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

22:50Dr. David Sinclair: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 sirtuins. We start with fasting, we get longevity in AMPK. 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, it stands for AMP activated kinase.

23:28Dr. David Sinclair: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 energy, chemical energy. So when you activate AMPK, you'll feel better. You'll have more energy and you'll 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.

24:11Dr. David Sinclair:Right. Well, let's name some of them. The Jains. The Jains in India. In India. 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 Isaminda Koglu, 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.

25:00This is what we saw in all these model organisms as well.

25:04Dr. David Sinclair:Yeah, there are dozens of studies showing that periods of 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.

25:40Dr. David Sinclair:Let's go through the diets. Okay, so there's a fasting mimicking diet. Walter Longo, a 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.

26:21Dr. David Sinclair:I wouldn't go longer than that because 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 to what's called chaperone mediated autophagy, the deep cleanse. And then there's time-restricted feeding, which is what I do, because I'm not very good at going beyond 24 hours. You want to have at least 16 hours of not eating or not eating very much.

26:52And not everybody's going to respond the same way. Like you said earlier, you know, we all have different lifestyles. We've got different genes. Jim Nelson's work's been sort of informative in this.

27:03Dr. David Sinclair:Yeah, so Jim did an important study in mice, Again, not humans, but it tells us that genetics is important because 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, it was close to 35 % of what a mouse would eat given food all the time, adlibetum we call it. And about half the strains of mice lived longer and then about a third of what the remaining ones lived shorter.

27:39Dr. David Sinclair: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 want to 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.

28:11Dr. David Sinclair: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? Withings, one of Lifespan's partners, makes some of the coolest devices that you can measure yourself with.

28:46Dr. David Sinclair:Watches, a blood pressure monitor, and advanced bathroom scales. I've actually been using Withings 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 Withings 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 Withings 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.

29:27Dr. David Sinclair: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. And that's important. You want to know what's happening as you change your lifestyle. So this is a motivational and fun thing to have on your phone.

30:06Dr. David Sinclair: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 GLP-1 drug to lose weight, if you do take one, and that's increasingly common, a Withings 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.

30:44Dr. David Sinclair:So we at Lifespan here are partnering with Withings because we share a common commitment to preventative health and also supporting medical research. As a Lifespan listener, we invite you to join us. Learn more about Withings or get a scale or just one of their other really cool smart devices at withings.com forward slash 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.

31:27Dr. David Sinclair:And 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 80, means you've got 20 % less chance of dying on any given day with this hazard ratio. So the numbers are the following. Non-vegetarians are at one, if you call that one. Compared to that, the next best one was semi-vegetarians at 0.92 and lacto-ovo vegetarians 0.91. Okay, so about almost a 10 % reduction in mortality, death.

32:12Dr. David Sinclair:and then you get into vegans, which point A5, so that's 15 % reduction in death. And then the best one was Pesco vegetarian. So getting a little bit of meat. A little bit of fish. Yeah, a little bit of meat from fish. Probably the fish oils in there are beneficial. And then you're down to 0.81. 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.

32:55This 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.

33:06Dr. David Sinclair:Well, the 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 SIRT2N enzyme called SIRT1, 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.

33:46Because it's like an early warning system? Right.

33:49Dr. David Sinclair:And they make these polyphenols in order to survive when they run out of, or running out of water and nutrients. We think that the faster they grow and that 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 a food has been stressed? Well, you can start with the generalization that if they're grown out in a field organically without pesticides, probably they're more stressed, right? But also there are foods that are intentionally stressed.

34:19Dr. David Sinclair: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, 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.

34:58Dr. David Sinclair: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. It's 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?

35:37Dr. David Sinclair: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 sirtuins that we work on, we didn't know what they were doing at first. It was like, 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.

36:19Dr. David Sinclair:So in the case of that worm, those worms weren't just longer lived. 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.

37:00Dr. David Sinclair:Even before birth, we're 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. The body doesn't expend energy to defend itself unless there's a need for it. And modern society is the worst thing. We've taken away those needs.

37:38Dr. David Sinclair: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 butt. Just get off your butt. We know that low level exercise alone is good. Right. And that 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.

38:19but exercise prevents senescence?

38:22Dr. David Sinclair: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. And - You're excreting all these chemicals into the bloodstream. 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.

39:03Dr. David Sinclair: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 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 memetic. There are others hyperbaric oxygen treatment. Right, or HBOT. Yeah, this is really fascinating because for a while we knew that wounds repair or heal faster when you give them more oxygen. But then people started putting themselves in hyperbaric chambers.

39:42Dr. David Sinclair: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, but 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 breathe in a bit more oxygen or pure oxygen.

40:17Dr. David Sinclair: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 you will have heard of this, like the ends of the shoelaces, the agulets they're called. If they wear out, it actually leads to cellular senescence, 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 molecule or a treatment that makes them grow back again, because 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 there are centers for all over the place, but that the research is still sort of catching up to the excitement.

