Restore Youthfulness & Vitality to the Aging Brain & Body | Dr. Tony Wyss-Coray

for the first time we could take an old brain and we could give factors from a young organism and ask is that going to change the age of the brain and that's indeed what it did. So we saw that uh there stem cells in the brain of these mice that they got reactivated there was less inflammation more activity um that we can measure in the brain and then most importantly we actually saw that their memory function improved. Welcome to the Huberman Lab podcast where we discuss science [music] and science-based tools for everyday life. [music] I'm Andrew Huberman and I'm a professor of neurobiology and opthalmology at Stamford School of Medicine. My guest today is Dr. Tony Weiss Corey. Dr. Tony Weiss Corey is a professor of neurology at Stamford School of Medicine and an expert in identifying factors that can help prevent and reverse organ. Today we discuss the factors that are present in young blood. Yes, you heard that right. And the factors that are present in blood after exercise that have been shown to rejuvenate the brain and other tissues in older individuals. Dr. Dr. Tony Weiss Cory's lab has discovered several proteins that are present in high amounts when we are young and that circulate in the blood and that diminish with age and if these are supplied to the aged body and brain can reverse key features of aging including improved cognition, tissue recovery from stress, damage and more. We also discussed how aging is nonlinear. It does not progress uniformly across the lifespan. And we discussed the fact that there are certain phases such as puberty, your early 40s and your early 60s when aging is accelerated and then slows again. We also discuss how different organs in your body age at different rates and how you can measure that. Today's discussion is a very important one because so often these days we hear about anti-aging and longevity. But today you're going to hear about the real science of organ rejuvenation. We also are going to talk about the role of sunlight, fasting, hormones, and the use of specific molecular approaches to improve your vitality and health. We also of course discuss exercise and social interactions, but in the context of the specific molecules they release into your blood to promote and enhance health and how you can leverage that information. Tony Weiss Corey is a celebrated pioneer in the science of these topics because of the rigor he applies to the work. He's not just talking about some molecule that someday there'll be a drug or some activity that we already know promotes health. He's an avid tool developer for measuring and reversing aging. So today we discuss all of that and you're sure to come away from the discussion with both tools to improve your immediate and long-term health as well as a deeper understanding of the biology. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Tony Weiss Corey. Dr. Tony Weiss Corey. Welcome. Thank you. Great to see another Stanford colleague here. You're a true pioneer. Your work is the first work that I heard of where somebody did a serious experiment taking blood from a younger organism, putting it into an older organism and observing very interesting things. If you would, could you tell us about that experiment and what if anything has been done in humans to examine whether young blood, such a loaded term, but young blood can be a rejuvenation factor for the more mature body or brain? Yeah. So we were actually not the first ones. Um okay but we collaborated with um the person who in sort of in more modern times uh used this model again. It's called parabiosis where um you have a surgical model where an old and a young mouse are paired and their circulation allows for exchange of blood from the young to the old animal. And my my colleague who uh recruited me actually to Stanford Tom Rando used this model to study aging of stem cells in the muscle. So he discovered that with old age the muscle sort of deteriorates and and doesn't regenerate. And when he used the mouse, an old mouse and paired it with a young mouse and then now this young circulation um infusing if you will the old muscle, he regenerated that muscle and u it looked almost like a young muscle. uh and at the same time we also observed effects in other tissues including in the brain and that's when we started to collaborate um and and explored uh what could the effects of the brain uh of of young factors on the brain uh be and in part we were also intrigued by that because we had separate studies in humans where we tried to find blood signatures of Alzheimer's disease and what we noticed is that we could see proteins that were correlated or even predictive of Alzheimer's disease. But the most striking difference was between younger and older people. So we saw that the concentration of their proteins was very different in young people and old people. And when you see something like that in biology always ask is this cause or effect? So do the proteins in our body change because they respond to the aging of the brain for example or do they actually drive the aging of the brain? And here Tom had this model that allowed him to ask that question or that allowed us together to ask that question because for the first time we could take an old brain and we could give factors from a young organism and ask is that going to change the age of the brain and that's indeed what it did. So we saw that uh there's stem cells in the brain of these mice that they got reactivated. There was less inflammation, more activity um that we can measure in the brain with um electrical activity of neurons. And then most importantly, we actually saw that their memory function improved. And so to your question, is that relevant for humans? So we actually try to translate that and we can talk more about this where that the stage of that field is right now to see whether that can be translated. Yeah, I would love to hear more about that. I um realize in your description that most of us think about blood of course delivering oxygen and red blood cells etc etc but of blood that's drawn as a good not the only but a good window into the health status the age status of a of an organism including us but what I'm hearing is that it's also delivering nutrients or proteins of some kind that can reverse some sort of clock and we'll get into later whether or not it's an organ specific clock or a bodywide clock. But I think um bloodborne factors generally I think of as a readout not um as a medicine but you're talking about bloodborne factors as medicine. Yeah. I think that's really the fascinating aspect of of of of this work that over the past few years people started to look at that many of these uh proteins and probably other molecules in the blood, they're not just reflecting the status of the of the body, if you will, but they're actively influencing how it works. And the composition changes dramatically from young to old. We have this picture that I always like to show when I give a a talk about our work where we have um several thousand individuals and we measure 3,000 proteins in them and then we use collars to show low levels or high levels of proteins and you see this dramatic change from young people to old people in a way that you can pick one sample and you can say this person must be about that old. And we can talk more about what people call clocks. But to your question, yes, there are factors in the blood that clearly can change the function of cells and organs. And what the field is trying to figure out is what are the key ones, which ones could we use to slow down aging or to keep the body healthy as long as you live. So what has been done in humans in terms of an equivalent or pseudoe equivalent experiment to the parabios experiment you described? To try to translate that um we started a company alkaist. Um to to see whether factors from the blood of individuals could influence first of all aging of a mouse brain. So we took blood from young people or old people and injected into mouse brain. we could show that young blood um could in fact mimic the effects of young mouse blood. So there were the similar factors in humans as in mice. And then we went a step further and worked uh collaborated very closely with a company um called Griffles who is producing clinical medicines um for for hospitals based on plasma donation. So they have centers where volunteers donate plasma and then they pull this and they isolate uh for example antibodies. So if you're immuno deficient or you had cancer therapy and you you are uh immunosuppressed you will get regular infusions of antibodies that are sourced from healthy people from these volunteers. Also if you lose a lot of blood you may get albamine which is the main protein in our blood. So this company had this manufacturing process where they collect thousands of donations and they process it into different medicines and this allowed us to test these different fractions and see which ones have an effect in the mice. And again we could find some of them that really were more powerful than others. And so we started some clinical trials in patients with Alzheimer's disease and Parkinson's disease and infused them with these fractions that we've shown uh have uh effects in mice and these were small trials but they looked promising and they're related to what people have been observing previously that if you get a blood transfusions often people have sort of feel invigorated it or their mind they say their mind got cleared or they they improved and this company actually Griffles had also run a clinical study that was blinded placebo controlled in patients with Alzheimer's disease where they first removed their plasma this is called therapeutic plasma exchange and then infused them back with