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

Starting point is 00:00:00 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 there's stem cells in the brain of these mice, that they got reactivated, there was less inflammation, more activity that we can measure in the brain. And then most importantly, we actually saw that their memory function improved.

Starting point is 00:00:27 Welcome to the Huberman Lab podcast, where we discuss. us science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Tony Weiss-Corey. Dr. Tony Weiss-Corey is a professor of neurology at Stanford School of Medicine, and an expert in identifying factors that can help prevent and reverse organ degeneration and aging. Today we discuss the factors that are present in young blood.

Starting point is 00:00:59 Yes, you heard that right, and the factors that are present in young blood. in blood after exercise that have been shown to rejuvenate the brain and other tissues in older individuals. Dr. Tony Weiss-Corey'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 discuss how aging is nonlinear. It does not progress uniformly across the lifespan. And we discuss 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.

Starting point is 00:01:41 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 things. 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.

Starting point is 00:02:16 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

Starting point is 00:02:45 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. Yeah.

Starting point is 00:03:07 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

Starting point is 00:03:26 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. Okay. But we collaborated with the person who in sort of in more modern times used this model again. It's called paribiosis where 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 colleague who recruited me actually to Stanford, Tom Randall,

Starting point is 00:04:09 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 doesn't regenerate. And when he used the mouse, an old mouse, and paired it with a young mouse, and now this young circulation infusing, if you will, the old muscle, he regenerated that muscle, and it looked almost like a young muscle. And at the same time, we also observed effects in other tissues, including in the brain. And that's when we started to collaborate and explored what could the effects of the brain, of young factors on the brain be.

Starting point is 00:04:53 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.

Starting point is 00:05:49 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 there's stem cells in the brain of these mice, that they got reactivated, there was less inflammation, more activity that we can measure in the brain with 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? We actually try to translate that. We can talk more about this, where the stage of that field is right now to see whether that can be translated.

Starting point is 00:06:35 Yeah, I would love to hear more about that. I realize in your description that most of us think about blood, of course, delivering oxygen, and red blood cells, et cetera, et cetera, but of blood that's drawn as a good, not the only, but a good window into the health status, the age status 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 body-wide clock. But I think blood-borne factors generally I think of as a readout, not as a medicine.

Starting point is 00:07:18 But you're talking about blood-borne factors. as medicine. Yeah. I think that's really the fascinating aspect of this work that over the past few years people started to look at, that many of these proteins and probably other molecules in the blood, they're not just reflecting the status of the body, if you will, but they're actively influencing how it works. And the composition changes dramatically from young to old.

Starting point is 00:07:49 We have this picture that I always like to show when I give a talk about our work, where we have 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 pseudo-equivalent experiment to the parabios experiment you described?

Starting point is 00:08:49 To try to translate that we started a company alchemist 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 brains that we could show that young blood 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, collaborated very closely with a company called Griffiths who is producing clinical medicines for hospitals based on plasma donation. So they have centers where volunteers donate plasma, and then they pool this and they isolate, for example, antibodies.

Starting point is 00:09:48 So if you're immunodeficient or you have cancer therapy and you are 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 albumin, 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 have effects in mice.

Starting point is 00:10:43 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 or their mind, they say their mind got cleared or they improved. And this company actually, Griffith had also run a couple of. 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 a major blood component, this albumin, which also contains other factors. And they saw clear

Starting point is 00:11:29 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 has?

Starting point is 00:11:53 I know people who have done it, yes. And I know people who, as a response, actually then supported the research that we have been doing in this field. There are companies now that offer, this is what is called therapeutic plasma exchange, and there was a small trial that was, again, placebo-controlled in 40 individuals from a company called Circular Therapeutics. And they then looked in these individuals.

Starting point is 00:12:22 These are healthy, older people, and they used some of these measures that allow us to assess how old the bodies or how old an organ is, called epigenetic clocks. and they could indeed see that some of the 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.

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Starting point is 00:16:02 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 the micro injuries that we're not aware of all the time, and that infusing young blood into that person 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-yuthful. Do you know whether or not the proteins that are contained in young blood, are inhibiting the damage-induced bad stuff

Starting point is 00:16:33 or it's supplying something that is really a kind of a youthful factor. Two different things. Yeah, yeah. And you could see where they'd interact, but the reason I'm getting granular here is because I think ultimately for a therapeutic, you'd want to be able to dissociate between these two.

Starting point is 00:16:50 Yeah, yeah, yeah. No, totally makes sense. And in a short, I answer it, it's all of the above. 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 factors and actually natural factors that can inhibit some of these detrimental factors. But then you have also active pro-growth factors, growth factors that stimulate the activity of cells and might maintain stem cells better.

