The Most Surprising Longevity Discoveries | Lifespan with Dr. David Sinclair Rewind

Welcome to Lifespan, a show where we discuss the cutting edge science of aging and how to live healthier at any stage of life. I'm David Sinclair, a scientist and professor working on understanding why we age and discovering new ways to slow and even reverse the aging process. On this show, I show an insider's look at the latest from my lab, the field and what's just around the corner. Hey everyone, welcome back to Lifespan. One of the most surprising things we learned in season one is that aging is not as fixed as we once believed. For most of human history, we assumed that aging was just the passage of time, the number of times the earth has gone around the sun. You're born, you grow up, you get older, and eventually the body wears out. But the science is now telling us that aging is a biological process, a universal one in every tissue that can be measured, slowed and in some cases, parts of it can even be reversed. In the first rewind episode, we focused on the practical side of longevity, the things you can do in daily life to help you live longer and healthier. I encourage you to check it out if you haven't already. But knowing what to do is only half the story. The deeper question is how and why any of it works. So, in this second rewind episode, we're going back to the most surprising longevity results that Matthew and I covered in season one. These are the moments that changed how we think about the biology of getting older and what may be possible as we learn to measure and modify that process. You'll hear about animals that live far longer than expected, genes that can dramatically extend lifespan in simple organisms, and biological clocks that can measure how old your body really is. We'll also revisit some of the more unexpected findings from season one, including why hyperbaric oxygen, heat, cold, red light, and even small molecules teach us about the body's ability to repair itself. We'll see why even small changes in the rate of aging could have major consequences, not only for you, but for medicine, healthcare and society itself. These are the discoveries that make longevity science so exciting because they show that aging is far less predetermined and far more controllable than you ever thought. Every insight in this episode has been reviewed against lifespan's scientific standards. The science we're revisiting remains accurate, relevant, and important today. This show is part of a broader effort to change how we age. I've launched lifespan, a global community where you can connect with me and with other experts, access evidence-based insights, and step-to-date with the latest advances in longevity science. I've also brought on a team of PhDs to produce lifespan magazine, a rigorous and accurate resource for people who want to live better and longer. lifespan is also proud to support medical research and the careers of young scientists. We here to support one another on our individual health journeys and discover what truly works together. To get involved, visit lifespan.com to sign up for early access and get bonus show content and access to lifespan magazine. There will also be exclusive asking anything sessions, a book club, and much more to come. Of course, this show is for informational purposes only, and it's not meant as medical advice, so please consult a qualified healthcare professional. The views expressed here are my own, and they're not those of Harvard University or Harvard Medical School. The full disclaimer is in the show notes. Don't forget to click the subscribe and notify buttons to make sure you don't miss any of our new episodes. There's no law that says we have to age, and we now are learning not just what causes aging, but how to reset the body so that it's young again. And we don't know how many times you can reset the body, but I'm betting that it's more than once. So what happens in a world where you can reset your age multiple times, maybe hundreds of times, that's when things get really interesting. And I think when people look at this podcast and listen to it a hundred years from now, they're going to say, yeah, that was the moment when humanity really changed. Aging is now controllable. We have the technology to control how fast we age, we can measure that, slow it down. This has never happened in human history before. If you look across the animal kingdom, there are all kinds of animals that age at different speeds, at different rates. Even though the root source of aging is the same for everything, we age at different rates. And people say, what gives you confidence that we can even live five years longer? Well, if we look at the animal kingdom, first of all, there are plenty of species that live that long. There is no reason why we can't do what they do. And if we learn how they do it, we can apply that to ourselves. So one of these animals that I know you're sort of fascinated by right now. In fact, there's a picture of them on your computer screen right now. One of your children works on these. Yeah, more Alex, our oldest child. These naked mole rights, they're fascinating. They're weird looking. They got sharp teeth and the rest of the body is long. It looks like a condom filled with war. Yeah, they're really weird. But what's exciting to work on them and Virgo Bonova is the professor that Alex works with. They found that these animals have particular traits, biologically, molecularly, that allow them to live decades longer than a typical rodent, which might live a bit over two years, rats over four years. That's similar animals and one lives. How long does a mole rat live? Over 30 years. Over 30 years and then normal rodents or other rodents, most rodents live a few, right? And what's important to realize is that there's a reason why that is animals that don't have a lot of predation, whales, mollusks, sharks, mole rats, underground, they don't get eaten. So they can put their energy into building a long lasting body and actually as a consequence, they reproduce slowly as well. But what's important is that you can build a longer live body and we can do that too. We can engineer ourselves. We can learn from these animals by studying what makes them live so long. We've got organisms that have learned how to live a lot longer than we do. Right. Well, we're essentially upright whales. That sounds crazy, but at the molecular level, if you look at the biochemistry, we're only separated by 40 million years, which is a blink of an eye in geological time. We actually could live as long as whales. There's not that much difference between us. And a whale lives, we know bo-head whales can live for hundreds of years, more than 200 years. We now have the genome of these animals, we can see that they have multiple copies of what we call longevity genes, some of which we discovered when I was in my 20s, these are genes that protect the body. Longevity genes actually get turned on by adversity and there are ways we can tweak them. But whales naturally have multiple copies and higher levels of these longevity protective mechanisms and the bristlecone pine has just warping amounts. And that's that connection that you're making there. You're like, oh, look, we see this in a bristlecone pine, we see this in whale. And oh, by the way, this gene also exists in humans. Yeah, we're not that different from a banana actually. Genomes of 40%. You're not that different from banana. Well, I'm not going to go there, Matt. But the important thing is that when you study other organisms, whether it's a banana or a yeast cell or a warmer fly, we can learn lessons about biology. And especially about aging, we can learn more about aging from a yeast cell, then we can about Alzheimer's or cancer. This is why you're dismissive about people's dismissive nis about like only in mice when people say, oh, we discovered this and people go, oh, only in mice. There's a lot we can learn from mice. Well, we can. And aging is one of these universal things. And what really is remarkable that we've learned in my library over the last 20 years is that the same genes that control aging in yeast work in worms. And flies mice and even humans. That's a big deal. We didn't know that 30 years ago. There are hundreds of longevity genes that are known, but they fall into three main buckets. The first one, it's called mTOR. It's a little m for mammal and TOR target of rapid mice. And so mTOR is a longevity gene that makes a protein that senses amino acid. So when you eat a big steak, mTOR activity actually is activated. And mTOR now says, okay, I got lots of protein. I'm going to make muscle. I'm going to burn energy. And that's why when you eat a steak, you actually, you build up muscle more than if you don't eat a lot of protein. Mice that are given a drug called rapamycin, which is used to suppress the immune system in patients. But you can take low doses as a human or give it in low doses to a mouse. Those mice live dramatically longer, even if you give them rapamycin when they're 20 months of age, which is a really old mouse, they still live longer. So low activity of mTOR is a signal that times a tough, you don't have enough food, hunker down, build a stronger body, survive. And the outcome of that is longer life for these mice. But it turns out it's not just for mice. You give rapamycin to a