41:04Dr. David Sinclair:Now we know actually that one of the huge benefits that 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 Spiegelman 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.

41:43Dr. David Sinclair: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 rest of the body healthy as well. One of the reasons we know that is because there's a gene that makes brown fat, make 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. You like talking about the mice that got this spoon together.

42:19Dr. David Sinclair:Oh yeah. So that one is a bit of a disappointment in the field that we had these dwarf mice that Mike Bonkowski, who was working in my lab, he was the guy that generated the longest lived 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 was 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.

42:54And so the researchers thought,

42:56Dr. David Sinclair:we'll just give them friends. So you give them - And they weren't 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 are about taking your body out of its comfort zone, right? They are. And some of them are really enjoyable.

43:26Dr. David Sinclair:I think sauna bathing, as 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.

44:13Talk a little bit about why NAD is important in our bodies.

44:17Dr. David Sinclair: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 co-discovered in the 2000s. It activates the sirtuins, and the sirtuins are 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.

45:04And this is because NAD is a sensor for adversity.

45:09Dr. David Sinclair:It is. If you exercise, it's known, and fast, it's known to raise NAD levels. But 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.

45:52Dr. David Sinclair:going back a number of years ago it was found that NR when given to mice extends their 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 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.

46:33Dr. David Sinclair:So they burn more fat. 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 2 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, 250 milligrams per day, up to a pretty large dose of gram a day, does raise NAD levels. But it takes about nine to 10 days to get to those peak levels. What we've also seen is, or others have seen, is lower inflammation, as well as some other markers, such as minor changes in body composition.

47:15When it comes to NMN, there's been a number of animal studies showing, for instance, similar to NR, restores NAD levels, it enhances insulin sensitivity.

47:27Dr. David Sinclair: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, preliminarily, 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 NMN? Early results, for instance, from Yoshino et al. in 2021 showed increased insulin stimulated glucose disposal. We talked about this a little bit when this study came out.

48:02You were pretty excited about it. Tell me why.

48:04Dr. David Sinclair:It's one of the first real proofs that NMN 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 are 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 hallmark of longevity. Keeping the glucose out of the bloodstream, keeping it low levels is a hallmark of wellness and ultimately longer life. So that's the beginning, but we have a lot more to figure out.

48:39Now, there are other NAD boosters, sirtuin-activating compounds. One of the ones that you've been really interested in is resveratrol. There have been a number of animal studies on resveratrol 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?

49:08Dr. David Sinclair:Well, they're similar to what we expected from the sirtuins. They defend the body. They raise the metabolic rate. They protect against free radicals. And when we see resveratrol given to these rodents, what the biggest surprise was, was that they were protected against a high-fat, so-called Western diet. Those mice on resveratrol, 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.

49:48Have those findings translated over as we've moved resveratrol into human studies?

49:54Dr. David Sinclair:Yes, somewhat. Not all studies have worked, but there are a number of them that have. And for instance, resveratrol has been shown to reduce fasting glucose and significantly increase insulin sensitivity. This was a study in 2019. And then again, in 2020, Batista 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've seen in animals and what we are seeing in these early human studies.

50:46Dr. David Sinclair: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 metformin. 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?

51:26Dr. David Sinclair:In humans, you mean? Well, 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, their type two diabetes may be 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 when we control for everything else, what we see is that the people who are on metformin are living longer.

52:07Dr. David Sinclair:Than 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 are very packages of information. They're membrane bound, so they're little vesicles about the size of a virus, so they travel between cells and intercells very easily.

52:46Dr. David Sinclair: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 micro RNAs, 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. And you need to have these messengers to coordinate the system in the same way you could imagine that the US Post.

53:19Dr. David Sinclair:And so these are little mail deliveries or cargoes 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.

53:59They have a disease there.

54:00Dr. David Sinclair:Right. You can say, okay, that comes from the pancreas. That 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. Right, just a blood test, even a finger prick 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 back into their bloodstreams, it can help with injury.

54:35Dr. David Sinclair: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.

55:21Dr. David Sinclair:Sleep shows a similar pattern. Large-scale analyses published in the Journal of the American Heart Association show that both too 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 partly because of its scientific foundation at Harvard where I work and also the founders own research and scientific rigor.

56:03Dr. David Sinclair:This is Will Ahmed of course. They're 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 Whoop Band, which is the one that I rarely 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 Whoop, against clinical grade ECGs and sleep recording devices.

56:42Dr. David Sinclair:Whoop 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 Whoop 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 more 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 has shot up to 90, putting me in the top few percent or so for my age.

57:21Dr. David Sinclair: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 Whoop who we really believe in. These are products 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 Whoop 5.0 smart band and a month of membership, go to join.whoop.com slash 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 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 and they retain youth so that they can keep dividing over and over and they don't become any particular certain cell type over time and stem cells can become more stem cells or they It can become any kind of cell.

58:30Dr. David Sinclair:And there's a few different types. Right. The two main classes are multipotent, which can make a few different types of tissues. These are cells that you typically 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. And 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. and 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 them getting old or even reverse the aging of the stem cells in situ where they exist.