Starting point is 00:17:36 So 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 smallest possible number of factors that you would need? need to have an effect, right? Sort of a cocktail. Now you could say our blood is nature's cocktail, right? It's the alexia of youth. It just sort of, or it's a fountain of youth that lives in us, but it dries out as we get

Starting point is 00:18:07 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 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 transcripts, so their gene expression in these cells, but they respond in different ways.

Starting point is 00:18:40 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 we originally described. But now in an unbiased way, we look at everything and we ask, what are the major effects? And then what you also see, that some organelles such as mitochondria, these are the energy producer units 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,

Starting point is 00:19:24 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 CRISPR 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,

Starting point is 00:19:59 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 nature is doing. Should I be banking my blood? You don't have to. 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 a similar concentration 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.

Starting point is 00:20:44 And that still has the beneficial effect. So 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 with a story about this Count Dracula who drank youthful blood. And I mean, does that mean that experiments were being done long ago? I'm not trying to get gruesome here.

Starting point is 00:21:11 But we know, for instance, bloodletting and a bunch of other. you know, scientifically dubious things have been used throughout history. But then again, to reduce iron load in the blood, some people will give blood. 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 vis-a-vis the science that we are now

Starting point is 00:21:38 aware of? Yeah, sort of in retrospect, I think where they came from is maybe more that people realize that blood is this essential fluid. If you get a cut and you bleed too much, you're dead, right? But then maybe also associated it with age or usefulness. I don't know exactly how. We have not done, and this question came up many times before, we have actually never fed mice young blood.

Starting point is 00:22:09 You could try that, right? 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, you know, the stomach acid environment of the stomach. But nobody's ever done it. I don't know where it comes from. Yeah, I mean, there's a lot of these questions. And bloodletting too, you know, it's blood-sending also, right?

Starting point is 00:22:39 These leeches release factors into the blood. And they must have done something. people would probably have done it. It's pretty wild. Again, 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 modern science. And we kind of go, well, there's sort of a mapping of some of the past to something that is, you know, clearly a scientific validation. I'm not promoting drinking blood.

Starting point is 00:23:10 I'm interested in organ-specific rates of aging. 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 it's possible that certain organs are more receptive to these youthful factors than others. I mean, even the brain has a blood-brain barrier. The gonads have a blood gonad barrier for interesting reasons. What is known about the rates of aging in different organs?

Starting point is 00:23:46 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 researchers have discovered, and this was first, I think Monica Driscoll was the first who's show in worms that when she looked, at the ultra-structural 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 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 organisms

Starting point is 00:24:40 And every 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 declined from early adulthood. And yet others 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 a person whose heart age is a little bit faster than their actual, the rest of their body? And then another person would be the lung or the brain.

Starting point is 00:25:33 And that's indeed what we seem to be seeing. And 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 companies now that can look at thousands of proteins in a drop of blood. And this is not Seranos. This is actually real platforms, real science, where in just the 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 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,

Starting point is 00:26:35 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, usually a few liver proteins, a few heart proteins. And we use them to assess injury or,

Starting point is 00:27:05 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.

Starting point is 00:27:41 So your liver may age faster 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 age is fast, you're going to get kidney disease. If your brain age is faster, you're more likely going to get Alzheimer's disease. Is this a test that anyone can now take? Is it commercially available?

Starting point is 00:28:26 Yeah, so that's a great question. We started a company with Paul Colleta called VeroBio. biosciences. Vero. Vero biosancies. And the mission is really to profile the age of organs to ideally eradicate chronic diseases and to 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,

Starting point is 00:29:03 you can potentially delay aging, right, and extend health span. And this is really the mission 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, first of all, which organ is the most sensitive, which intervention you can use, and then whether your organ response or not by repeated testing

Starting point is 00:29:37 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 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?

Starting point is 00:30:14 It seems spectacular. I realize in addition, let's say we're going to start a new medication, maybe taking a new drug for ADHD, not for me, I don't have ADHD fortunately, but people are doing this all the time now trying different drugs for different things or taking something to lower their APOB, as it were. And then you could monitor how that impacts for better or worse the age of a particular organ 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.

Starting point is 00:31:07 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 stage is 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, 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.

Starting point is 00:31:50 Yeah. We had David Faganbaum, Dr. David Faganbaum, he's an MD University of Pennsylvania, professor of medicine, who himself was diagnosed with Castleman's disease and took it upon himself to try essentially every approved drug as a last-ditch effort. He was dying, basically. And he came up with a combination, a small kid of already approved medications. And he's now been alive 11 years since his essentially death diagnosis. Or excuse me, death prognosis.