yeast cell or a fly or a worm, they also live longer. So you can tap in with these drugs into this universal longevity program, one of which is mTOR. Bucket 2 is AMPK. It's called AMP activated kinase. And in this case, we don't want less of it. We want more of it. We want to activate AMPK. So how do you do that? You actually eat less. You fast. And that'll turn on AMPK. It'll do a few things. It'll make your body more sensitive to insulin, suck the sugar out of your bloodstream, which can be toxic if it stays high. But it also ramps up the energy producing centers of the body, these membrane filled bags, which are actually ancient, back to the day. living in our bodies called mitochondria. To help keep this show freely available, lifespan partners with a select group of companies that I believe in, and who also share our commitment to evidence-based science and supporting medical research. One of those partners is Ketone IQ. I've long been interested in how fasting may affect brain health, and you've likely heard of ketones in the context of the ketogenic diet or in fasting. And by cutting back on carbohydrates, what you're actually doing is flipping a switch that tells your body to start producing these molecules as an alternative energy source besides glucose. Ketone IQ is a drink whose active ingredient is a ketone precursor called R13 butendial. Now you don't have to remember that, but what's interesting is that your liver converts the drink into beta hydroxybutyrate, which your brain and your muscle can use for energy. There's interesting research into the effects of ketones. In 2012, for example, the first study of its kind showed that consuming an exogenous ketone raises blood beta hydroxybutyrate levels to that typically seen during a long fast or a ketogenic diet. Then in 2018, a study published in Alzheimer's and dementia asked what fuel can the aging brain still use. As cognitive impairment progressed, the researchers found that the brain became less able to use glucose, its usual fuel, and what actually happened was that ketone uptake remained relatively preserved. That's really important because it suggests that even when the aging brain struggles to use sugar for energy, it can probably still use ketones as the alternative fuel. Then in 2021, a randomized trial testing the effects of a ketone on adults with obesity showed improved processing speed, improved working memory, and more blood flow in the brain, which is increasingly important as you get older. Finally, I want to mention a study from 2022 where researchers gave participants ketone monoesters before a soccer match and measured their reaction time and other aspects of cognitive performance. The ketone supplementation helped reduce cognitive decline during fatigue. That's also one of the reasons that I take ketone IQ often before I record this show. If you would like to try ketone IQ, we're offering our audience a 30% off discount for your first monthly order at ketone.com/lifespan. Or at the checkout, just use code "lifespan." And the gene that you work on, that you've been working on for a really long time? Well, it's a family of genes. We have seven of these, what we call sertuins. We link them to aging when I was a postdoc at MIT back in the 1990s. And what we're looking at as a group was what can make yeast cells live longer? And there was one mutation that led us to a gene called sertu, SIR2, which stands for silent information regulator number two. And information is the key. But this set of sertuin genes, this family, has been shown in yeast and worms and flies, mice, and now humans, to be a really important central regulator of longevity. We showed, now going back to 2005, that fasting activates the sertuins. And later we showed exercise activates these genes. So a lot of the things that we're told by doctors to do to live longer and be healthier, we think acts through the sertuins in concert with these other two sets of genes we just talked about. How do they work? Remember I said sertuins are, SIR stands for silent information regulator. So what does that mean? Silence is the bundling of the DNA, silencing them. So you don't want the liver gene on in the brain. Information is the DNA and they regulate it. So sertuins, it's in the name. And in fact, in the 1990s, that's why I've been working ever since on trying to understand and test my information theory of aging, part of the problem with aging we think is that that beautiful packaging of the DNA that allows a cell to remain a skin cell forever or brain cell essentially forever is lost. You start to get this unspooling of the DNA and genes that shouldn't be on start to come on over time. Genes that shouldn't be readable are now readable. And so you have like all this extra information floating out there that the cells can read. And because the cells are now reading large parts of the code instead of the very specific parts of the code, they get confused. Right. And we call it x differentiation. Differenciation is the common term for cells becoming a certain cell type. And we've coined the term x differentiation which is essentially cellular confusion. They become a more of a generalized cell type rather than a specific one because genes that shouldn't be on start to come on over time. And that we think is a root cause, if not the root cause of aging itself. You believe that x differentiation is the root cause of many, if not most diseases? I don't just believe it. I think it's now a fact. When you look at Alzheimer's disease and unfortunately up until the last few years, we were treating it at the end stage of the process of aging, which results in plaques and tangles and dementia. But the process that led to that disease was happening from birth and that's aging. So Alzheimer's, just to take one example, is an age-related disease that's not just age-related. It's actually 90% of it is caused by the aging process, this unspooling, this x differentiation. If we were able to slow that down, you'd have Alzheimer's much later. And now we're showing in my lab, we can reverse the age of a brain in an animal. And when we do that, we're showing and we will continue to test this, that those diseases go away. Proving that those diseases are actually caused by aging. It was in 2013, a paper came out from Steve Horvath's lab, and there was another paper by Greg Hannum, that showed that if you measure the chemicals that are controlling this bundling and spooling of the genome to specify cell type, there are certain sites on the genes that you can measure. The chemical is specifically called DNA methylation. It's very simple, it's just a carbon with 300 genes. This chemical cells add to the DNA, stick to the DNA, as you're developing in the womb, to make a brain cell different than a liver cell, different pattern. But over time, there are changes that are predictable, and they change in a linear fashion, so that if I took your skin cell or your blood and I measured the DNA methylation pattern across the genome, across that six feet in one cell or in thousands of cells, which is how we do it, I can then plug that into a program and it'll spit out your actual biological age. Not your birthday candles, which is based on how many times the earth has gone around the sun. It's how old you really are. So theoretically, if I wanted to check my biological age every week, I could do that for $50 a year, essentially. Exactly. And eventually, it'll be a little home device. You can do it every morning if you feel like. And your argument is, and I'm on board with this too. This is far, far more important to our understanding of our general sense of health and our general state of propensity for disease, and then our chronological age ever was. Right. And we find that people who haven't done the right things, who haven't exercised and haven't maintained a good diet, have an older biological age, and we'll die sooner because of it. We can now measure the aging process with accuracy, which is, it blows my mind that we now have our biological credit score, which we can, by the way, we can alter. Aging is malleable. That number doesn't stay the same, and it doesn't have to continue to tick up every year. And in yeast and mice. Well, and in humans now. We've just discussed how blood-based biological age testing can reveal what's happening at the cellular level. We're also learning that different parts of the body age at different rates, what we call tissue-specific aging. This means that physical signs of aging, especially in tissues like the skin, may also provide important clues about a person's biological age and overall health. I think most people can picture their elder self. And when they do, they see their skin. It's a little more wrinkly. It's a little more saggy. It's a little thinner. And this actually means something more than just appearances. And we know this from this 2012 study where researchers took the photos of about 300 elderly people. And they gave them to another cohort of people to rate. They rated for the age. Is that the Lothian birth cohort, Nambra? Right. So they looked at people from 1921 onwards. And it was fascinating. They rated them for a bunch of things. They're age, they're health, attractiveness, facial symmetry. This is just based on the appearance on the photograph, by the way. No, you're not meeting these people. You're not taking any tests. We're