. One is cryotherapy or cold exposure will build up what's called brown fat. Mhm. Uh we didn't know brown fat existed in humans until about 5 years ago. Typically, it's across your back and in other regions. You can see with a PET scan, but otherwise, it's pretty invisible. Just looks like fat. But, brown fat's 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? Uh we're not sure yet. We're not sure. Um and I want the answer to that question. But, it 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 is all good. So, my my friend Ray Cronise and I have written on this and Andrew Bremer at and at the NIH, we call it the metabolic winter hypothesis. And essentially, it's saying that, you know, 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 we force ourselves to. And uh we think that that's possibly largely respons So, if not, you know, maybe partly, perhaps largely, responsible for the the di- diabetic problem we have. What? Okay. So, if 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 and we eat the kind of diets that 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 advice? I Whatever you're about to tell me now, 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 cuz 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. What I do is I spend about 15 minutes at 150°. 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 is saturated. The roof's dripping on you hot water. But that that I I don't know if the steam helps, but I I certainly love the feeling of being in there, and my skin starts to be healthier cuz 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 4° C. So, that that's so cold that it 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 just in the last year is finding ways to tweak the cells and the tissues of 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% older Meaning they just they had more like clumps everywhere. Uh those methyl groups were were added to the DNA. Yes. Right. Right. Okay. So, we had given them heart disease and and Alzheimer's or dementia, we'd given them all these diseases, but by measuring the clock, what we had 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 won 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 the lab and basically clone you. I could take your cells, make a stem cell pool, Mhm. 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, uh dogs, cats, sheep, monkeys, those animals we can reset the clock 100%, and those animals actually live a normal lifespan. That tells us that the instructions to be young are still in the cell somewhere. Mhm. As though there's a backup hard drive that tells the epigenome, those spools, how 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 a 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. So, what is it that you're breaking in that process that that makes it so dysfunctional? Yeah. So, in terms of the clock, let's just start with that. Shinya 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 a stem cell because it's 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? Uh well, so when you go back far enough and lose 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 partial reset the clock so that 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 en masse. When it's cell by cell, DNA strand by DNA strand, like how the hell do you get this to take effect uh 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 AAV, into the eye. It's a tiny little prick. Um it's the same virus that's 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 in the world right now. We give it give it to the old mice. We give them an antibiotic 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 OSK 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 damaged damage to the eye. The first one we did was a Hail Mary. So, the a lab near ours, across the road, works on rejuvenating the spine and the optic nerve. Just crazy. Yeah, cuz 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, we we The question was, if we turn the clock back a lot with our 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 your mind, you you have a dementia, you take a course of doxycycline for a few weeks and then stop, switch it off again, and you you 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 we've been very careful to not just blast the cell with these factors permanently. We've titrated what 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 uh this virus throughout the 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 it appears to be safe, but of course there's a lot more work to do. I I'm a scientist and I'm developing drugs after 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 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 we've actually published results that in mice if you give them an NAD booster molecule that will turn on these Pac-Man enzymes called sirtuins, those mice when they're old can now run 50% further. In fact, some of our old mice ran so far that the the treadmill stopped because mice are not supposed to run more than 3 km. 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. Um 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, uh there are there's one called NR, which is stand 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&M's. Please don't do that. That's not healthy. Um, and then the cell turns NMN into NAD. And you can take all three, actually, and or 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 NAD levels of older people and and young people alike up to levels that we think you could really achieve even with uh 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 1 experimentation with NMN. Yeah. So, my father has been on the same regimen as me, resveratrol, for over a decade, the red wine molecule. Um, he's been on metformin longer than me cuz he had he was a borderline diabetic, type 2 diabetic. Uh, and he's also on NMN now. And uh he seems to be doing great. He's now 80. When he was in his 70s, he was he was slowing down. His He was starting to say the same things twice. You