um a major blood component this albamine which also contains other factors and they saw for clear significant benefits and this was in 500 patients. So the field is trying to figure out next steps and hopefully do really one of these large clinical studies where you can then say this actually works and could get FDA approval. Have you done one of these? I haven't. I haven't. Are you close with anyone who who has? I know people who have done it. Yes. And I know people who as a response actually then supported the research that we have to been doing in this field. Um there are companies now that offer this what is called therapeutic plasma exchange and there was a small trial that was again placebo controlled in 40 individuals uh from a company called circulate therapeutics and they then looked in these individuals. These are healthy older people and they use some of these measures that allow us to assess how old an organ how old the body is or how old an organ is called epigenetic clocks. Um, and they could indeed see that some of the uh organs looked younger or the body overall looked younger. There's some improvements in function. Not dramatic but suggesting that there might be something there. I'd like to take a quick break to acknowledge one of our sponsors, David. David makes protein bars unlike any other. Their newest bar, the Bronze Bar, has 20 gram of protein, only 150 calories, and zero gram of sugar. I have to say, these are the best tasting protein bars I've ever had, and I've tried a lot of protein bars over the years. These new David bars have a marshmallow base, and they're covered in chocolate coating, and they're absolutely incredible. I of course eat regular whole foods. I eat meat, chicken, fish, eggs, fruits, vegetables, etc. But I also make it a point to eat one or two David bars per day as a snack, which makes it easy to hit my protein goal of 1 gram of protein per pound of body weight. And that allows me to take in the protein I need without consuming excess calories. 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It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium are vital for the functioning of all cells in your body, especially your neurons or your nerve cells. Drinking Element makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. My days tend to start really fast, meaning I have to jump right into work or right into exercise. So, to make sure that I'm hydrated and I have sufficient electrolytes, when I first wake up in the morning, I drink 16 to 32 ounces of water with an element packet dissolved in it. I also drink Element dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I'm sweating a lot and losing water and electrolytes. Element has a bunch of great tasting flavors. In fact, I love them all. I love the watermelon, the raspberry, the citrus, and I really love the lemonade flavor. So, if you'd like to try Element, you can go to drinkelement.com/huberman to claim a free Element sample pack with any purchase. Again, that's to claim a free sample pack. I can imagine a situation where there are factors in blood that can damage tissues that arise when there's some sort of injury. Let's say a heart attack or even a a hip fracture um you know pick pick an injury. I can also imagine a situation where the blood of very healthy vigorous younger organisms is devoid of all of that. So, when I'm thinking about what could be in young blood that could be rejuvenating, I can imagine that there's sort of a possible double dissociation there. That as we get older, we're having little, let's just call them micro injuries that we're not aware of all the time. And that infusing young blood into that person um would make them feel better. So, you're counteracting the bad stuff. But there's another picture where you're supplying something that's pro- youthful. Do you know whether or not the proteins that are contained in young blood are inhibiting the damage induced bad stuff or it's supplying something that is really a kind of a youthful factor? Two different things. Yeah. Yeah. Right. And and you could see where they would interact. But the reason I'm getting granular here is because I think ultimately for a therapeutic you'd want to be able to um dissociate between these two. Yeah. Yeah. Yeah. No, it totally makes sense. And in a short I answer it. It's all of the above. Um, so what we see is with age there's an increase in many what we call inflammatory proteins and we actually identified some and in mice if we knock them out or if we neutralize them then cognition improves in the mice in old mice. So there you have examples of uh factors and actually natural factors that can inhibit some of these detrimental factors. But then you have also um active progrowth factors, growth factors that um stimulate the activity of cells and might you know maintain stem cells better. So they're they're truly beneficial factors, right? The challenge in this field has been to figure out which ones are the most important ones and is there a a smallest possible number of factors that you would need to have an effect, right? Sort of a cocktail. Now, you could say our blood is nature's cocktail, right? It's the the alexia of youth. It just sort of or it's the fountain of youth that lives in us, but it dries out as we get older. But it also accumulates. There's also an accumulation of bad stuff. So it's not just a loss of that fountain. We have now tools where we can in mice again we can look at every cell in the body of a mouse and we can ask how does to the cells in an old mouse respond to young blood. And what you see is that almost every cell changes their behavior when we measure their transcript. So their gene expression in these cells but they respond in different ways and it's expected because they have different what we call receptors. So one cell may respond to one factor and another cell to another one. And what's also interesting we see a lot of stem cells seem to be targets of these young factors which sort of proves what what we originally described but now in an unbiased way. We look at everything and we ask what are the major effects and then you what you also see that some organels such as mitochondria these are the energy producer units in in inside cells they are key targets of these rejuvenating effects. So it all makes sense based on what we know from the aging field, what we know from stem cells and maintenance of stem cells. But pinpointing which factor you would need to have this rejuvenating effect or which one you have to block has been extremely challenging because you almost have to go into the organism and then we call this crisper tools where you can knock out one gene after another and ask which one is the important one. We can't really do this easily in vivo yet, but that's almost what we need to do. So, unfortunately, in the past 10 years, you know, there's individual factors that people keep describing, but I think we have not really come up with a good method to integrate multiple different factors that could provide or sort of an amplified benefit and mimic what what nature is doing. Should I be banking my blood? You don't have to um because what we find even though there's differences clear differences from one person to another overall if you have the blood of a young person that blood has overall the similar concentrations from another young person and it would still be beneficial to you. So all the blood that we ever used in our studies was always a pool from multiple individuals and that still has the beneficial effect. So for for these type of studies, you would not have to bank your own blood. Is the lore around Dracula based on this general logic? And if so, how do you think that lore arose? Meaning, I don't think somebody sat back and thought, "Oh, I can make up this story about this Count Dracula who, you know, drank youthful blood." And um I mean, does that mean that experiments were being done long ago? I'm not trying to get gruesome here, but we know for instance blood letting and a bunch of other um you know scientifically dubious uh uh things have been used throughout history. But then again to reduce iron load in the blood, some people will give blood. Um it's also a nice thing to do for your blood bank. They need blood in hospitals and too much iron load isn't good. We know that. So what's known about the origins of the Dracula story visa v the science that we are now aware of? Yeah. sort of in retrospect, I think where they came from is maybe more that people realize that, you know, blood is this essential fluid. If you get a cut and you bleed too much, you're dead, right? Um but then maybe also associated it with um with age or youthfulness. I don't know exactly how we have not done and you know this question came up many times before. We have actually never fed mice young blood. You could try that, right? To because it would have to be absorbed. The factors would have to be absorbed into the body. I wouldn't be surprised if some of them wouldn't have beneficial effects and survive sort of the the you know the the the the stomach um acid environment of the stomach, but uh nobody's ever done it. I don't know where it comes from but it's [gasps and laughter] yeah I mean there's a lot of these questions and blood letting too you know it's blood thinning also right the um these leeches release factors into the blood and they must have done something otherwise people would probably not have done it it's pretty wild I again not I'm not trying to be gruesome or medieval here it's just you know now and again something from the historical text shows up in um modern science and we kind of go, well, there's sort of a mapping of of some of the past to to something that is, you know, clearly of a scientific validation. I'm not promoting drinking blood. I'm