just looking at their photos and saying, "Are they healthy or not? Are they old or not?" So what did they find? That if you follow those people out seven years from the time that that photo was taken, there was a really high degree of predictability that the people who were rated as older looking. Whether or not they were actually older chronologically or not, if they were older looking, they were more likely to die. There wasn't correlation between these people's appearances, even though that was predictive, and their biological clock. But there's a distinction. that needs to be made. - Well, they were measuring the blood clock in that case. And so what we've learned since is that their various tissues have different clocks. And it helps to have a specific clock for that particular tissue. So that others have since gone on to make skin clocks. And they seem to work better for measuring the age of the skin. - And Mariana Baroni, who's a friend and colleague of yours from Brazil, she let a study that was published in 2020 showing that when you do this, when you build this epigenetic clock based on methylation of skin cells, it does predict biological age quite well. - It does. And there's a good reason why skin is gonna age probably faster than the rest of the body, though it's still a good indicator. And that is that it's exposed to the elements. We know that if you grow up in Australia, like I did, that the UV light is going to create DNA damage that accelerates the epigenetic changes that lead to aging. So someone like me is gonna have probably older skin than someone my identical twin if they had moved to Norway. - Aging isn't just a set of outward changes we see in the mirror. Those, of course, are just the visible symptoms of a deeper biological shift happening within ourselves and in our tissues. And one of the biggest questions in longevity science has been what controls that process? And can we slow it down or even restore it to its youthful state? - There's a genetic pathway that gets triggered by low energy. And these genes called sertuins, they respond to low energy, they respond to other stresses as well, such as high heat, low amino acids, high salt. The sertuins will get activated by these, what we call, "hormetic effects." What doesn't kill them makes them stronger. And in this case, low energy lead to the activation of these enzymes called sertuins. - What's actually happening with the sertuins, when yeast or any other model organism is calorie restricted, is fasted. - Their role is to extend the lifespan. So what they're doing down at the very minute part of the cell is they're protecting DNA and making sure genes stay on when they should be on. But what's happening to boost their activity during caloric restriction, this low glucose level. - We have a little better understanding now of how sertuins are turned on by fasting. We talked about two other classes of longevity genes, MTOR and AMPK. Do you want to go really briefly through how these genes are impacted when we restrict calories, when we fast? - The first one is MTOR, which stands for mammalian target of rapamycin. What we know from many animal studies, even in yeast, if you down-regulate the activity of this MTOR protein complex, you get longer life. Why? Because it's activating a process called autophagy, which recycles proteins. So when you're hungry, this autophagy will get all the old proteins, put them in the recycling bin, and then bring them out as fresh proteins. And that seems to be really important for longevity. In fact, even if you just inhibit MTOR and stimulate autophagy, that's sufficient to extend the lifespan of flies and even mice by dramatic amounts, even 30%. - So in MTOR, we start with fasting, we get longevity. In sertuins, we start with fasting, we get longevity in AMPK. - Same thing. - Same thing. - But in a different process. Exactly, it's doing something else. And in this case, when you're hungry, AMPK will go up. AMPK, if you're wondering, stands for AMP activated kinase. And that's just an enzyme that responds to low energy. So when you're hungry, you'll make more of it. And one of the main things that it does is it makes more mitochondria. We lose mitochondria as we get older. And when we exercise, we get more. And this is a way of artificially stimulating that production. Why do we need more mitochondria? Well, they're important for metabolizing things that you eat. But one of the main things that they are used for is to make chemical energy. So when you activate AMPK, you'll feel better. You'll have more energy. And you also fight aging. - There's these large populations and subgroups of populations all across the world who have fasted as a part of tradition and culture for hundreds, thousands of years. - Right. Well, let's name some of them. - The genes, the genes in India. - And the Christians fast. There's Ramadan for Muslims. These are not just coincidences. These aren't just religious practices. It's clear that humanity has figured out that you feel better, you look better. You ultimately are disease resistant. You might even help cure diseases by going through these periods of being hungry or at least not having food in your tummy. - Now let's get into these really interesting like sort of gold standard studies. There is one out of the Baylor College of Medicine. It was run by Isom Indicoglu. And it showed that fasting from dawn to sunset for four weeks improved blood pressure, reduced BMI, decreased weight circumference, and it upregulated DNA repair proteins. This is what we saw in all these model organisms as well. - Yeah, there are dozens of studies showing that peer to fasting is beneficial to people who are obese. Not just because they lose weight, but they turn on their body's defenses. They become more insulin sensitive and their glucose levels come down. Also showing that people of regular weight like me can benefit from fasting. There's a number of studies there. But what's really interesting is that certain diseases type one diabetes, multiple sclerosis, even cancer. Those diseases seem to also benefit from fasting, including when you combine chemotherapy with fasting. You get this double benefit for many types of cancers. Let's go through the diets. Okay, so there's a fasting mimicking diet. Walter Longo, colleague of mine from UCLA, is a proponent of that. Walter's done some great work over the last few years he and his group have shown that on this fasting mimicking diet, which they can send to your home, that actually helps cancer patients survive and get over chemotherapy quicker. Again, more evidence that fasting is good, not just for longevity, but for diseases. So that's one. The next one, let's talk about, which a lot of people call intermittent fasting, we'll just call it fasting. This is a period if you go longer than a day. Some people do three days, some people go for a week. I wouldn't go longer than that 'cause then you'll start chewing up your muscle which you don't want to do. But these long extended periods are doing a real deep cleanse on the body. And turning on that autophagy, that process of recycling proteins very deeply, especially once you get beyond the three-day mark when your metabolism switches into what's called shaperone mediated autophagy, the deep cleanse. And then there's time restricted feeding, which is what I do, 'cause I'm not very good at going beyond 24 hours. You wanna have at least 16 hours of not eating, or not eating very much. And not everybody's gonna respond the same way. Like you said earlier, we all have different lifestyles. We've got different genes. Jim Nelson's work's been sort of informative in this. Yeah, so Jim did an important study in mice, again, not humans, but it tells us that genetics is important. 'Cause he took very similar mouse strains, strains of some called black six and then some white ones. And he crossed them together to make of genetic diversity, a colony of about a hundred different types of mice, and put them on the standard caloric restriction protocol, which by recollection was close to 35% of what a mouse would eat, given food all the time, ad libidium we call it. And about half the strains of mice lived longer. And then about a third of what the remaining ones lived shorter. And that was a shock because we thought caloric restriction always works. That's not true. It can depend on your genetics. And we've now learned that some strains of mice and probably humans as well are much more sensitive to this diet, these types of diets. And you probably wanna do it a little less than someone else. And you only do that. Know that if you try it on yourself and measure things. If you've listened to this show or heard me on stage, you've probably heard me say that you can't optimize what you don't measure. That's what we do as scientists. And it's true also when it comes to body metrics. Many people only measure their total body weight, if anything. But this only tells a small part of the story. You don't know if you're losing fat or muscle, or even where the fat is being lost from. For instance, let's talk about visceral fat, the evil fat that sits around your organs, and is associated with increased risk of cardiovascular disease, diabetes, and death. Getting rid of visceral fat or at least minimizing it can have a strong impact on your long-term health and longevity. So how can you