know, typical 70-year-old. Um, 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 up 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 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. Um, 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 it was a great proof of of something that we were trying to figure out. And it led to drugs that went into humans that looked really promising. Um I got embroiled in a scientific and a a corporate war. So, 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 scientist started companies is wrong. Okay, and you know, and then I spent about a week in bed saying, "Fuck 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 and or if we're right." And so for another 3 years, we 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. Cuz 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, um and I say that because it's validated science, is that we showed that resveratrol does bind to the Pac-Man, and it is responsible for this. And we now have new information that we haven't published, but I'll I'll tell your audience about it. We've made a mouse that is resistant to activation of the Pac-Man. Mhm. 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. Which is better? The rapid munching or Rapid munching's better cuz the rapid was we think was responsible for the health benefits that the longevity of So what you're showing is by slowing it down you cause real problems and thusly if you have resveratrol in 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 is blocked. 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 were right. Um but but interestingly, the world has moved on. Mhm. Right? Well, I'm 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 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 Mhm. 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. It's probably close to a gram. Every day? Every day, yeah. Okay. Uh resveratrol, roughly a gram. Are you taking NMN 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 biochemistry, so I And you said you took an MRI of your heart. Right. Which I love. Um what are things that we should be testing? Assume for a second I'm I'm willing to go all the way, do any crazy tests to know if what I'm doing is working. Um what would you recommend? Well, I avoid uh x-rays and CT scans unless I have to. Sure. Right. If you If your doctor says go for it, please don't refuse that. But otherwise, don't do it for fun. Don't do it cuz you're curious. Uh because those CT scans will break your DNA. And when we we break the mouse's DNA, it's a it's age goes up by 50%. So Whoa. Right. So avoid DNA breaks as much as possible. Um what I do is I take a blood test from a company called InsideTracker, which in full disclosure I 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. Mhm. 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 cuz you don't you don't want to fly blind. You don't know if for you you're doing harm or doing good. Um 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 variants in your genome for relatively little cost. I think it's $99 now. Uh I gave a test of that kind to my whole family as Christmas present. And what we've learned is that some of our members lab members uh 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. Uh some people measure their telomere lengths. Um do you have to get a biopsy to do that or can you do it from blood? Blood test is fine. What is up my friend? Tom Bilyeu here and I have a big question to ask you. How would you rate your level of personal discipline on a scale of one to 10? If your answer is anything less than a 10, I've got something cool for you. And let me tell you right now, discipline by its very nature means compelling yourself to do difficult things that are stressful, boring, which is what kills most people, or possibly scary or even painful. Now, here is the thing, achieving huge goals and stretching to reach your potential requires you to do those challenging, stressful things and to stick with them even when it gets boring and it will get boring. Building your levels of personal discipline is not easy, but let me tell you it pays off. In fact, I will tell you you're never going to achieve anything meaningful unless you develop discipline. All right, I've just released a class from Impact Theory University called How to Build Ironclad Discipline that teaches you the process of building yourself up in this area so that you can push yourself to do the hard things that greatness is going to require of you. All right, click the link on the screen, register for this class right now and let's get to work. I will see you inside this workshop Theory University. Until then, my friends, be legendary. Peace out. For a long time, I was really focused on living forever and that was the dominant thing I thought about as I mapped out my life and then about a year or two ago it started to feel more important to recognize my mortality and part of it was I I had really lost faith that it was going to happen in my lifetime. And I definitely want it to happen. In researching you for this episode, I am regaining belief that it we really may hit health escape velocity in my life. And so, in the first half of the show, I want to talk about um, why we age exactly and you've gotten extraordinarily good at mapping that out with real conviction and then in the second half we'll talk about what we can do on an individual level to really slow that down uh, or possibly even reverse it. So, I want people to stick with me cuz I'm actually going to start with a story and a quote. And um I want to make sure that people know the map of where we're going. So, first the story. On Christmas Eve um I was throwing a little party for my family and it was a poker party. We had a dealer come. 40 years old. And the energy's high. Imagine balloons everywhere. It was actually a birthday party. Happens to be somebody's born uh in my family on uh Christmas Eve. And go into the kitchen to get a drink and my wife runs in and says, "We think the