interested in organ specific rates of aging. Um, and then I also want to circle back to organ specific delivery of nutrients because what you're talking about is blood infusion goes everywhere. It goes into the general circulation. you've mainly focused on the brain, but um it's possible that certain organs are more uh receptive to these youthful factors than others. I mean, even the brain has a bloodb brain barrier. The gonads have a blood gonad barrier for interesting reasons. What is known about the rates of aging in different organs? Do they happen in parallel or no? And how different organs respond to these youthful factors? Yeah. So it's really interesting that you know intuitively you think an organism just ages sort of as a whole in synchrony we would say right but what uh researchers have discovered and this was first I think Monica Driscoll uh was the first to show in worms that when she looked at at the ultraructural level that some of these organs in the worm seem to look more aged than others and over the years now we have molecular tools where we can look at a single cell level or within an organ. And what we clearly see is that organs and cells within uh an organism can have slightly different rates of aging. And the way we conclude that is if we look at all these tissues in many different organism and we every you know period of weeks or months in mice for example we harvest tissues from different animals. We can see these trajectories that some of them are relatively stable for a long time and then they start to decline where others continue decline from early adulthood and and yet others you know may maintain almost until the animal expires. So that allows you then on an individual level to ask if you compare now one individual to another, do their organs age exactly in the same way or is maybe there a person um whose heart ages a little bit faster than their actual the rest of their body and in another person it would be the lung or the brain. And that's indeed what we seem to be seeing. And [clears throat] the way we did this in humans and maybe we can talk about this now is again we look at these proteins and there's company companies now that can look at thousands of proteins in a drop of blood and this is not Sranos. This is this actually real um platforms real science where uh in in just a drop of blood there's companies that measure 11,000 proteins. Now the concentration of these 11,000 proteins and there's large population based cohorts uh where people follow healthy people over two decades or even longer now and they collected blood and so we can profile this blood now and we can ask are proteins in that blood related to what diseases people develop or how they age. And the way how we make this what people call a clock for a specific organ is we look in your blood for proteins for example from the brain. So out of these thousands of proteins that we can measure in the blood. Some of them originate from your brain. Some originate from the lung, from the liver, from the heart. And we've always used that in clinical medicine, but we measure only a handful of proteins. It's usually a few liver proteins, a few heart proteins and we use them to assess injury or um uh loss of function. So if your liver is damaged, that's what we detect. But here we have now an opportunity to look in thousands of people at proteins that come for example from the liver and ask how do they change with age? And that allows us to then estimate the age of the liver in an individual. And what we find is that for most people, the age of your organs is pretty much in sync with your body. But for some individuals, you have more or less of a deviation. So your liver may age faster um than that of the rest of the population and the rest of your body. And what is really super exciting, we call this an age gap. So the difference between your actual age and the estimated age of your organ. And that's a very strong predictor of your future risk to develop disease in that organ. So in other words, if your heart shows to age faster, you're more likely to get heart disease or a heart attack. If your kidney ages fast, you're going to get kidney disease. If your brain ages faster, you're more likely going to get Alzheimer's disease. Is this a test that anyone can now take? Is it commercially available? Yeah. So, that's a great question. We started a company uh with Paul Ketta um called Vero Biosciences. Vero Vero Biosciences. And the mission is really to profile the age of organs to ideally eradicate chronic diseases and to um maintain or to predict which organ is going to age. Because what we find is that if you have an organ that ages faster, if you can detect that and you can do an intervention, you can potentially delay aging, right? And extend health span. And this is really the mission of uh of Vero. The Vero Compass uses a combination of this biological signature together with clinical and wearable data to create a platform that can predict how you respond, which or first of all which organ is the most sensitive, which intervention you can use and then whether your organ responds or not by repeated testing and sort of creating a continuous loop where I tell you which organ is of concern. You get medical advice based on other data that uh we can obtain from you and then you may get an intervention could be a classic medical treatment but it could also be a change in your lifestyle exercise change of diet type of exercise but have it tailored to your specific needs and then we can test does that intervention actually change the age of your organ. It seems spectacular. I realized in addition, let's say I were going to start a new medication. Um maybe uh taking a new drug for ADHD. Not for me. I don't have ADHD fortunately. But you know, people are doing this all the time now, trying different drugs for different things or uh taking something to lower their APO as it were. And then you could monitor how that impacts for better or worse the the age of a particular organ or or set of organs. Exactly. Absolutely. So in many diseases, complex diseases, Alzheimer's disease in particular, we know that people have probably different forms of Alzheimer's disease and we know there are risk factors that predispose you to have Alzheimer's disease, but most of the trials now are done in all comers with the disease who already have the diagnosis. And so you could imagine that if you have these predictors of change, the predictors of risk and you get actually more resolution and we can talk about that in a minute. What the next stages of this type of research, you may get different profiles in people and say okay let's test this new drug in this type of Alzheimer's disease who has a very particular risk profile uh rather than in everyone. and then the drug fails. I think we may have tested a lot of drugs out there that might actually be beneficial, but because we apply them to everyone and we apply them too late, they fail and we throw them away. Yeah. We had um David Fagenbomb, Dr. Dr. David Fagenbomb, he's an MD uh University of Pennsylvania professor of medicine um who himself was diagnosed with Castleman's disease and took it upon himself to try essentially every approved drug as a lastditch effort. He was dying basically and he came up with a combination a small kit of already approved medications and he's now been alive 11 years since his essentially death diagnosis or excuse me death prognosis. Um and he has a a a um not for-p profofit called every cure where people with um diseases that have resisted all other forms of treatment people can go there and they use AI to come up with you know reasonable candidates to try because as he he said exactly what you said which is that many of the solutions to diseases that are common may already exist but they've been swamped by the variation in those diseases when when looked at in clinical trials. So, uh, the idea that we're that we're already sitting on good treatments and cures that wouldn't have to pass through all the testing is very interesting. There's also very little incentive for drug companies to invest in those because they've passed through their um, patent window. So, there's not a lot of money to be made. Sometimes another problem. I have a question that I promise I'm just going to be I I've had this podcast long enough to know that I don't tap dance around things anymore. David Sinclair has been very um I'm not trying to attack David but I want to know David has been very vocal about NAD and the NMN pathway which is you know upstream of of and NR others have talked about NR there's you know true niogen I'm not trying to go after any one person or company but for a while there was a lot of excitement mainly generated by David that um NAD which goes down across development into adulthood uh might be a prolongevity treatment. I confess I take NMN um powder. I don't get paid to say this. I know I won't doesn't even matter what company I get it from cuz I buy it like everybody else. Um I don't have any belief that it's going to increase my lifespan, but it seems to have a pro energy effect that I like. For some reason, it makes my hair grow very fast and my nails grow very thick, which is a side effect I wasn't looking for. Okay, maybe I should try it, too. My sister experiences the same thing. But you know, this is all anecdata, right? Again, I make no money for saying this, but I've seen a lot of criticism of the NAD hypothesis of longevity. And so, is there any evidence that increasing NAD levels either through NMN or through NR or direct infusion or injection of NAD, any of those things can actually extend the lifespan of humans and or experimental models. Yeah. Yeah, I mean this is not my area of expertise but um just as a blank statement there is no human intervention that can