measure it? Widdings, one of life spans partners, make some of the coolest devices that you can measure yourself with. Watchers, a blood pressure monitor, and advanced bathroom scales. I've actually been using Widdings' devices for over 13 years, since they first came out with their Wi-Fi scale. I've got all the valuable data on my scale and also on my phone, along with actually those of my kids as they were growing up. The Widdings body scan scale can help estimate muscle mass, fat mass, visceral fat, among other things. Let me show you what my body looks like in 3D, my digital twin on the Widdings app. So here it is. You can see at the bottom here, changes in lean mass, visceral fat, bone mass. And if you click on that, up comes my digital twin spinning around here. And so the numbers speak for themselves. I've got 11.3% fat on my arms, which is low, 14% torso, low. And visceral fat, which we mentioned is the evil fat, 2.7, which is good. So you can look at muscle, you can look at a lot of different things. So what the app is telling me is that I'm doing well, and I'm on the lower end compared to other people in my age range. And of course, you can do this as well. I've actually watched my muscle percent grow as I've changed my diet and exercise. That's important. want to know what's happening as you change your lifestyle. So this is a motivational and fun thing to have on your phone, and in the past couple of months, by changing my diet and exercise regimens, I've lost over 12 pounds, and importantly, I was able to ensure that I didn't also lose any of my muscle mass, which is a common problem when you're eating less. And though I didn't use a gel P1 drug to lose weight, if you do take one, and that's increasingly common, a within scale can really help ensure that you lose only fat, not muscle. It's the only smart scale that also comes with an FDA-cleared ECG that can analyze your heart rhythm, and even detect atrial fibrillation, which is a heart condition that can cause stroke and even heart failure. So we at Lifespan here are partnering with withings because we share a common commitment to preventive health and also supporting medical research. As a Lifespan listener, we invite you to join us. And more about withings, or get a scale, or just one of their other really cool smart devices at withings.com/Lifespan, or for 10% off, use the code "Lifespan." Let's talk about these primarily plant-based diets. There was a really big study by the Adventist Health Group 2013. Let's talk about that because what they calculated was the chance of dying based on various diets. And these were thousands of people. What they found was that what's called the hazard ratio went down the more vegetarian and vegan you were. What does that mean? Your chance of dying goes down. And the number goes from zero to one. Whereas one is you're pretty likely to die tomorrow. Whereas a low number, which is around A, means you've got 20% less chance of dying on any given day with this hazard ratio. So the numbers are the following. And vegetarians are at one, if you call that one, compared to that, the next best one was semi-vegetarians at.92 and octolovo or lacto-overvegetarians.91. So about almost a 10% reduction in mortality, death. And then you get into vegans, which point A5, so there's 15% reduction in death. And then the best one was pesto vegetarians. So getting a little bit of meat. Yeah, a little bit of meat from fish, probably the fish oils in there are beneficial. And then you're down to.81. So that's a 19% reduction in your chance of death at any given day, late in life. Okay, now that's all caused mortality. But we can also now see this in biologic aging because we now have clocks that we can use to measure our biological age. And there are studies now also that are showing that these diets are effectively reducing biological aging as well. This idea of Xenohormesis, this idea of not just eating a plant-based diet, but specifically focusing on plants that have experienced stress. Talk about that. Well, Xenohormesis concept, Conrad Howitz and I coined this term in the mid-2000s, trying to explain why so many plant molecules are good for us. It just cannot be a coincidence. And we came up with this idea really prompted by a 2003 nature paper that we co-published that found that there were at least 20 plant molecules called polyphenols that activate the Sir-2 and enzyme called Sir-1, the number one out of the seven family members. And when I looked into it, these polyphenols do remarkable things to the body. So the idea is that we've evolved mechanisms to sense when our food supply, the plants that we eat are stressed. Because it's like an early warning system. Right. And they make these polyphenols in order to survive when they run out of water and nutrients. We think that the faster they grow and the less stress that they have, the better. It's actually more profitable for a farmer to grow plants that grow really quickly and have no stress. But are they better for us? Absolutely not. So how do we know if our food has been stressed? Well, you can start with the generalization that if they grow out in a field organically without pesticides, probably they're more stressed, right? But also there are foods that are intentionally stressed. What's worth noting here is that this idea doesn't just apply to plants. In we humans, mild biological stress can activate ancient survival pathways that help cells repair damage, maintain function and potentially extend health span. So in the 1980s, it was all about just free radicals. We didn't know that aging could actually be controlled by any genes. Well, certainly not single genes. And Cynthia came along as a young graduate student and looked for worms that would live longer and she mutated them and found a strain of worm, a mutant worm that was living twice as long. So instead of living for 15 days, 30 days. And that was a remarkable finding because when she dissected the worms, bred them out, found that it was due to a single gene mutation. And when she cloned the gene and found out where it was, it was in a gene that sensed insulin. The insulin receptor gene called DAF2. That was remarkable because it had nothing to do with free radicals, it had nothing to do with DNA damage. It was a signaling molecule. And that was the start of a revolution in understanding how to control aging by using genes and supplements and drugs that turn on the body's defenses. And this was the first so-called longevity gene. Yeah, I would say that was the first. It came very close to the work that we were doing at MIT. A single gene alteration can have a huge impact on an organism's lifespan. And these genes, there's a few of them now that we've identified. And all of them seem to work on a very similar circuit that all starts with adversity. That's right. These signaling proteins, like the DAF2 one that Cynthia discovered and the serotones that we work on. We didn't know what they were doing at first. This is crazy. It's got nothing to do with DNA repair and free radicals. But then when we tracked what they were actually doing, it turns out they're speaking to the rest of the cell to keep the cell healthy and alive. So in the case of that worm, those worms won't just longer live. The program to survive was activated. Those worms are stress resistant. You can hit them with heat. You can hit them with cold. You can starve them or just put them in happy conditions. They live longer. The paradigm is that normally a worm responds to its environment. If it's starved, it'll hunker down, it'll survive. But here we had a worm that was mimicking starvation and was able to have the benefits without having to starve itself. And that adversity we've evolved to fight back. And so in the past, our bodies were constantly fighting disease and deterioration throughout life, even before birth. We were fighting against entropy, things are falling apart. The aging clock that we can now measure begins at conception. But if you fast forward to now, our society is built on comfort. We've got, most countries have enough food and shelter. We can sit down. We don't have to run away from predators very often. And this is a real problem because these longevity defenses that normally would be activated by being cold and hungry and running are lethargic. But the body doesn't expand energy to defend itself unless there's a need for it. And modern society is the worst thing. Eating. Take away those needs. Yeah, we love comfort. It feels good. But that's the worst thing for long-term health. We need to trick the body into getting out of its comfort zone by doing these things. We've talked about eating the right foods, including foods that are stressed, eating less often. There's another really easy way to do this though. Right. And that's, get off your boat. Just get off your boat. We know that low-level exercise alone is good. Right. And there's a reason why vigorous exercise is so important beyond just walking and standing. It's that you have hypoxia. Low levels of oxygen are undoubtedly good for you, even though they may not feel good. Exercise prevents senescence? Let's start with what a senescent cell is. So when the epigenome becomes too dysregulated, cells can either die. They can become a cancer, but what the body tries to do is to prevent that by shutting these cells down and make them more like