dealer's having a heart attack." She's like, "You need to get in there right now." And so, I rush in to the room where this is all set up and he's just sitting there holding his head like this. And I said, "I don't think he's having a heart attack. I think he's having a stroke." And you know, long story short, he ends up not surviving. Oh no. And so, he was in a um coma for I guess 5 days and and they end up taking him off life support life support and he passes away. And I was like, "This guy's 40." And so the question really becomes, how do we get good at understanding where we're at biologically? What is our real age? Not our as you say, not the number of times that the Earth has gone around the sun. But how old are we really from a uh the things that we can measure and are they giving us real information? So, that's the story. Now, the quote. This is you in your own podcast. This is a quote pulled from your first episode. 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. We have the technology to control how fast we age. We can measure that, slow it down, and even reverse it. It's going to fundamentally change the course of human history. I've the [ __ ] chills, man. So, that's a big statement. It's a bold statement. And what I want to do now is walk through what do we know, how do we measure it, and then we'll later get to what we do about it. But, I'm a big believer if you understand the mechanisms, you can make change. What are the mechanisms? Why, for real, why do we age? Yeah. Yeah, so when I wrote my book, Lifespan, um it was a theory um about why we age. And when I boiled it down to its essence, um I realized and I theorized that aging was a loss of information. So, in our body we have two types of information when we're born, or even when we're conceived. There's the one that we all know about. We can get our DNA read. That's the genome. But, there's this other layer called the epigenome. And why is that important? Because if you just have DNA and there's 6 ft of it if in every cell, uh it's just a chemical. It's not going to give you life. What gives you life is the the system that reads the DNA the right way. But, we've got this chemical that's like a a hard disk drive or flash memory that has these letters. ATCG. That's it. Period. They're just four four chemicals that get strung in different order. Mhm. And the cell can write those down, can build those chains, and that's how we copy the DNA. I don't I I run the risk of taking us off track here, but I'm very curious. How Where does it get the letters? The the enzyme or the protein Enzyme proteins synonyms? Okay. So, where does the protein go gra- Is there a bucket of letters like I had as a kid that it like reaches into and grabs one of the letters out? There are. Yeah, they're floating around. And then the literally ATCGs are just around. They are. That's so weird. with the building blocks of DNA and proteins. One are the DNA bases, ATCG. They float around. And because they're they're not just floating around, they're buzzing around. And so an enzyme sees probably 10,000 molecules in a second. It's really quick. And it picks the ones it wants. So, okay, I want an A. And it's it's basing it's looking at the DNA and it says, you need a C right now. And it reaches out, grabs a C. You need a G now. It grabs a G. That's literally what's happening? Yes. That is insane. I cannot believe I've never asked that question. That You're freaking me out. All right, keep going. And how does it know whether it's a G or a C to put down? Mhm. Cuz it's copying the DNA. You've got one strand that has the ACTG. And that that protein will look for what matches the G. And a G always matches a C. And an A always matches a T. So, there are pairs of DNA that make the rungs in that ladder of that spiral, that double helix. Mhm. But you generally you actually need a template. That's why we have double strands. One of them is a template, the other one you then match to that. In the other direction. So, it's not like my fly here, which is a zipper that goes up. It's a zipper that does that as it's being built. Interesting. Uh but we we get that from our parents, right? Without any DNA, there's nothing to copy. Uh getting back to the memory, there's something I I think you'd like to hear. Uh cuz you're very much into uh digital and NFT world. It It turns out that the best way to store memory now is biologically. In a little test tube, we can store all of human information. And we're we're built what we but humanity is building the machines to write down those letters and store all the world's information in order and then the readers is get that information back out. So, why is that important? Because computers don't last for a thousand years, and you can't fit all the world's data in a test tube, but technology is pretty much there to be able to do that. Whoa. Okay, so that's insane. Going back to the reader, the reader is that little um protein enzyme that's grabbing the the matching pairs and building it up, and so all day long it's just like here's a half and I need to match that half. Is that the idea? Yeah. Well, there there are two things you can do with DNA. You can copy the DNA so that the cell has extra chromosomes that then divide and you have new cells. That's copying the genetic material, but then you can also use the gene, um so it's a string of a few thousand of those letters, to make more protein. And so instead of make copying it making DNA, this is where RNA comes in. So, we've heard about RNA-based vaccines, mRNA, is one type. The cell makes the mRNA, it's called messenger RNA cuz it's a messenger, and now that message, which might be a thousand of these letters, floats away from the chromosome, and another machine grabs that and now has its own template to grab not DNA bases, not the ATCG, but amino acids, 20 of them. So, it's programmed to look for these um sentences, basically. So, rather than an individual letter, I'm here for a whole sentence or a maybe even a chapter. It tells me to do something. And is