extend lifespan that has been tested or validated. There are many that have shown beneficial effects in animal models including NMN and you know all these metabolites. Um there's actually a clinical study that shows that if you take these supplements they increase your levels in the blood. That's a good clinical study, but it doesn't show that it has an effect on lifespan or even on frailty or any other tangible outcome. And this is the case with many other medications that might be beneficial, but they have simply not been tested in a clinical trial. They have been tested in disease sometimes and they are you know very good drugs to treat a person who is sick but they have not test been tested in healthy elder people and see whether they reduce aging or increase health span. There's really nothing out there except exercise and diets. Um those have sort of proven um effects. There's a very good study from a researcher in in in Singapore who tested 10 different preparations of of NMN and she found that many of them actually don't contain what is on the label. That doesn't surprise me and that's the case for most supplements for half the supplements. There's, you know, many resources out there you can check or you can just ask CHPT. Um there's not in there what it says. And with NMN apparently and according to Chachi PT um is very unstable and so it it degrades quite quickly. So you want to make sure I think with any supplement if you want to try it make sure it's from a good source um and that it has that it has been third party tested. Yeah. And and and you use it within the you know time frame. Yeah. No, I I appreciate you saying that. I um like I said, I I don't expect to live longer because of taking NAD. I just sort of like the effect that it appears to give me. I'd like to talk about the relationship between things that increase vitality that are abundant in youth versus their possible role in decreasing longevity. I've been fascinated by this for a long time. So, um bear with me here. Uh and I'll try and set the stage and then I'll be quiet. Puberty is perhaps the fastest rate of aging that we undergo in our entire lifespan. Within two years, we transform as an organism. Right? Some people progress through puberty much faster. Other people seem to have a more protracted puberty. And here I'm defining puberty as the acquisition of secondary sex characteristics, facial hair, etc. Uh uh reproductive uh ability, etc. Okay. So um puberty is a constellation of things that obviously differs in males and females. It's correlated with hormones like testosterone, estrogen, gonadotropins, etc. But really it's a brain thing that switches on that then start initiates all of this. So there have been many attempts in the the kind of health and wellness space to take the hormones usually testosterone, estrogen and growth hormone being the three primary ones and then supply those to people in adulthood. Pmenopausal women taking estrogen and or testosterone nowadays quite frequent this happens a lot. Uh men taking testosterone either because they need to quote unquote replace it or they're just trying to augment what they already have. growth hormone. Certainly all of these things dosed appropriately we know will increase vitality, energy, libido, recovery from exercise in some cases maybe cognition etc. But it's also been demonstrated that when you increase growth hormone and IGF-1 that you decrease lifespan. This is seen in large dogs versus small dogs. The reason larger dogs live so much shorter lives than small dogs is because of the dosing of IGF-1. So, how do you look at the balance between vitality and longevity? And are there factors that can increase both vitality and longevity? Because to my knowledge, the things that these hormones mainly that increase vitality, well, if they allow you to exercise more and perhaps be leaner, then perhaps they buy you some time, additional time in life, but they also decrease the amount of time you have alive. So, it's a very interesting interplay and most people um conflate longevity and vitality. That's an an excellent question and you know short answer is we don't know. We don't really know and in the aging field this is called antagonistic pleotrophy. So something that is good when you're young can be bad when you're old, right? It it relates to this to this concept. And humans are of course you know they're sort of exempt from evolution uh if you will right so our natural lifespan is probably around 30 to 40 if you look back in history that's how long people lived I mean there were always individuals who had you know exceptional lifespan but most people would die much earlier and infections um and it was probably mostly infectious diseases Um, but you know, you could could argue from an evolutionary perspective, once you're sexually mature, you reproduced, and you guaranteed your offspring, which is around 30 to 40 years, nature doesn't care about you anymore. And so, there's no longer, it's very brutal to hear, but as long as your kids are are sufficient enough to raise, an infant can't raise itself. That's right. a seven-year-old maybe could if they were very industrious, you know, but but kids need us at least until they're in their late teens, And then, you know, you you may have some evolutionary pressure to maintain individuals who have knowledge and wisdom to help the, you know, the the group to survive. But that's probably a much weaker um force of evolution to keep you alive, right? And so that's why people increasingly see now that there these inflection points that you know menopause but also in men around age 30 to 40 dramatic changes in the composition again of the blood. We just looked at this mentioned earlier. If you look at the composition of the blood across human lifespan from 20 to 90 we call these waves of aging. The first wave is around 35 years of age. dramatic changes in concentrations of lots of factors and not just in women in men as well. 35. It's a degra degradation, any improvement. Some go up, some go down. And you know, it's it's speculative, but does that have something to do with this is how long nature needs us and then it doesn't care. And you know the the fact that we live now 80 or even longer on average, right, is really thanks to hygiene and you know um certain medications that you know blood pressure and and heart disease that we have. I have a friend who's called me over the weekend. He's got some antibiotics. Brutal infection that that could almost took out his vision in one eye. Antibiotics infused. Boom. Done. And I know some listeners don't like antibiotics and they're concerned about it. I'll tell you, if you have a brutal infection that's aggressive and it's near your brain or your eye and you get on systemic antibiotics and they're the right one, you are one lucky individual. And if you don't, you're you could be looking at excavating one or both eyes. It's brutal. Yeah. Yeah. Wonderful. Many different infections. Antibiotics are, you know, a lifesaver. Absolutely. Yeah. So, um, it's a really good point and actually my my my friend Tom Rando uh mentioned earlier he always makes that point that, you know, a lot of the study look at lifespan as an outcome in animal models, but they don't really look at how active or, you know, what what is sort of the the level of that extended lifespan is are they just hanging in there these organisms or are they still strong and and and vital? right? Is the vitality still there? And and I think we don't we haven't found a magic that would keep everything together for a longer period of time and certainly not in humans. If you're a regular listener of the Huberman Lab podcast, you've no doubt heard me talk about the vitamin mineral probiotic drink AG1. And if you've been on the fence about it, now's an awesome time to give it a try. For the next few weeks, AG1 is giving away a full supplement package with your first subscription to AG1. 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Lately, I've been um somewhat surprised, although not entirely, by some of the data on um sunlight exposure and lifespan. There's this really interesting large-scale study out of Sweden where people the more sunlight exposure people got, the longer they live. Even smokers who get more sunlight appear to on average these are averages folks seem to so overlapping distributions but live longer than um non-smokers who don't get sufficient sunlight. Now getting a lot of sunlight is also correlated with outdoor activity, fresh air, a number of things. So it's it's far from perfect study but um yeah the interplay between vitality and I think of sunlight as provitality um and longevity is such an interesting one because the dance that we seem to be playing now with medications and could be supplements but really medication and lifestyle is what can we do and take to get more life but also to enjoy that life more. And there are certain things like growth hormone which will make people feel much more youthful, much more youthful, skin, hair, even cognition etc. Ability to maintain or put on muscle, lose fat and on and on. But higher IGF-1 and growth hormone, broadly speaking, means a shorter life. Yeah. Maybe comes at a price. Yeah. Yeah. So I guess um I mean that can be determined individually whether or not somebody wants to make that tradeoff. But what I'm excited about are the things that are possibly in these uh blood transfusions that come from younger humans, maybe us, but younger humans, you said pulled um that are getting to cellular function in a different way that are restoring vitality and longevity. And maybe there are a few candidates that you could discuss with us and what pathways they impinge on. I probably won't be familiar with the specific molecules, but are they impacting DNA, the the epiggenome, are they