zombies. They are alive, but they're not dividing and they're causing havoc. You're just greeting all these chemicals and the bloodstreams. They are. It's called the SASP, the senescence associated secretory phenotype. And these proteins cause inflammation. They also cause cancer. So the fewer senescent cells you have in your body, the better. And we're starting to find that lifestyle and supplementation and some drugs can slow their formation, but also we can kill them off. And there's this study, the one you're referring to, which took 34 individuals for a 12-week exercise program and looked at the amount of senescent cells circulating in their immune, in the blood immune system. And it was dramatically lower in the exercise people, arguing that you can actually kill off or reverse that process. Exercise is not the only adversity mimetic. There are others hyperbaric oxygen treatment. Right. Or H-B-O-T. Yeah, this is really fascinating because for a while we knew that wounds repair or heal faster when you give them a oxygen. But then people started putting themselves in hyperbaric chambers. The military, certainly the Navy have been doing this for a long time to prevent the bends. But it's found to be quite therapeutic, particularly for neurological disorders. It's been increasingly for aging itself. And we should say what a hyperbaric chamber is. Right. The hyperbaric chamber is a room or sometimes just a little tube. where the pressure is increased. And when the pressure is increased, the amount of oxygen that you get when you breathe is increased. - Right, you can go up a couple of atmospheres or more. And you supplement that with oxygen. You can breathe in a bit more oxygen or pure oxygen. What the science says is that it actually can reverse an aspect of aging, which is telomere shortening. The ends of the chromosomes, many of us will have you or will have heard of this. Like the ends of the shoelaces, the egglets they're called. If they wear out, it actually leads to cellulose and essence, these zombie cells. And this happens over time as we get older. And what we've been looking for, we scientists for many years is a molecular treatment that makes them grow back again. 'Cause that should help slow down aging and give us longer life. - Let's shift now to talking about cold therapy, which is another thing that a lot of people are experimenting with now. Another thing that they're centers for all over the place. But that the research is still sort of catching up to the excitement. - Now we know actually that one of the huge benefits you get from being cold is the production of brown fat. So what is brown fat? Brown fat, or often called beige fat, is found in babies. It's typically to allow them to stay warm because they don't shiver until they're about one year of age. And what was discovered about 10 years ago at Harvard by Bruce Beagleman and Ron Kahn, a couple of my colleagues, is that adults also have some brown fat. And they discovered this with pet scanning. And they found it mostly exists on your back in your shoulder blades. And when you get cold, it revs up. You get more of this brown fat. And this is a good thing because brown fat is extremely healthy. It revs up metabolism. It burns white fat. And we think that there are these factors, little chemicals, little proteins that get secreted out of brown fat that make the risk of the body healthy as well. One of the reasons we know that is because there's a gene that makes brown fat, makes cells turn brown from white to beige to brown. And it's called PRDM16. And mice that lack this gene, they don't have brown fat, but they also develop type 2 diabetes and cardiovascular disease as a result. - Do you like talking about the mice that got to spoon together? - Oh yeah. So that one is a bit of a disappointment in the field that we had these dwarf mice. That Mike Bunkowski, who was working in my lab, he was the guy that generated the longest live mouse, he called it Yoda. And it was very long lived because it had a mutation in a gene for the growth hormone receptor, which means there were small and dwarfs. And these little small dwarf mice would live up to three times longer than a normal mouse. It was quite an amazing thing. And the field was rejoicing. Wow, we figured out how to make mammals live that much longer. And then it was noticed that they were shivering, little cold mice. And so the researchers thought, we'll just give them friends. So you give them-- - They were shivering because the lab was cold. They were shivering because-- - They didn't have a companion. You know mice like to live not solitary, but with other mice. And so they gave them a buddy, each of these dwarfs had a buddy. And then the majority of the lifespan extension went away. - When they got their buddy. - Yeah. - Which is super disappointing, right? But what it told us was that a large effect of longevity was due to them being cold. All of these things were about taking your body out of its comfort. - They are, yeah. - And some of them are really enjoyable. I think sauna bathing is cold in Europe is super enjoyable. And it also is good for your skin. You get to sweat and get those pores unclogged. But this is one of the most ancient therapies for longevity. There's absolutely no doubt that men who partake in sauna bathing a few times a week have a dramatic reduction up to 20% in the rate of cardiovascular disease and mortality caused by heart attacks. - What's remarkable is that many of the longevity benefits associated with exercise, fasting, and heat exposure appear to stem from the same underlying biology. A critical player is a molecule called NAD, which helps our cells generate energy and activate the body's aging and defense pathways. - Talk a little bit about how why NAD is important in our bodies. - Our cells use NAD to transfer hydrogen atoms between proteins and even DNA. That is really important for life. And without it, we can't make chemical energy, which is in the form of ATP. NAD is found in abundance. There's many grams of it in the body. It's probably with the exception of ATP, the most abundant molecule we have in the body. It helps us make energy, but it also has this other function that's just as important that we worked on and just co-discovered in the 2000s. It activates the serotones. And the serotones at these defensive enzymes that send out the troops. The problem is, as we get older, we make less NAD and we also destroy it more. For reasons that we don't fully understand, but it leads to a decline in our ability to fight off aging and the diseases that it causes. - And this is because NAD is a sensor for adversity. - It is. If you exercise, it's known and fast. It's known to raise NAD levels. But even though even if you exercise and have the healthiest diet, you're still going to have lower NAD levels by the time you're in the latter half of your life. So that's why these supplements are thought to help because they'll boost up those older levels of NAD to where they were when you were young. - Because NAD levels decline as we age, researchers have spent years asking an important question. Can we restore those levels and in doing so support the body's natural longevity pathways? That's what led to a growing interest in NAD precursors or NAD boosters like NMN and NR. - Going back a number of years ago, it was found that NR when given to my sixth end to the lifespan by about 9%, but it was given to them late in life at about 700 days, which is a pretty old mouse. This has been like a 70 year old human, but it still worked. But there were also improvements in health. They had more mitochondria, which is the energy. They had more athleticism, less inflammation. And so that was the first real study that said, okay, maybe supplementing with these molecules like NR or NMN might have some long term health benefits as well in humans. - Among the other health benefits that have been seen by researchers who have given NR to animals in the lab, enhanced oxidative metabolism. - So they burn more fat? - Yeah. - They get thinner. And that also means that they're burning more oxygen. And that's thought to be really good at staving off diabetes, type two diabetes as well as improving lifespan. - Let's carry this now into the human studies that have sought to show similar health benefits to what we've seen in rodents. - With NR, there have been a handful of studies in humans showing that low dose to 150 milligrams per day, up to a pretty large dose of gram a day, does raise any D levels. And but it takes about nine to 10 days to get to those peak levels. What we've also seen is, others have seen is lower inflammation as well as some other markers, such as minor changes in body composition. - When it comes to NMM, there's been a number of animal studies showing, for instance, similar to NR, restores NAD levels, it enhances insulin sensitivity. - Shinemi showed that it actually was pretty good at slowing down the effects of aging. We've been doing these studies for the last few years in my lab. Now, preliminary, these mice have less frailty. We've reported that out in the scientific community. They seem to be younger, having better activity, better mitochondrial function, they run further. The lifespan looks promising. - What are we seeing in the human studies for NMM? Early results, for instance, from Yoshino et al. in 2021, showed increased