that something to create a new protein? Is that what all of these do? Mostly. Okay. Mostly. You can you can make RNAs and you can make uh protein but and DNA, but mostly we're we're we're, you know, pretty much made of protein. Those proteins are either structural, from muscle, or they carry out chemical reactions, making new DNA, making proteins, making lipids, making energy. Without making energy, both of us would be dead in less than 30 seconds. We need to always be making it. Uh it's quite we're always 30 seconds away from death as you mentioned. Life is tenuous when you get down to that level. Um And so what what happens with aging is that the ability of the cell to know which genes to read goes awry. Those proteins that would normally turn on a gene that makes a brain cell know to be a brain cell get lost. Those proteins instead of reading the brain cell gene will go off and get distracted and start reading a liver gene or a skin cell gene. Okay, so now here's where I think we have to get away from metaphor, distracted, and now get into and I know your theory quite well because I've gone through it so many times. But there's a part of it that I don't understand well and that's the sirtuins. So since we haven't said that word yet today, um talk to me or explain what is the when the the reading of the information begins to go wrong, what happens that causes that to go wrong cuz it's not like the the protein gets bored and starts watching baseball, right? So it's not distracted in that way. But there actually is something going on that we can actually see and understand. What is that thing? Well, so the sirtuins, we have seven of these genes that make seven different proteins in our cells each one. Uh they're very ancient. So the sirtuin actually controls which genes are on and off. Okay, so the spooling of the DNA? Yeah. So So that 6 ft of DNA is not just flailing around in liquid. That would not be life. What the cell does from conception and be before that. Tell people why that wouldn't be life. You threw that off, but that's actually really fascinating. So if the DNA is just a fully naked strand that could be read in its entirety, you don't have life. That isn't self evidently clear. Why wouldn't that be life? Well, you need to organize it very well because we're multicellular. A bacterium doesn't need to worry about it cuz it's just one cell. It knows what it needs to do and it's offspring are very similar. Our bodies are made of a trillion cells and each one literally is different. All right. Even if you measure an adjacent cell, it's behaving slightly differently. But if you take a brain cell, a nerve cell compared to a liver cell, it's totally different. But remember they have that same 6 ft of DNA. So what we need to do as multicellular organisms to survive is to get rid of not rid of but but hide and compact and silence parts of our DNA that are not useful for that cell type. So the reader isn't told, "Your job is to read and recreate liver cells." It's told, "Read whatever is exposed." And there's some other mechanism that says, "Your job is to hide everything that isn't a liver cell." And that's a sirtuin. The sirtuin is the one that hides everything. Yeah, and sir stands for silent information regulator. And that was the clue to this whole information theory of aging. It was right there in the name. Mhm. And what we find is that those spools so if if you zoom let's zoom up on the genome now, you'll see that most of it is compacted cuz most of the genome is is not used. We use a few percent of it. is another word for your strand of DNA. Correct. Yes. So most of it is is bundled up in these little packages. And when we say it's bundled up, is it put in something? Yes. just squished together in a way that's impossible to read? It's really precisely packaged. There are four proteins called histones. Okay, and they make a a circular little ball and they love DNA. So what happens is the DNA wraps around those histones so you get two wraps around one histone and it's wrapped around by a sirtuin. In part? In part, but there are there are enzymes that do this as well. More machines that grab DNA and wrap it around twice, grab another histone, stick it in it next to it, and wrap it around more. So, it's it's like spooling. You're wrapping string around a a ball and then you get these balls on a string, it's called. And that, for the technically minded, is called chromatin. And if you take those balls on a string and then wrap those up into bigger bundles, eventually you get what we call a chromosome, which you can see with your eye, or at least with a pretty weak microscope. Mhm. This is incredible. We start bundling it. We have the sirtuins. Their job is to silence the vast majority of the information on the DNA and then we have this other enzyme that comes in and it its job is to read what is exposed. So, the information theory is you've got the whole all the possible things. Hey, you're an eye cell, you're an eyebrow, you're uh heart cell, you're a brain cell, you're an amygdala brain cell. So, it's like all of these incredibly specific instructions. Mhm. And they're all linked together and so what we have to do is come up with some very intricate clean way of um making sure that the right information is read at the right time. And the solution that nature has given us is this wrapping of DNA bundling of DNA, I think is the word that most people use, to make it impossible to read everything but certain sections. But what parts of the bundle are exposed are epigenetics at work, which are based on environmental cues that we give our body. Well, kind of. Epigenetics refers to all those machines that bundle up the DNA and read the DNA. That's the epigenetic system. It like um in a computer, the code would would be one thing, and then all the machinery to read that code, which is the computer, um is the epigen- epigenome. So, which is kind of complex. You can't say, "Oh, that's an epigenome protein." There There are hundreds. But sirtuins are major players. And