impacting mitochondrial function? If you would maybe pick your two or three favorite candidates, if you if you can, I know some of these are still under study. The factors often are growth factors. Um, GDF11 is is one of them that has been described. Growth and differentiation factor. There is you know IGF-1 actually also has been described to be in young blood is is higher. There are factors that have been identified through an approach that is similar to transferring young versus old. So what one of my trainees did, Saul Va when he was a graduate student in my lab, he did these parabiosis experiments and then his lab and my lab independently um did an experiment where we exercised mice, young mice, we took their blood and we injected it in nonex exercise mice and we could show that the beneficial effects of exercise on the brain were transmitted again by blood. Were you going young to young? So we went young to young. Saul went young to old and could show that he can has a stronger effect on uh on these brains than just uh young blood. If it's exercise young blood, it's even better. So surprising to me because um I think of exercise as a purposeful stress that induces inflammatory molecules that then induce an adaptation. Are there factors that are liberated during exercise, brain derived neutrophic factor, etc. that are that are prohealth and vitality that are not designed to get a an adaptation that are just good stuff coming out of the cells when we exercise? What both actually he and my lab found is that somehow this exercise seemed to trigger the release of factors from the liver that then go to the brain and make the brain function better. In our case, we described the protein that's called clusterin. It's has many different roles. It can bind to lipids. It's also called apoloprotein J. It's involved in coagulation and complement pathway. very complicated. We couldn't quite figure out how does it have these uh effects but we could show that if we rec if we make re combinant synthetic uh clusterin and injected into mice we could mimic some of the effects. This is clusterin. Yeah, it's in the compliment pathway. uh compliment um initially identified as part of the immune system uh coat cells as a part of the eat me signal uh in the immune system system or the eat me system um but does many other things too right involved in synapse formation and remodeling and we know from Beth Stevens work and others um wild wild yeah wild and then uh Saul found another factor that's called GLDH um that again uh he can clearly show has an effect um But how exactly does that is is not clear. Most recently he does did another really creative experiment where he um did caloric restriction of mice and again that's sort of a an accepted you know beneficial effect and longevity promoting potentially um and takes the plasma from mice puts it into other mice and again can isolate factors that mimic this effect because of of intermittent fasting. Yeah. What this tells us is that this is physiology, right? We call this physiology, but organs in our body communicate with each other and there's an orchestration of effects that leads to factors that are released into the blood and then they go to different organs and have in this case beneficial effects. So the exercise effect is not just because you think you're exercising, but they're actually factors released that seem to benefit your brain. So interesting. There's this idea that was at least to me first put forth in a book called Spark. Do you know John Ry's book? It's some it's you know came out some years ago. He's a a physician I believe trained at Harvard Med. um and he talked about the essential requirements for movement and brain plasticity. This was early days of understanding neuroplasticity but uh he talked about brain derived neutrophic factor other things are liberated by by exercise but he described some interesting experiments in there of for instance there's a a um a sea dwelling creature that swims around and has a fairly elaborate nervous system at least for it but then at some point in its life settles down on a rock and eats its own nervous system um basically and there's been some interesting experiments looking at what happens when you get that organism or other organisms I believe I think it was that organism but other organisms to continue moving it seems like there's feedback from the process of moving the musculature and it could be neur neuromuscular in origin it could be hormonal in origin I I don't think we know that it comes from muscle but there's something about the requirement for movement that signals to the brain that it needs to continue to exist and not just the motor portions of the brain and that it or the portions of the brain controlling motor activity, but that the body may supply chemical or other types of feedback to the brain that if if it's moving and continues to move that the brain needs to continue to be robust, which I find very interesting because few things to me explain how movement of the body would signal vitality of the brain aside from hormone factors. But it kind of makes sense, right? Continuing to move the body is essential for keeping the brain healthy. Yeah. And I mean exercise interventions, you know, there's thousands of studies that show that exercise is beneficial cardiovascular, but also other exercise. Yeah. Now it seems everyone's excited about resistance training. I mean, I think both is is clearly the answer. I mean, you're you look good. What what's uh I mean, you're you're not in your 80s, but um do I might be Do you exercise? Right. Right. Yeah, that would be impressive. Um, what what is your exercise regimen? People will want to know. Yeah, I I I run. I like running outdoors. I like the sun. [laughter] Um, I I try to get two runs, 5 to 10k per week. Yeah, that's the main exercise I do. I do some Pilates in the morning. I'm struck by how quickly the body degrades after an injury, especially if that injury occurs after age 60. When we are injured as kids, we heal up like it's amazing, right? I mean, kids getting cuts and then just like what happened? It just they heal right up. Do we know why we heal more quickly as kids than as adults? We do know that the immune system ages like everything and it has this bias that it goes from a more specific response to a non-specific response and that is often associated with inflammation. So, it's it's possible that um part of it is that if you have a wound, there's too much of an inflammatory response and less of a healing response. But we also s know from from aging organisms that if you have a cut, there is more of um um there's proteins in the extracellular matrix like collagens and things like that that are often overproduced. and they may interfere with a quick healing response. So I think everything is a little bit out of tune and that might be the reason uh but it's not really something I would know the details. I've always been fascinated by the fact that if we get a cut on the surface of our body um that it may or may not heal with a scar, but if we get a cut on the inside of our mouth, which is loaded with bacteria and warm and moist and in contact with the outside world all day long, it tends to heal with either zero or much less of a scar. There has to be something in the mouth. Fascinating. healing and I believe people are studying this but someone's got to figure this out and it could be saliva wild right I mean the the rate of healing I know there's a lot of blood supply but there's also a lot of blood supply to the nose and and to the hands and there's scars form on the hands and on the nose yeah there's also scarring in babies right may not leave or a cut in a baby may not leave any uh trace but the same type of of wound in an older person may may leave a um a scar for the rest of their life. Yeah. So, how do we move past correlation and to really understand um causitive stuff? So, we'll get back to lifestyle factors, but I mean it's so very clear from the animal studies and from the human studies that you described that there's something in young blood or things in young blood that are pro-rejuvenation for the brain and other tissues. How do we get to a a real prolongevity molecule medication treatment or prohealth maybe more right? I think most people in the field are not really interested in extending lifespan which would be longevity but health span. So, and we talked about this before, right? That you try to maintain the function of your organs until you die. So that your brain would still be functioning your cognitively intact. All your organs would still be functioned relatively well and then you know you fall asleep and and that's the end of your life. Um and not necessarily extending lifespan as you said. It could be that we extend lifespan and you just have 10 more miserable years. That's certainly nobody would want that, right? But I think to get to causation, we need these types of experiments, physiological experiments in animal models first to isolate individual factors and then test them on an individual basis with very rigorous methods which we can do and say okay this factor has the capacity to maintain for example brain function in the mouse. And then we have to test it in humans and do it in a in a careful clinically uh controlled trial where people are blinded whether they got the treatment or not and do a big enough study that we can say okay this truly works and then we have a drug. How close are we to the clinical trial? There are different molecules. Colossal is actually another one. It's this um protein that um has been described to have beneficial effects on multiple different organs. The biology again not exactly clear but K L O T H O clone that's right. Yeah. Yeah. Um and you know there's there's companies trying to move this