insulin's stimulated glucose disposal. We talked about this a little bit when this study came out. You were pretty excited about it, tell me why. - It's one of the first real proofs that NMM does something in humans the way it works in mice. So this was a 10 week study. It's well done. It's randomized, placebo controlled. It was 250 milligrams, which is a relatively low dose. Remember, I'm taking in my clinical trials or a gram and two grams. This is 250 milligrams. Nevertheless, it improved what you said, insulin stimulated glucose disposal. That's basically insulin sensitivity. And that's a whole mark of longevity, keeping the glucose out of the bloodstream, keeping it low levels. There's a whole mark of wellness, and ultimately longer life. So that's the beginning, but we have a lot more to figure out. Now, there are other NAD boosters serve to inactivating compounds. One of the ones that you've been really interested in is respiratory. There have been a number of animal studies on respiratory going back almost 20 years now. We're seeing extended replicative lifespan in yeast. We're seeing activation of AMPK in rodents. What are these things telling you? Well, they're similar to what we expected from the sertuins. They defend the body. They raise the metabolic rate. They protect against free radicals. And when we see residual given to these rodents, what the biggest surprise was that they were protected against a high fat so-called Western diet. Those mice are in residual, even though they were really obese on this really chunky meal. They lived as long as the lean mice that we had as the control group. And that was really-- as far as I know, the first study of any that showed that you could mimic caloric restriction with a molecule and be fat, but live as healthy as a lean animal. Have those findings translated over as we've moved respiratory into human studies? Yes, somewhat. I'm not all studies have worked, but there are a number of them that have. for instance. risk of COVID-19. Reservoir was being shown to reduce fast in glucose and significantly increase insulin sensitivity. This was a study in 2019. And then again in 2020, Battista and George et al showed that a randomized control study with 25 individuals ranging from 30 to 60 year olds with a slightly high BMI of 30 were able to lower their cholesterol levels, their urea levels, which is important for kidney function as well as raise their good cholesterol, the HDL. But once again we don't know long term what this is going to do, but the trajectory seems good when we consider it in the context of what we see in animals and what we are seeing in these early human studies. Resveratrol is not the only molecule that appears to activate some of these same longevity pathways. In fact, one of the most widely studied compounds in aging research is a drug that's been used safely for many decades to treat diabetes. Of course, I'm talking about midformin. Really one of the most exciting classes of drugs is also sort of actually kind of the most boring because it's been around for so very long. An AMPK activator called Metformin, which hundreds of millions of people around the world already take for diabetes. What are sort of the intermediary things that we're seeing with metformin? In humans you mean? In animals that we can look for in humans. Right. And this is where we can speak to a lot of data because millions of people have taken metformin. And one of the most interesting things about it is you can do a retrospective study of tens of thousands of elderly people on metformin and ask, "Okay, they're type 2 diabetes maybe you've reduced and slowed down." But what about other diseases that they're susceptible to cancer, heart disease, Alzheimer's frailty? And the answer that's quite remarkable is that metformin lowers the risk of all those other diseases. So we control for everything else what we see is that the people who are on metformin are living longer. Then people who don't have type 2 diabetes. Medications and some supplements can be powerful and other medical interventions could take things to a whole new level, exosomes stem cells and cellular reprogramming or what we now call cellular restoration. These raise one of the biggest questions in longevity science. Can we move beyond slowing aspects of aging to actually reversing the age of organs and tissues? There is an explosion of research going on about exosomes. Exosomes were very packages of information. Their membrane balance are their little physicals about the size of a virus so they travel between cells and intercells very easily. And inside, it's not just one message, there's multiple messages. There's peptides inside. There's DNA, there's RNA, even what are called microRNAs, which are similar to peptides, very small pieces. In this case of nucleic acid material that can go from the brain to other tissues, from tissues back up to the brain. And this is essentially the way the body can coordinate. So if there's an injury on your hand, your brain will know. Or if your brain gets injured, the rest of your body knows. You need to have these messages to coordinate the system in the same way you could imagine that the US post. And so these are little male deliveries of cargos that we can both intercept and read. Perhaps we can use these to diagnose diseases, including cancer, but also we can make more of them and infuse them into people to give a false alarm, perhaps even to simulate this adversity and make us live longer. And before we get to those therapeutic processes, one of the really fast-moving avenues for using exosomes is basically collecting them from the blood, counting them up, and being able to diagnose different injuries. And even like you can pull from people's blood, these exosomes, and then you can say like, oh, they have an injury here, they have a disease there. Right. You can say, okay, that comes from the pancreas. But it is a signature of a stage three pancreatic cancer. So we may be able to use these to diagnose cancer years in advance. Without biopsying just a blood test or even a fingerprint at home, send it off and diagnose cancer. And that would be reason enough to be excited, I think, about the potential for exosomes to tell us what's going on in our bodies, but what else we're learning right now about exosomes is that if we supplement these into the bodies of mice, like by injecting them into their, back into their bloodstreams, it can help with injury. And just to be clear, exosomes are a highly validated scientific pursuit. And there are biotech companies, pharmaceutical companies, building giant factories for billions of dollars to make exosomes to treat diseases. The question is, do they work for long-term health and longevity and how safe they are to be used over decades that we don't know yet? One of the most consistent findings in longevity science is that small and measurable behaviors add up over time. For example, in a 2011 study that was published in the Lancet, a reputable journal, researchers followed over 400,000 people. What they found was that just 15 minutes of moderate exercise per day was associated with a roughly three-year increase in life expectancy, which is huge. Sleep shows a similar pattern. Large-scale analyses published in the Journal of the American Heart Association show that both two little and too much sleep are both associated with increased cardiovascular and mortality risk. So here at Lifespan, one of our most important missions is to support medical research. So down the line, all of us can lead longer and healthier lives. We're grateful to you, our community, who supports us in this effort. We're also grateful to our partners, who help us in this mission. So this brings me to a wearable that I'm particularly fond of. Especially because of its scientific foundation at Harvard, where I work. And also the founders own research in scientific rigor, as well are made of course. There are only a couple of blocks away from this studio up the street. And whenever I go visit, I see a thriving company that's mission-oriented to help people live better, longer lives, including all of us. And of course, I'm talking about the Woot Band, which is the one that I really take off my wrist. This wearable is a health and fitness coach that gives me insights into my sleep, my recovery and my body's strain. Researchers have studied how accurate these devices are. And in a 2022 study, they compared six wearable devices, including Woot Band, against clinical grade ECGs and sleep recording devices. Woot Band showed strong accuracy for heart rate and heart rate variability measurements during sleep. I can see using this device how my daily behaviors also are impacting my health day-to-day. For example, wearing the Woot over the last two months, I've seen dramatic improvements in my personal biomarkers, indicating that the changes that I'm making to my lifestyle, including a much healthier diet and my exercise, is definitely having positive effects on my body. For example, my resting heart rate has gone down to 45, and my heart rate variability, which you want to be higher, the number is shot up to 90, putting me in the top few percent or so for my age. It's not only interesting and useful, but it's also important to build up a record about my body that I can aim for when I'm older. So for example, when I'm 90, I can go back and