they, from birth, say that this gene needs to stay off because it's a liver gene that's working in the shouldn't work in the brain. So, don't expose it. Don't expose it. So, we've got bundles bundles bundles, a big loop. Bundles bundles bundles. And some of these loops are really important for when we're developing as an embryo. Mhm. One of these big loops, it's called Hox, and there are 13 Hox genes, h o x. And they get read in a certain order. The first ones get read and tell the the little embryo, "This is your tail." Uh which eventually goes away in humans, but we have a tail. And then it all is your midsection, then this is your your upper body, then your neck, then your head. That's what this Hox does. Wow. And and eventually, once you're born, it gets bundled away. Okay, we don't need those anymore. We've built the body. It's got a head and a tail. Mhm. Hox is there. But when we were looking at older cells, um in mice and in humans, guess what? That bundle of Hox developmental genes started to open up again, cuz the sirtuins got moved away and did some other things during aging. And now we've got genes that tell us head to tail coming on in our body when they shouldn't. And that's part of the problem with aging, which is genes getting turned on when they should be kept off for decades. Uh and then cells start to get confused. Does the revealing of the wrong things, that unbundling, does it happen because the sirtuins are not re-bundling them, or are they actively going in and unbundling things that they shouldn't? Well, what we think is happening is that they physically move away to other parts of the DNA molecule where they shouldn't normally be. That's the distraction. They get called away to do other things. They are very good at handling emergencies. These are emergency survival proteins that they've two roles. One is to make sure that everything's good every day, super optimal health, stay young. But they also through, I think, evolution and very early in evolution, their role was to put out the fire. Uh and so they they go away. They actually leave where they should so that they're bundling and for a few minutes until the emergency is fixed, they actually float away, go repair something. So, it might be a broken chromosome somewhere else over on another chromosome. They go there, they fix it, and then somehow they find their way back to make sure that bundle is, you know, maintained. But if you keep doing that, and we every cell gets at least one broken chromosome every day. Wow. And that's so that's trillions in in body every day. These sirtuins get, I call it distracted, but basically they're doing this other role, putting out the fire, and then coming back. If you do that for decades, eventually some of them they're lost. They don't find their way back, and these loops that shouldn't of DNA that should never be turned on start to come on. Mhm. I may have been wrong then. Maybe distracted isn't a metaphor. It's they literally have so much work to do, which would make sense. And so now, to actually use a metaphor, you talk about, for people that know what a CD is, uh that you would get these scratches in your CDs, and it would cause the songs to not play right. It was really obnoxious, actually. And that idea of aging, you're going to get these scratches. You're going to get the the fires that have to be put out. The sirtuin is going to get busy dealing with breaks and whatever. And so, it's got to go handle that, put out that fire, deal with that break. Um and as we age, there's an accumulation of damage that we do, and so these things are constantly busy, and therein lies the information theory of aging, that the sirtuins are too busy to maintain the integrity of the bundling of the DNA in a given region, which will be different everywhere. But, it's no longer holding to the integrity of just be a brain cell, just be a liver cell, just be a pancreas cell. And the readers are only instructed to read what's exposed. And so, now if your brain cell also has a little bit sticking up for skin cell or tail or whatever, now all of a sudden you have a dysfunctional cell in your brain. That's aging, as I see it. That cells lose their identity. We call it ex-differentiation, which is an old theory, but this is what we we've given a name to it. And so, cells when you're developing from an egg, fertilized egg, to a baby, to a an adult, that's called differentiation. Okay? Cells get their identity. The bundles and loops get established. That's youth. That's health. Ex-differentiation is what happens after that. Mhm. Uh but then the question is, with the scratches on the CD, can you get rid of them? Can you polish them? Can you get those bundles that have been exposed to go back to where they came from and reset the age of the cell? And get the brain to wake up and remember, "Oh crap. Oh yeah, I forgot. I am actually a brain cell or an eye cell." So, this was the big question that I had after figuring that other stuff out we just talked about, was is there a backup copy of a youthful epigenome? What does that mean? Does the cell know that that loop that's come out Mhm. that it needs to go back in? How do you know You know time? Well, we inherited that from our parents, that pattern. Does it memorize that like, okay, if I'm a sirtuin, am I only floating around a given area? So, I know, hey, this is how it's supposed to look, so we get some signal that it's like, okay, we're done growing, head, tail. Bundle those back. And now this is what it should look like forever. And how would it know that? Well, what it what the cell does, in part, is it put puts chemical tags on regions that need to be bundled up. Known as methylation. That's DNA methylation. Right. Okay. And you can also put methyls, these little chemicals, hydrogens, uh on a on a carbon. You can also put them on those bundling proteins called histones, which we talked about. Beads on a string can be modified. But the most important one for long-term maintenance of the epigenome is this DNA methylation. Uh once