59:06Dr. David Sinclair:And 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. All right, and there's been a lot of research showing that stem cells can have a therapeutic effect in like specific parts of the body. But when we talk about this like aging umbrella in general, There was one study, actually two studies, a 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.

59:51It lowered the levels of cytokines. It improved their mental state. And they had a reported quality of life improvement as well.

59:59Dr. David Sinclair:Yeah, I mean, 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 slash supplements. And when that doesn't work and things fail, you can then rebuild the body, replace cells, put in new 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. And you had quite a few published studies on that are pretty darn exciting.

1:00:34We're talking about cellular reprogramming.

1:00:36Dr. David Sinclair: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 gonna be a therapy anytime soon. I don't recommend it. But what a wonderful student, Wan 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.

1:01:25And he did this by, instead of using all five Yalmanaka factors, he used three of them.

1:01:30Dr. David Sinclair:Three, and the C-MIC, 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. Wang 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.

1:02:11Dr. David Sinclair: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 at 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 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 or others that are there, melanocytes to produce the color. There's a new type of stem cell.

1:02:50Dr. David Sinclair:It's called the HAP, 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 them getting expelled. But also you want to maintain their function as well, which is all about preserving their epigenome, their ability to remember the type of cell that they are.

1:03:28Dr. David Sinclair:More externally, what we've known for, you know, since the 1960s is that the hair follicle shrinks and gets small, caused in part by dihydrotestosterone. And when that happens, the hair becomes thinner and thinner until it stops going through what's called the anagen 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. Let's start with topical treatments. These are creams that you rub on your head. Do these things work? Oh, they undoubtedly work. This is minoxinol, also known as Rogaine.

1:04:06Dr. David Sinclair: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 Rogaine or Minoxinol, it works quite effectively to slow that aging process. Yeah, there's a study that showed after a year, if you combine Trentinon, which is retin-A, with a little bit of minoxidil, it resulted in regrowth in 66 % of the people after a year.

1:04:49That's it.

1:04:50Dr. David Sinclair:Oh, but there's an alternative that doctors are recommending, which is taking a pill. Propecia. Propecia, also known as finasteride. Finasteride, Propecia. This is a once a day pill that inhibits testosterone. Well, more specifically, dihydrotestosterone. DHT. Right, DHT is converted by 5-alpha reductase, an enzyme that's found throughout the body. now 5-dihydrotestosterone is important in the body it reduces fat, it's good for the heart, 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 and actually there was a study on that there was a study of 3 ,690 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.

1:05:42Dr. David Sinclair:And 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 Propecia. Yeah, there's a bunch, including mood swings. Well, you can 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 that 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.

1:06:17Dr. David Sinclair: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. And 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. And 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.

1:06:57Dr. David Sinclair:They are. It's a 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.

1:07:34Dr. David Sinclair:There are some of them. There's one called GDF-15, for example. But 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.

1:08:10Dr. David Sinclair:And they found that there were remarkably stressful periods of those people's 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, a 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.

1:08:55Increasingly over the years, we've gotten better and better and better at that.

1:08:57Dr. David Sinclair: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.

1:09:37Dr. David Sinclair: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, if you eat 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 wound 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.

1:10:08And these are giving us the DHAs and the EPAs because there's three different kinds of these, right?

1:10:12Dr. David Sinclair: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, and you can't obviously get as much. You have to focus on other types of food that have what's called alpha-linoleic acid or ALA, which is converted slowly, not efficiently, but by the body into the two types we just mentioned that are important, the DHA and importantly, the EPA. Focus then on flaxseed, walnuts, chia seeds, that's where you get your ALA. Linseed oil is where it was first discovered, ALA, linoleic acid.

1:10:52Dr. David Sinclair: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 our cells? 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. They actually be wrapped with insulation tape or insulating material. And that's what these fats do. and these are membranes that wrap around.

1:11:24Dr. David Sinclair: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 that there's two reasons. One is better blood flow and also better neuronal activity and slowing aging of those cells. that involves the sirtuins, this third protective survival pathway that can be activated of course by this, the food and also by exercise.

1:11:58We've seen this in a number of both human and animal studies.

1:12:01Dr. David Sinclair: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-exercising adults that were told for six months to do extra aerobic exercise. So Blumenthal and his colleagues found, what was it, 2019, that this greatly improved executive function, concentration focused. And 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.

1:12:38Dr. David Sinclair: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, Pereira 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-derived neurotrophic factor. And we use that as a way of indicating the youthfulness of the brain and regrowth of new nerve cells.

1:13:13Dr. David Sinclair: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 amyloid beta production by 5%. That's, you don't want to mess with amyloid beta, 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, this study from 2010, Capuccio et al., 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's sleep.

1:14:03Dr. David Sinclair: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 this 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 in season one what has held up what new discoveries are emerging.

1:15:03Dr. David Sinclair: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.

1:15:41Dr. David Sinclair: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