into humans into human trials. um some of these other factors I think their their companies are trying uh or inhibiting detrimental factors and with with you know individual clinical trials you could get there um in the next 5 10 years there may be something that has an effect I think we will not have a [snorts] factor an individual factor that just has you know this miracle effect on everything this is very clear from the studies of young blood. It's many different factors and they target different pathways, different cell types in different tissues. So you really need to you may have to decide, you know, for this organ we need this treatment, for this organ we need that treatment to optimize its function and keep it, you know, running at full capacity until you're 100 years old. I'm not suggesting anyone do this, but I I do seem to hear now and again that people are taking cloth already. Um not surprising. People will, you know, get ahead of the curve, so to speak. Yeah, I've also read people taking this GDF11. Um I don't know where to get it. I'm guessing it's just Mexico and um Central and South America. There there are a lot of clinics that do this sort of thing. I I will put out a a true story. Um cautionary note a friend who when whenever people say I have a friend it's you know but this is a medical doctor um who had a back pain that was uh giving him a lot of issues and he went to a stem cell clinic in Mexico got an injection of stem cells into a spinal disc which my neurosurgeon friends tell me is a terrible idea. Turns out the disc cannot accept cellular injections. a neuros a ch a chair of neurosurgery told me that. So you can come at me if you want folks, but he's the chair of neurosurgery at a prominent medical school. So that the disc cannot accept direct injections of foreign cells. Anyway, this guy went a different guy, different MD went uh and got this injection and ended up with a um an egg-sized infection that left him paralyzed. He was fortunate enough to be uh airlifted to a certain clinic and uh in the United States and uh told he was that's it. You're done. We're going to have to just sever your spinal cord. Uh he was uh taken to another clinic where fortunately they were able to excise this um this infection and he's mobile today. He will tell you and I'll tell you that you have to be very very careful getting injections of cells in anywhere but the regulations out of country often are are not as stringent and I tell that story because a number of people are excited about stem cells they're excited about these technologies but it it really can be quite dangerous and again this you know is what we discussed earlier the this you know experience that we have in the medical field that you really need to test something in people in a very controlled fashion very carefully with the dose and and and then test it in a blinded fashion ideally so that you know it really works and it's safe and what you mentioned earlier with stem cells there are no such treatments that have been tested rigorously and for many of these other factors they work in some animal models there are some mouse studies that showed they might have an effect. But you cannot translate that to humans. It's just a long road and I would be extremely cautious to take anything that is not really prescribed to you from a from a clinician that you trust. Thank you. Uh by way of contrast, um plateletri plasma PRP is approved by the FDA. People who are undergoing fertility treatments will get injected into their ovary. People are getting PRP injected into their shoulders, their knees, their whatever. Uh I'm not trying to be disparaging of this. It is FDA approved. To my knowledge, plateletri plasma does not contain stem cells. That's correct. But it seems to be beneficial enough and safe enough that the FDA has approved it. Uh what is the deal with plateletri plasma? What has it been shown to be actually useful for? Because just because something is allowed for one indication and is used broadly for a bunch of things doesn't mean that there's evidence that it works for all those things. That's right. That's right. So plateletri plasma has these platelets in there that are full of growth factors. They have these granules that help in wound healing is a primary function. And um somehow that seems to be beneficial in sports injuries. it's often given and as far as I know I think it's from your own blood you you you concentrate these platelets and then they release these factors so you may have a massive load of growth factors that help you heal these various tissues that you mentioned yeah I haven't tried it but I know people who have and and reported some positive effect I've heard also a lot about exoomes and [snorts] there are some clinics I believe where I think exoomes are FDA approved as a treatment What are exoomes and what what have they been shown to be useful for in studies andor clinical? I don't know in clinical studies how they're used, but um so cells can release sort of little packages of material that is filled with proteins, but there's also RNA molecules in there, lipids, metabolites. And some cells do this all the time. cancer cells for example do it. But also some immune cells have a very active release of these little um sort of like little packages, vesicles we call them, that are filled with um again all these different molecules in the [snorts] blood. You find large numbers of these exosomes and that's where they're usually purified from. Different cells have different cargo in these in these vesicles and it seems that they function to some extent to deliver information from one cell to another. It's still a very new field but people explore you know whether they can be used for for treatment purposes but also for diagnostic purposes. Do they tell you something about a specific organ or a tumor that is developing? So when we measure these proteins that we talked about earlier in the blood um we actually measure what's in the exosomes also. So these exosomes they float basically like immune cells they float in the blood and uh we open them up and we measure what's inside. We should probably talk about some of the things that damage vitality and longevity. accident and injury aside, we know that smoking, especially nicotine, um damages DNA, uh increases inflammation and will shorten your life. I don't think there's any debate about that, right? But what about some of the other things that might produce low-level DNA damage? In particular, these days, I'm very interested in EMFs. I I don't actually believe that the low levels of EMFs that are present in most technologies are damaging in the acute uh way that you know being near them is going to harm you. But there is the idea that things can be cumulative, right? I mean I get one X-ray every few years when I go to the dentist, but there's a reason the clinic the the technician runs behind uh the wall. Uh he or she doesn't want to be exposed to that on a daily basis. So how do we feel about things that at a low dose don't damage DNA um or mutate proteins either but that if we are exposed to them over a lot of time could very well do that. What are your thoughts on this? A very difficult question. I mean you could ask the same question about any chemical that we invent and we put into food or we get exposed to right the you know the plastic we you know we drink out of cups hot stuff out of a cup that is coated with plastic and you know we're full of plastic. How is that going to change our lifespan? It hasn't in a in a measurable way so far, right? But we don't know what's going to happen in 20 30 years or if people you know synthesize a compound that is detrimental that it doesn't look detrimental. It has been tested and is safe but as you said if it accumulates maybe or in combination with other stuff it may be detrimental. I think about this from time to time and and I wonder about what's in my environment that I can easily control. I try not to drink out of plastic. Um, uh, you know, I try and drink out of cans that don't have BPAs and things like that if I can. Yeah, if you if you go down that route, you know, it drives you crazy and you could, you know, sort of not do anything anymore or not eat anything. Well, it's getting harder nowadays to to live a clean life. I mean, how long were you in Switzerland before you came to the States? I was 26. Yeah. You were weaned in a very clean environment. very you know uh that's not just a a uh stereotype about about the Swiss being things are yes very tidy and clean the streets are remarkably clean you could drink out of the lake in Zurich right maybe not the lake but you know most most there's still fountains with ground water where you can drink in any village basically yeah if you're lucky enough to grow up in a place where the tap water is clean the food tends to be pretty devoid of dyes and preservatives Um, and your home is centered around eating mostly whole foods, foods that you cook, fresh fruits and vegetables and freshly prepared, right? Even desserts that are fresh that are prepared, right? As opposed to a lot of packaged foods. It seems that that that's a far and away different experience than most certainly Americans get nowadays, right? And you wonder what the effect of that is going to be. We simply don't know. Yeah, we don't know. And I know now there's a big, you know, kind of attack on food dyes as the thing and there no there's no smoking gun data on any of those. But yeah, I think the cumulative effects of things are are worth considering. I think for most people, I try not to think too much about it, but I also I mean growing up in an environment where, you know, we had a big vegetable garden. I have a vegetable garden, you know, I have lots of fruit trees and try to get, you know, stuff out of my own