you put a DNA methyl, carbon, hydrogen, hydrogen on a DNA uh molecule, which it goes on the letter C, not all four, but mostly it's on the C, little bit on an A, uh then that tags that gene for a certain behavior. Mostly it means shut that gene down and leave it alone. But over time, possibly due to sirtuins moving away, perhaps other things, uh that DNA methylation pattern across the genome, there are millions of these little tags, starts to go away. They're dissolved or broken down somehow. Well, there are enzymes called DNA demethylases that take them off. And they they start to do that job when they shouldn't. Why would we do that job ever? What's the use case for that? There must be one. Uh yeah, well, cells that come from stem cells need to grow into different cell types. Mhm. Uh we have stem cells that grow skin, stem cells that grow new cells. At all times. Yeah, we need those. If we get damage, we need to rebuild. If you If I cut part of your liver out, it'll regrow into a a new liver cuz you've got stem cells. Our gut is always replacing itself cuz it's it's hitting all sorts of things down there. Mhm. So, they're little stem cells. But, for those stem cells to rebuild five or 10 different other cell types, you need to be able to alter that pattern of DNA methylation even when you're an adult. But, that system goes wrong in a way that doesn't make us healthier. Does the opposite. It makes cells more stupid. Cells forget what type of cell they should be, and that's ex-differentiation. But, now the question is can you redifferentiate? Can you get them to go back to the way they were? as stem cells? If stem cells are the ones that carry that like pluripotency of like we could become anything cuz it sounds like I mean to your point about the liver cell, there are already some that are doing this that know, "Ooh, the liver's gone. I know what I need to do though to rebuild it." Yeah. And so, is that just that that mechanism is limited to the liver and the intestines and therefore it's not doing that job elsewhere or Well, we could have we could have reversed aging just by making all cells a stem cell. We have the technology to do that. That was the 2016 Nobel Prize. Shinya Yamanaka, uh Professor Yamanaka, discovered that there are four genes that if you put into adult cells will erase all their identity, all those loops and bundles would just get erased, those methyls would get erased, and then you have a primordial pluripotent stem cell. And any high school student can do that these days. Just put four genes into them. That's insane. Okay, but you don't want to do that cuz you would become the world's biggest tumor. That doesn't sound fun. Yeah, that's not age reversal. That's instant death. Um and if you do that in a mouse, I I we haven't done much of this, but there are labs that do this. Uh the mice die within a couple of days. They just get riddled with tumors. Well, over time if you do it a little bit, they get tumors, but if if you turn it up a lot, then the cells just forget what to do and the mouse dies. Even without tumors. The cells just need to know how to work. So, you don't want to do the Yamanaka treatment in a living thing other than a cell in the dish. But, we did stand on the shoulders of uh Professor Yamanaka because we thought, what if we could find a combination of those genes that doesn't take you all the way back to zero to be a stem cell, but it could take you back to an earlier state that would never go back to being a stem cell cuz we don't want to get cancer while we're getting younger. And so, it'd be like uh polishing the scratches on your CD, but make sure you don't do it too much cuz you'll erase everything. You got to maintain some surface. Uh and it it was a few years of work and I had a student in the lab, uh brilliant, hard-working guy, uh Youancheng Lu. And Youancheng was pretty frustrated. He kept putting genes into these old cells in the dish, and they would turn cancerous or they would die. That was one of two uh uh outcomes of this uh this binary. So, they would either replicate uncontrollably Yep. without remembering when to shut off or they just uh give up. I'm out of here. This is too crazy. Uh but, we hit upon a magical combination. And he was literally about to quit his PhD. He said, "I can't do this anymore. Woah. I got to change topics. I'm I'm I'm out of here cuz it's never going to work. David, you're insane. You can't partially reverse aging. It's not going to work. Um and he had every reason to believe that. I mean, how crazy is it that the cell would remember, okay, this gene here needs to go back to that state, and this gene over here needs to do that. How could there be a memory in the cell of youth? And we didn't know Nobody knew until we did the experiment. And the experiment that I said he should do before he quits was to don't use all four of these Yamanaka genes. And And in fact, one of them causes cancer. We know that. So, it didn't take too much of a genius to say, "Look, just leave out that gene. It's called C-Myc." Uh and see if the other three would work. Uh and no one knew if three was sufficient. Most people thought it wasn't. And he put those three genes in and they're called O for Oct4, Sox2, S, and Klf4. OSK. And if you're wondering, what do these genes actually do? They make proteins that turn genes on and off during development. All right? Starting to see the theme here? And they work with sirtuins and those DNA methyls. All right. So, he put in those three genes into old human cells in the dish and they they looked fine. They kept growing. They didn't turn into a tumor. They didn't grow uncontrollably. And they didn't die. And then we measured the patterns of which genes were on and off. They resembled a young cell again. And that was a eureka moment in the lab, I would say. We could reverse aging in the skin in a dish. But the real experiment that changed everything was he then made a virus, a domesticated virus. We call it an AAV. Uh and he could now deliver those genes into a living