aim to be what I am in my 50s. If you're a regular listener to lifespan, you'll know that we only partner with companies like Woot, who we really believe in. There's a product that we use daily, and these companies align with our mission of supporting medical research. If you want to try it and get a free Woot 5.0 Smart Band and a month of membership, go to join.woot.com/lifespan or use the code "lifespan". Let's move then into an area of research that is even further along. Let's start with a little primer. Stem cells are cells that can divide asymmetrically to produce cells that go on to make tissues. So for skin, you need stem cells to make all the skin that grows over your lifetime. They retain youth so that they can keep dividing over and over and they don't become any particular certain cell type over time. Stem cells can become more stem cells or they can become any kind of cell. There's a few different types. The two main classes are multi potent, which can make a few different types of tissues. These are cells that you can get from an embryo. We can go all the way back to age zero and what are called pluripotent stem cells, which can make any type of cell and any type of tissue. So if you want to build a mini human brain or rebuild a kidney out of a skin cell, you have to wind the clock all the way back to zero and start again. That's called inducing a pluripotent stem cell state. What we're looking at now is how do you rejuvenate the existing stem cells and stop then getting old or even reverse the aging of the stem cells in situ where they exist. We'll get to that, but this is the reprogramming technology that should work not just on normal cells, but even stem cells to make them young, truly young again. There's been a lot of research showing that stem cells can have a therapeutic effect in specific parts of the body. When we talk about this aging umbrella in general, there was one study, actually two studies, the phase one study to phase two study from researchers at the University of Miami in 2017 that gave stem cell therapy. Harvested stem cells from younger donors gave them to older frail patients and small scale, but it showed improvements in the distances that these people could walk. It lowered the levels of cytokines. It improved their mental state and they had a reported quality of life improvement as well. That's remarkable. I think the future looks like this that we can keep our bodies healthy by eating right, doing physical exercise, taking the right medicine sessions, supplements. And when that doesn't work and things fail, you can then rebuild the body, replace cells, put in your organs. And that way we'll live probably many decades longer than we can currently live. And then there's one more thing that in the future we may be able to do. And this leads us to this thing that you're doing in your lab right now. If you had quite a few public studies on that are pretty darn exciting, we're talking about cellular reprogramming. Well, this is the big one. We've been working for many years on slowing aging. But we've wondered how do you get that to be reversed? Is there a reset switch in an old cell? And we think we found it. We're standing, of course, on the shoulders of Shinya Yamanaka, who showed you can reset the age of a cell back to zero. But that of course causes cancer. And if you do that in a mouse, it'll die within days. So that's not going to be a therapy anytime soon. I don't recommend it. But what a wonderful student, one Cheng Lu did a few years ago in my lab was he found a set of genes that are Yamanaka factors that were able to reverse the age of cells and tissues in an animal and in human cells to a certain point going back about 80% of age, but not to zero. So that this was a new, safe approach without any negative side effects. And he did this by instead of using all five Yamanaka factors, he used three of them. Three. And the C-Mec, which is the M, we definitely don't want that in there or LIN28. These are what are called oncogenic genes, cancer causing genes. So we left those out. And surprisingly, those other three O, S, and K for short worked, not just in cells in the dish, but even in the whole animal. We focused on the eye because we thought reversing blindness would be pretty cool and could be a drug, a very quick drug to develop relative to the whole body. And it worked. One Cheng sent me a text of a picture of an eye where he also regenerated the optic nerve that was crushed. And then he went on to restore vision in mice that were given glaucoma, which is pressure in the eye and even restore eyesight to blind old mice. Advances in stem cell research, as well as cellular restoration, are showing that some aspects of aging are indeed reversible. One of the clearest everyday examples of this is hair loss. So why on a just a fundamental level does hair loss occur? Well, it really goes back to stem cells. These are the cells that keep dividing asymmetrically, giving rise to other cell types. And that they reside in the bulge of the hair follicle. And there are a variety of types. There are some that are just there to produce the keratin in the hair. There are others that are there. Melanocytes to produce the color. There's a new type of stem cell. It's called the hair follicle associated pluripotent stem cell that people have found you can now isolate and turn into bone and muscle. We don't know what roles they exactly play. But what happens, what we think happens during aging and was only recently discovered is that the important stem cells for hair regrowth get kicked out of the hair follicle. They get spat out, which was unexpected. We thought that they died, but they actually get expelled. So what that means is that you want to prevent that from being them getting expelled. But also you want to maintain the function as well, which is all about preserving their epigenome, their ability to remember the type of cell that they are. More externally, what we've known for, you know, since the 1960s is that the hair follicle shrinks and gets small, causing part by our dihydrotestosterone. And when that happens, the hair becomes thinner and thinner until it stops going through what's called the antigen phase, which is the hair growth phase. And this is really what like a lot of the treatments are aimed at preventing. There's topical treatments, there's pills, there's some other stuff, but let's start with topical treatments. These are creams that you rub on your head. Do these things work? Are they undoubtedly worked? This is minoxonal, also known as rogane. So what it does is it stimulates nitric oxide production. Nitric oxide is important in Viagra, opens up the blood vessels. Retin A also works for promoting antigen. Yeah, that's a little known fact. If you have some retinol cream, 0.5%, you can rub it on your skin to reduce wrinkles, but you can also rub it on the parts of your hair that are thinning out or you don't want to lose hair. And especially in combination with rogane or minoxonal, it works quite effectively to slow that aging process. Yeah, there was a study that showed after a year, if you combine trentanon, which is retinate, with a little bit of minoxidil, it resulted in regrowth in 66% of the people after you. That's up. But there's an alternative that doctors are recommending, which is taking a pill. Propecia. Propecia, also known as finistaride. Finistaride, Propecia. This is a once a day pill that inhibits testosterone. Well, more specifically dihydrotestosterone, which is convert, right, DHT is converted by a 5L for a ductase and enzyme that's found throughout the body. Now, 5 dihydrotestosterone is important in the body. It reduces fat, it's good for the hard, good for the mind. It has some other downsides. It actually helps your prostate grow as you get older and you need to go to the bathroom. So the real question is, what are the best levels for optimal longevity? Actually, there was a study on that. There was a study of 3690 men that found that the levels of that hormone were optimal if they were relatively low, but within a middle range of 9.8 to 15.8 nanomoles per liter. Those were the men that lived the longest. This really relates to one of the problems with inhibited testosterone, which is that it lowers sex drive. That's a potential side effect to propitia. Yeah, there's a bunch, including mood swings. Well, you can be get depressed and breast tenderness as well. There's another intervention that has as far as we can tell almost no side effects whatsoever. Yeah, laser beams, I didn't think this was real. It sounds crazy. You shine light on your head and your hair will grow again. Come on, but I looked into it and it's actually been approved by the FDA as a treatment. There are combs that have red laser light and caps that you can wear. These are typically treatments for 10, 15 minutes a day or every other day. They literally have been proven clinical trials to slow down hair loss as well as regrow some aspects of hair, in not everybody, but in the majority of people. This is called LLLT. Low laser light therapy. Let's talk about platelet-rich plasma injections. Another thing that's gaining popularity for a variety of conditions, a lot of athletes use these to recuperate after sports injuries, but people are increasingly using these for hair loss as well. They are. It's platelet-rich plasma PRP. And what you