garden. That's a luxury, of course, for a lot of people. Um, but as you said, you can, you know, you can also buy uh fresh fruit. It's more work, right? It's more work than just buying a readymade food, but you know what you're cooking and what's in there. I'm fascinated these days by the um the data on organic versus non-organic fruits and vegetables. I I spend the extra money on organic, but the more I look into it, the more you find that the differences aren't that great. Now taste can be different and ideally you're sourcing from local farms but I have a a friend um actually I'll just he he'll be okay with me saying this. We had uh he's a physician Dr. Teaos Solommani. He's a dermologist um whose son ran an experiment for his uh school project uh looking at uh the differences between organic and non-organic fruits and vegetables in terms of what contaminants and and things uh are on them, pesticides, etc. and found this is one kids study but um uh essentially no significant differences in that particular set uh set of batches of fruits and vegetables and so that is I would say reassuring on the one hand because it means that people who can't afford organic will um probably be doing about as well as people who can but I think if you can grow your own or or access from local farms I mean surely it's cleaner I mean the highest rates of endocrine disruptors are found in rural areas. I always thought that being in a big city was the most dangerous for your lungs and endocrine health. And we had Sha uh Shauna Swan on the podcast. Serious researcher in this area and she said, "No, I mean if you live in an area where they're um spraying crops, cancer risk, endocrine disruption. It's very serious." Also association with Parkinson's disease and Yeah. Right. [clears throat] I'd like to take a quick break and acknowledge one of our sponsors, Function. Last year, I became a Function member after searching for the most comprehensive approach to lab testing. Function provides over 100 advanced lab tests that give you a key snapshot of your entire bodily health. This snapshot offers you with insights on your heart health, hormone health, immune functioning, nutrient levels, and much more. They've also recently added tests for toxins such as BPA exposure from harmful plastics, and tests for PASES or forever chemicals. function not only provides testing of over 100 biomarkers key to your physical and mental health, but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas. For example, in one of my first tests with function, I learned that I had elevated levels of mercury in my blood. Function not only helped me detect that, but offered insights into how best to reduce my mercury levels, which included limiting my tuna consumption. I've been eating a lot of tuna while also making an effort to eat more leafy greens and supplementing with knack and acetylcysteine, both of which can support glutathione production and detoxification. And I should say by taking a second function test, that approach worked. Comprehensive blood testing is vitally important. There's so many things related to your mental and physical health that can only be detected in a blood test. The problem is blood testing has always been very expensive and complicated. In contrast, I've been super impressed by Function's simplicity and at the level of cost. It is very affordable. As a consequence, I decided to join their scientific advisory board, and I'm thrilled that they're sponsoring the podcast. If you'd like to try Function, you can go to functionhealth.com/huberman. Function currently has a wait list of over 250,000 people, but they're offering early access to Hubberman podcast listeners. Again, that's functionhealth.com/huberman to get early access to Function. Well, as long as we're talking about food, we should talk about not eating. We should talk about fasting. So many studies now showing in worms, in mice, in monkeys, and perhaps even in humans that subcaloric intake or inter uh for long periods of time or perhaps intermittent fasting, we can talk about how we define that um can extend life. How is that thought to work? Is it the reduction in this mTor malian target? Is it um reduction inflammation? Is it clearing of senocence cells? Give us the the overview and and any specifics about intermittent fasting and and perhaps start by saying how you define intermittent fasting. Is it daily or is it 2 three days? I think just to answer that there is no definition. Okay. There is no definition and the whole field is also MS. Um you know it's again taking studies in mice for example um and then translating them to humans you know that the lifespan the their whole rhythm um their environment is so different from our environment right that to translate these um is is always a stretch and there's no clinical studies that show a clear benefit of of fasting in humans and some studies in monkeys actually suggest that it's detrimental um for monkeys to fast for example they had more um uh I think worse kidney function and things like that um so overall in from animal studies it's very clear that you activate sort of beneficial pathways they're very diverse um again we can now use unbiased um assessment of any different cell types in an organism at you know gene expression across thousands of genes and we see that different cells respond in different ways and you get functional improvements but they're very broad. They're in part reduced inflammation. Um other cells um you get benefits on their energy metabolism, protein turnover, how they handle sort of what we call the garbage that accumulates in cells. um overall from these animal studies clearly benefits from reducing calorie intake. Uh also less what we call oxidative damage. So it's like you you burn a fire, right? And if if that fire is really intense, you may cause more damage. But how you translate this really to tangible benefits in humans, I'm not sure. Do you practice intermittent fasting? rarely you like breakfast. I I tried um you know Longo's uh diet uh a few times where I reduce you reduce calorie. Walter Longo, I'm familiar with him. What's what's the the contour of the diet? So it's mostly you switch to a ketogenic diet. So a fatrich diet. So your metabolism changes basically from a regular sort of glucosriven diet to burning fat. Um, and you feel that when you start to starve that somehow it's almost like your body changes a little bit in um you you get a bit more alert almost. And in a way that makes sense, right? If you think you're out there in a wild in the wild, whether you're an animal or a human being, if you don't have enough food, the last thing you want is that your brain doesn't work well, right? I imagine the catakolamines, dopamine or epinephrine and epinephrine increase. So you get more alert, right? A little hangry. Yeah. Hangry. Exactly. Got it. But um I'm not sure how long that lasts and how beneficial this is in the long run. But yeah, I've done it a a few times. You know, you do one week, you you lower your calories, I think down to a thousand per day. So it's pretty pretty brutal, but only for 5 days and then we go back to normal. Yeah. I know of a few people who've done um long-term fasts, so three or four days with just water and electrolytes, maybe some ketones, and they were very overweight, carrying a lot of excess body fat, and when they returned to eating, claimed that their appetite was forever changed, in particular, the types of foods they were hungry for. And um that's thought to be uh an effect on the gut microbiome, which then impacts the brain. So, there may be a place for those longer fasts. um uh what do they call the medically supervised fast? I generally just like caffeine, electrolytes, and water until about 10 or 11:00 a.m. Um and then I like to eat no later than no later than nowadays at 700 p.m. because I go to bed a little earlier. So is that intermittent fasting or is that just um being a busy person who wants to still sleep well and exercise, you know? Yeah, it is sort of a fast, right? Uh I mean in English we call it a break fast. Um um and and it is like you know 12 hours maybe where you have no food and I think that that probably triggers some metabolic activity that is different than if you continue to eat. I think the worst is probably for the body to eat all the time like a lot of people snack the whole day. That's not how we were um how we evolved, right? That we evolved being starved on a regular basis. But is that a good thing or a bad thing? For sure, our body is used to it. That's that's that's a fair statement. It can handle it. I can't do the one meal per day thing because that meal ends up being so large that I get a lot of gastric discomfort and then it disrupts my sleep. And that's what I'd like to discuss also is sleep. If there's been at least one, there's probably been three in my mind, but at least one major triumph in the public health discussion over the last let's say 10 years. It's and we can really truly thank the great Matt Walker for this um who wrote Why We Sleep. You know, he was the first person to really say, "Hey, these are all the terrible things that are going to happen to you if you don't sleep enough." And everyone needs different amounts. I'm fine on six hours, so I don't believe everyone needs eight. I I seven I'm great but I'm fine on six, especially with a little nap here and there. But Matt got people scared. Then he got people thinking about how to improve their sleep. And I and others have spent time on this. I think that's one of the great victories of of public health communication around um the best science. Uh the other would be the importance of exercise um both cardiovascular and resistance training. But during sleep, we know that there's this so-called glimpmphatic clearance. the the clearance of junk