organism, which in our case is typically an old mouse. And he did a very clever thing. He He said, "I want to work on the eye." His father had a biotech company that that is trying to solve um blindness, cure blindness. And I said, "The eye? You're kidding me. I know nothing about the eye. Blindness has never been cured. Uh you know, how's how's it going to be possible to deliver this into an eye? Let's just do the liver. I understand the liver. It's It's easy. We'll just get it in." He said, "No, you trust me. I've got a good feeling about the eye." like, all right, fine. And I've I've learned over the years if somebody really wants to do something, let them go do it and usually they're right. That there's this thing in science where you have this gut feeling but you're not really sure where it's coming from. There's a spirituality. Yeah. And I've learned to tap into that as do students. It's one of the things I teach them. So he took an old mouse. Actually, the first experiment was he actually caused the mouse to become blind. And then he put the virus into the eye just straight in. Turned on his three Yamanaka genes, OSK. Uh And then he looked four weeks later at what happened in that eye. And he found out that the optic nerve that was damaged started and it for the most part grew back. And that never happens. Optic nerves don't grow back. If you go blind from damaging your eye, you're not going to see again. Same with the spinal cord, same with your brain damage. The central nervous system with nerves in your body does not grow back. It's a fact of biology. And here was Wang Cheng showing he was able to do that. So why is that relevant to aging? Because when you're very young, if you damage your optic nerve or even your spine or your brain, it can grow back. But we lose that ability as we get older. And here was Wang Cheng taking the eye back so young that it could regenerate and function. But then he did something very clever. He then put it into a mouse that we gave glaucoma to. So pressure in the eye damages vision. And then he also did it to old mice that had just aged and were blind as well. And he started to cure blindness with his treatment. And we could now measure the age of those nerve cells and they were literally younger. And those those bundles and those loops, we can measure those and the DNA methylation, the chemicals, we can measure those. And he was sending them back 75-80% of their age, but not to zero. Or not 100%. So, he sent me I I don't know if I still got it on my phone, but it's recorded in my book because uh he sent me this text that said, "David, I got to show you these photos." And he sent me an image of the nerve, which is a long strand. It's orange. Uh we stain it orange so you can see it. And the damaged one just looked like there were a few dead cells, but the one that was reprogrammed was bright orange. All the cells, almost all, had survived the damage, and then they started to grow back towards the brain, from the eye to the brain. And you could see it's like a jellyfish tail. And he sent me pictures of that. And he said, "I thought I was going to fail, but do you see what I'm seeing?" And I said, "Yeah, I see it." So, what are you seeing? And I said, "The future." Wow. And that is literally what we saw. So, now we know you can reprogram other tissues. You don't doesn't have to be the optic nerve. It can be the retina. It can be the cone cells of the eye. Uh and so we're re- reversing aging of the eye. That's not hard at all. But we can reverse the age of the liver, the skin. Other labs are doing the spleen, thymus, Jesus. through this method. So, it's it seems to be a somewhat, if not universal method of resetting the age of the body safely. Safely is the key. Mhm. And because I started a biotech company called Life Biosciences that wants to cure blindness and other age-related diseases using this method, uh for the last 2 and 1/2 years we've been doing safety studies in mice, and now we're in non-human primates. And those animals are fine. We can blast these three genes in the animal, and they're fine. They don't get tumors. Their eyes are healthy. You don't get uh malformation of the eye. So, it's great. We lucked out. Humanity lucked out that we can actually do this, and that there's a backup copy of youth in each of our cells that can be tapped into. That's crazy. Do we know what is going on that allows it to realize what it's supposed to look like, what the bundling of that cell is supposed to look like? Because that is what's going on, right? It suddenly remembers, oh, these are sticking out, they shouldn't. Right. And how do we go from it has so many fires to put out that it's just roaming all over the place and it can't get back? How do we sort of give it that breather to come back and go, not only do I remember how to bundle this, but I've got the time to dedicate to bundling it correctly again? Mhm. Well, the bundling it it takes a few days um and a week, you're getting pretty close. A month, you've now got vision back. Um and then actually, by the way, if you stop the treatment, we now I didn't know this when we talked last, but when you stop the treatment, it's long-lasting. That mouse will still have young eyes 6 months later. And I always not I I still do. I want to test how many times can you reset Mhm. Uh cuz if it's if it's once, it's interesting. If it's 100 times, it's super interesting. No joke. Uh and we we couldn't do that experiment cuz the mice were dying from old age with super young eyes. So, we got to reset once, but we'll Now we're resetting entire mice. Uh and by the way, you mentioned earlier the quote from my podcast, we can actually control aging in the other direction. We now know how to distract and move the sirtuins away. We cut chromosomes and let them move away. Uh and those gene packages open up the same as aging. So, we can make a mouse poor things, but we can make them age rapidly. So, if you were to come to my lab, I could show you a mouse that's a twin and it's brother Let's say brother and sister, the brother will be 50% older than its sister, but they were born on the same day. Woah. And now we're reversing the age of those mice. We're have a our our main mouse is called Lisa by coincidence, and we're taking Lisa and we're going to rejuvenate her uh so that she hopefully gets back to being like her brother. her and now you want to see if you can take her back. Jesus, man. Like this is I mean, you said that this is going to be remembered as the moment that human history changed. I mean, but that's crazy. If this ends up working out, like this is really bananas. 