get done is you go into a clinic, they'll take out your blood, they'll spin out the cells, take the platelet-rich plasma and inject it either into your veins for longevity, or in most cases put it into your scalp in many different places with a needle. Is there an anti-aging pathway involved in the PRP, do you think? Well, undoubtedly. We know that when you fuse the blood systems, the circulatory systems of an old mouse and a young mouse, the young mouse makes the old mouse rejuvenated and younger. We don't know all the components in there. There are some of them, there's one called GDF-15 for example, but then we don't know what's in this mixture that promotes hair growth. When it's found, it'll be purified and probably be given as a cream or an injectable, but until then it's this messy PRP treatment. Would that be the case with graying hair too? It could be because graying is part of not just a genetic program, but can be accelerated by things that are also known to accelerate aging itself such as psychological stress. In 2021, a group of researchers had a look at what was happening in people's lives during that gray hair growth period. And they found that they were remarkably stressful periods of those people lives where they didn't stop working, they didn't sleep, they didn't go on a vacation. And so I think it's very clear that stress can induce gray hair at loss of color from the hair, but what's also remarkable about that finding is that it proves that gray hair is reversible. Which means that what we're talking about here is an epigenetic effect. Sure. I mean anything that is genetic is essentially irreversible. So this is an epigenetic effect. These findings suggest that aging is a whole body process. And one of the most important places that we see that process play out is in the brain where age-related diseases remain one of the biggest medical challenges that we face. Increasingly over the years, you've gotten better and better and better. Right, we're living longer, but we're not living better because the brain is still aging and getting these diseases, Alzheimer's and other types of dementia are becoming more prevalent because we're living longer, but not whole body, not holistically slowing down the aging process. So we have to make a breakthrough. And what we're going to talk about today is a totally new approach to treating dementia. And that is boosting the body's defenses against not just Alzheimer's, but against aging itself. We've talked previously about the Mediterranean diet. And one of the reasons is that it's very clear in over a dozen studies that a Mediterranean type diet protects the brain from aging and can even reverse aspects of aging in the elderly with mild cognitive impairments. Even with a normal diet, you often don't get enough of these omega-3 fatty acids, which are the types that we don't make ourselves. If you're only meat and you don't eat fish, the animals, besides fish, you're not getting a lot of them. And they're the building blocks of the brain. So we need a lot of them. And they've been shown in a number of studies to help with many different things from wind healing and of course depression. Now what are the sources? Well, if you eat fish, you're probably in good shape. You've got salmon and mackerel, krill, sardines. These are good sources of omega-3s. And these are giving us the DHAs and the EPAs, because there's three different kinds of these, right? Well, there are lots. But the three main ones that people talk about are EPA and DHA. And that's been shown to greatly improve memory and counteract depression. Now, that if you're a plant-based person, you can't obviously get as much. You have to focus on other types of food that have what's called alpha-linolac acid or ALA, which is converted slowly, not efficiently, by the body, into the two types we just mentioned that are important, the DHA and importantly the EPA. Focus then on flax seed, walnuts, chia seeds. That's where you get your ALA. Linced oil is where it was first discovered. ALA, linolac acid, there's a lot of it in there as well. So we know we should be consuming these omega-3s. But why? What are they doing in ourselves? So it turns out these omega-3s actually form a structural component of the brain. They insert along with other fats in the brain. So fat is actually good for the brain. A lot of our brain is made up of these fats. The reason is that the nerves aren't naked, much like an electrical wire. You don't have them lying around your house naked. It actually be wrapped with insulation tape or insulating material. And that's what these fats do. And these are membranes that wrap around. It's called the myelin sheath. And these fats actually, some of them are omega-3s. And the more omega-3s you have in your diet, the more you'll have in those membranes. And that protects from inflammation and damage. And helps the nerves function and repair if they get damaged. We also have to exercise for brain health. The reason we think that is is that there's two reasons. One is better blood flow and also better neuronal activity and slowing aging of those cells. That involves the sertuins. This third protective survival pathway. They can be activated, of course, by this. The food and also by exercise. We've seen this in a number of both human and animal studies. Well, that's right. There are a number of studies that we could talk about. The one that stood out for me in our research was the one that involved 160 sedentary sitting down non-execising adults that were told for six months to do extra aerobic exercise. So Blumenthal and his colleagues found, or was it, 2019, that this greatly improved executive function, concentration focused. So just a little bit of exercise, six months of exercise improved for these people. They're all over the age of 55, improved dramatically their ability to do these things. Well, they did. And I think that that's one of the main reasons for exercising. You might want to do it, not just because you feel better, but you will think better too. It doesn't have to include aerobic exercise. There's one where there's strength exercise. So if you don't like running, pick up some weights because what's been found in this study, this is 2013 per era, and colleagues found that in an elderly cohort, they had 451 people, just 10 weeks of strength training, increased the level of factors that grow new brain cells, new nerves. This marker is called BDNF, or Brain Drive Neuotropic Factor. And we use that as a way of indicating the youthfulness of the brain and regrowth of new nerve cells. Exercise appears to help protect the brain by improving blood flow and even stimulating the growth of new neurons or nerve cells. But one of the most important things the brain also needs in order to repair and reset itself is something many people chronically lack sleep. One night of sleep deprivation increases amylobella production by 5%. That's. You don't want to mess with amylobella, right? No, that will accumulate in your brain. It's very hard to get rid of. And I was also shocked to read that it's not just the brain that ages if you don't sleep. In humans looking at a million people to study from 2010, Capucho Adel, what they found was that in people that had very little sleep, the risk of dying was higher than those that got a natural normal night sleep. This is really stressful times. And just lack of sleep makes it worse, and physically we will regret it decades later. I hope you enjoyed the second look back at some of the most surprising results we covered in season one. When Matthew and I recorded those conversations, longevity science was already moving quickly, but since then the field has accelerated even more. We're now measuring aging with more precision, testing interventions much more rigorously, and using AI to enhance scientific research. We're also beginning to ask questions that would have sounded impossible not long ago. Can we slow aging? Can we restore youthful function to old tissues? Can we move from treating age-related diseases one at a time to targeting their underlying biology? And finally, can we reset the age of the body? In the coming season, we'll go deeper into the science of aging, but also into what it means for your life. What has changed since season one? What has held up? What new discoveries are emerging? And what could the next era of longevity science mean for health, medicine, and the future of human potential? I can't wait for you to see the first episodes. It takes everything we've been building towards and opens the door to a new way of thinking about aging. If you want to learn more and join our growing community, visit lifespan.com to get early access to future episodes, lifespan magazine, show notes, and much more. As a member, you'll also be helping us support vital medical research to extend healthy life. If you enjoyed this episode, please hit the subscribe button and be notified about new episodes that we're putting out. This will help us continue to make a better show for you. Feel free to share this with family and friends. And for the latest discoveries in longevity science, follow us on Instagram at lifespan and on X at Join lifespan. From all of us here at lifespan, thank you for being part of this growing community. I'll see you very soon for season two. And remember, life's short, so let's change that together.