from uh all the tissues but in particular from the brain uh that's facilitated by the ga hence glimp fatic um have you guys looked at lymph between young and old animals I'm fascinated by that would be very interesting to do because it's the debris from the blood right it's the well it's the debris from the extracellular space that doesn't get picked up by the blood I mean it's essentially the the extra bad stuff, all the ammonia and cellar debris and fragments. I would love for you guys to do an experiment looking at lymph from young and old. I mean, we looked at the cerebrospinal fluid, but it's of course different. And that again differs dramatically with age. The composition changes dramatically. And I had a fellow who was heroic enough or crazy enough to collect um young CSF from from animals, from mice. kilo. Wow. And then infuse it uh via a pump um over a month into old animals. And she could show that you can regenerate the brain um improve cognitive function in these mice. And um oligodendritty, these cells that wrap the connections between neurons, it's like the they produce the the the plastic around the wire, right? If you will. they were the the the strongest target if we looked in an unbiased way. Uh and so she's studying that now in her own lab. But it shows you in another way how a fluid changes from young to old and the young fluid somehow um has beneficial factors that benefit uh the old brain and so I wouldn't be surprised that um there could be beneficial factor in the glimp or the the lymphatics that um might benefit an old organism. We thought about it but it's I think in mice it's extremely difficult. There's also the interstial fluid itself that people have collected but they usually collected by infusing artificial spinal fluid and then um you you almost wash out what it's in there. people have used that in the neurotransmitter field and also more recently to look at you know a beta or accumulation of of of protein deposits in the brain. Why not just go straight to humans? I mean I feel like random lab for a long time. I've worked on so many different species including humans but it seems like given the relatively equal expense of doing exploratory science in mice and humans that unless there's a question you can only address in mice why not just take CSF from young and old humans and and oh yeah that's we have done yeah oh okay CSF is no problem yeah so we measure proteins in the CSF and again thousands of proteins and we ask are there proteins that correlate with cognitive function, with resilience or decline. What's really interesting is so we did this in a completely unbiased way. You find um proteins that go up and go down together with with uh cognition. So that positively or negatively correlate and almost all the top proteins are synaptic proteins. We then use the top two, the one that goes up the most and goes down the most and made a ratio of the two. And that ratio is a very strong predictor uh for cognitive resilience or or decline. And what's scary is that ratio continues to change from early adulthood. So you get you get a continuous basically degradation of that signal and we get uh very prominent um risk uh prediction between the top and the bottom quartile and this is based on 3,000 individuals where we had CSF from and it's independent of pathological markers. So we also had people with Alzheimer's and um uh Alzheimer's disease in there at different stages of disease. So if you look for what is only predicted of cognitive function based on a memory test, we find these synaptic proteins are very strong predictors. Um so again suggesting that the composition change and then you can ask is this a reflection of the change or is it actually driving the change and it seems to be both. Again, it's always tough to get to causality, but uh anytime I see a study that looks in a correlative way at, you know, like which athletes live the longest, it's very interesting, right? I mean, I have no desire to run a marathon. but if I knew that it was going to add 20 years to my life or 15 years, I might start becoming a marathoner, but a recent study showed that um it's the pole vters. Not going to get into that. and the gymnasts and I think the high jumpers and the sprinters. So the fast twitch muscle folks that they get a substantial longevity effect you know 5 to eight years on average more than their you know age match cohorts even compared to other highly trained athletes. So I see a result like that and then of course the the reductionist scientist in me says okay so is it the running is it the jumping is it but then you think like oh using the corey model I mean you can essentially look at the blood from sprinters versus marathoners and of course they're going to differ these are different people after all very different lifestyles in a number of different ways but you have to kind of wonder again whether or not the fe I wonder whether the feedback signals from the body there's such some feedback signals in the form of a chemical that says, "Okay, this body is moving fast, jumping, um, and doing explosive activity essentially on a regular basis that supplies the brain with a a cocktail of things presumably that keeps neurons healthy, keeps them um, you know, keeps the olodenderytes proliferating, right? Uh, that make sure that you know you got plenty of myelin to for those fast fast transmission signals. Um, and to me that's where I like the field of health span and and lifespan, but especially health span really needs to go because otherwise it's just like pick the exercise you're going to do regularly. That's great. That's a great first step. But then ultimately it really does become about quality of life. And if so, the importance of doing these kinds of studies to me is is immense because otherwise it's just sort of like well you do a little cardio, you do a little this, do a little that and um I don't know. I mean that's like saying oh you can get the same level of social connection and from social media as you can can from inerson connect. It's two totally different landscapes. So I'm anyway I'm struck by the idea that exercise is not one thing and that there may be there are certain forms of exercise that are much more potent which it means there probably molecules associated with certain forms of of exercise that are much more potent in terms of brain function. Yeah, that's very interesting. So John Long at at Stanford has a lab and he looked uh at metabolites in the blood of um dogs, sprinter dogs, um horses that do races and then also human sprinters. And he found this um interesting modified uh amino acid uh that is conjugated to lactate, lacy it's called. And that compound seems to spike uh with these extreme bursts of muscle activity. Um and he could then show in animals that it's actually beneficial and mediate some of the beneficial effects. He identified the receptor. So it's a really very exciting uh direction of research. But it it speaks to what you're saying, right, that there's different ways, different forms of exercise, and they may have different effects and they may all be beneficial, better than not doing anything, but they may have different effects and and you may be able to harness one or the other, and also some of us may benefit more from one or the other. It's extremely hard to do a rigorous clinical study on any of this, right? Because obviously if you exercise, you always know it. So you can't be blinded. And if you hate it or if you love it, your brain is probably going to send very different signals, right? I mean, I have friends who just hate exercise and they never want to do it. So how are you going to tell them, you know, you should do this or that? Uh well, if it buys you life anyway, I I'm fortunate that I've always loved exercise. I've always loved it. I feel great going into it. I feel great during and I feel after. I mean, sometimes it's painful, but I always enjoy it. But I realize that not everyone uh not everyone feels that way. Right. our our colleague uh Robert Seapolski told me about a study where they have rodents run on a wheel regularly and um rodents love to run on wheels as you know and they um they of course experience reductions in blood pressure, blood lipids improve etc after the exercise right during the exercise and immediately after there's inflammation but you get the adaptation they improve but if you tether the running of that animal you like it's sort of like your parabolic is experiment. If you tether the running of that animal to another animal that's trapped in a running wheel, it can't leave the running wheel and it has to run when the other one runs. They're doing the same exercise and they're genetically identical animals and the one that's forced to run experiences long-term increases in blood pressure, stress, uh markers of stress and um and deficits in memory associated with hippocample not damage but rewiring. So you realize that the um the choice is big in all of this. That's for me running on a treadmill in a room versus outside. I'm exactly the same way. I mean not to spin off into every study but a lot of Stanford citations here. Our colleague Joe Parvevesi uh neurosurgeon did this amazing experiment where he stimulates uh for other reasons he landed in the anterior mids singulate cortex and when he stimulates there people feel as if there's some um impending pressure on them like they're driving into a storm and they feel motivated they feel the the subjectively tenacity and it turns out that the anterior singulate cortex grows in people who successfully diet who push through challenges in exercise and cognitive of things. So pushing oursel, you can tell your friends that if you enjoy doing something, you actually get less benefit. Yeah, maybe if…

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