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 uh 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 where we run out of energy as we get older. There's a list, a long laundry list. And most of the people in in my field have said, "Okay, we've we've figured out aging. We've got this list. We put it in a nice pie 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 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. Uh 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 to store movies. Um 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. Uh, in the same way that records and uh, 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 um, code, but what is analog about the epigenome? This Reading about it in your book is the first time that um, I began to imagine it in a different way. Well, it's very clear that 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 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 could 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 read. 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 we're 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. Mhm. And then our essence 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 the packaging's 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. Cuz it's going to die if that if it doesn't fix it or worse uh 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 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 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 articulable shapes and they actually move. Is that accurate? Um that's essentially it. It's it's super exciting when you realize that proteins aren't just blobs or powders in the cell. They're actually little 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 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 you we've got about 20,000 different types of enzymes in the body. Uh 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 are doing the ping pong game. And without those, we're screwed. We basically will will age more rapidly. Conversely, what's really exciting is 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 Pac-Man doing this, you exercise, you diet, take 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 Pac-Man 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 uh more Bob the Builder and it's going around tearing some things apart, putting some things back together? Yeah, it's it's more like Bob the Builder, but it I think a good example for at least the enzymes that we work on called sirtuins that protect the body. They're they're like a little tiny pair of scissors. They chip up clip off chemicals called acetals. And in doing so, when they clip off the acetals 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 that hose 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 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. That makes them go in 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, yeast 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. 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-tooth cats again. Got to Got 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. 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 this 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, no. What you actually want to do is stress the system." Won't that stress of I just ran from a lion, a [ __ ] I'm starving, won't that begin to stack up and become problematic? Well, actually, if if you step on a snail, it's going to die. So, there there's certain amounts of stress that 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 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 that's the secret. Then let's really dive into that. So, I'm guessing you're talking about where 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 as 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 overfeed, Yeah. um, they actually have the same benefits as the animal that has a chronic deficit of calories? All right. Well, 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, our my colleagues, um, discovered what 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 much as they want, and they do. They eat about 90% of what a mouse having free access to food would eat. Uh, 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, um, 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 comes back to bite you when you're old. What we think is that these repair systems are a good one young. So, the idea is it's called antagonistic pleiotropy, and I think it's right, and that is that we evolve to stay healthy and alive and fit till we're 40, and then the the forces of natural selection decline after that cuz we've essentially bred. Right. We've often had children, but we don't need to stick around beyond that, and building a 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 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, and 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 in middle of the food chain. Only now we we actually barely have a chance of dying before 70 or or 80 unless we're unlucky. You know, give us another five million years of evolution, we could evolve 200-year lifespans. 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. You and I have to eat 30% more calories every day just to make our normal amount of ATP. And you go, "Well, why would I do that?" Well, it turns out generating heat is what those calories do. And you and I are warm-blooded animals.