Starting point is 00:32:17 And he has a not-for-profit called Every Cure, where people with... 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 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 looked at in clinical trials. So the idea 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 patent window. So there's not a lot of money to be made. Yeah, that's sometimes another problem. I have a question that I promise, I'm just going to be, I've had this podcast long enough to know that I don't tap dance around things anymore.

Starting point is 00:33:10 David Sinclair has been very, 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 an 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 NAD, which goes down across development into adulthood, might be a pro-laugivity treatment. I confess, I take NMN powder.

Starting point is 00:33:46 I don't get paid to say this. I don't know. It doesn't even matter what company I get it from because I buy it like everybody else. 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. Maybe I should try it too. My sister experiences the same thing, but this is all anecdotal, right? Again, I make no money for saying this.

Starting point is 00:34:10 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, I mean, this is not my area of expertise, but 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 NMNN, and, you know, all these metabolites.

Starting point is 00:34:55 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 very good drugs to treat a person who is sick,

Starting point is 00:35:28 but they have not 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. Those have sort of proven effects. There's a very good study from a researcher in Singapore. who tested 10 different preparations 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,

Starting point is 00:36:04 there's many resources out there you can check or you can just ask CHAPT. There's not in there what it says. And with NMN apparently, and according to chat GPT, is very unstable. And so 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. Third-party tested. That it has been third-party tested, yeah. And you use it within the, you know, time frame.

Starting point is 00:36:34 Yeah. No, I appreciate you saying that. Like I said, I don't expect to live longer because of taking an idea. 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.

Starting point is 00:36:55 I've been fascinated by this for a long time. So bear with me here 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.

Starting point is 00:37:16 Other people seem to have a more protracted puberty. And here I'm defining puberty as the acquisition of secondary sex characteristics, facial hair, et cetera, reproductive ability, et cetera. So puberty is a constellation of things that obviously differs in males and females. It's correlated with hormones like testosterone, estrogen, gonadotropins, et cetera. 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 kind of health and wellness space to take the hormones, usually, testosterone, estrogen, and growth hormone being the three primary ones,

Starting point is 00:37:58 and then supply those to people in adulthood. Perimenopausal women taking estrogen and or testosterone nowadays quite frequent. This happens a lot. 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 dose appropriately, we know, will increase vitality. energy, libido, recovery from exercise, in some cases, maybe cognition, et cetera. But it's also been demonstrated that when you increase growth hormone in IGF1, that you

Starting point is 00:38:29 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 IGF1. 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,

Starting point is 00:38:59 then perhaps they buy you some 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 conflate longevity and vitality. That's 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 play a trophy.

Starting point is 00:39:25 So something that is good when you're young can be bad when you're old, right? It relates to this concept. And humans are, of course, you know, they're sort of exempt from evolution, if you will, right? So our natural lifespan is probably around 30 to 40, if you're. 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. Of what?

Starting point is 00:39:53 Infections, it was probably mostly infectious diseases. But, you know, you 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. As long as your kids are sufficient enough to raise it. Exactly.

Starting point is 00:40:23 An infant can't raise itself. That's right. A seven-year-old maybe could if they were very industrious, you know, but kids need us at least until they're in their late teens. And then, you know, you may have some evolutionary pressure to maintain individuals who have knowledge and wisdom to help the group to survive. But that's probably a much weaker force of evolution to keep you alive, right?

Starting point is 00:40:54 And so that's why people increasingly see now that there are 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.

Starting point is 00:41:24 And not just in women, in men as well. 35. To degradation? Any improvements? Some go up. Some go down. And, you know, it's speculative. But does that have something to do with this is how long nature needs us?

Starting point is 00:41:40 and then it doesn't care. And, you know, the fact that we live now 80 or even longer on average, right, is really thanks to hygiene and, you know, certain medications that, you know, blood pressure and heart disease that we have been able. I have a friend who's called me over the weekend and he's got some. Antibiotics, absolutely. I mean, he's got a brutal infection that could almost took out his vision in one eye. Antibiotics infused, boom, done.

Starting point is 00:42:10 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 could be looking at excavating one or both eyes. It's brutal. Yeah. Yeah. Yeah.

Starting point is 00:42:29 For many different infections, antibiotics are, you know, a lifesaver. Absolutely. Yeah, so it's a really good point. And actually, my friend, Tom Randolph 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 is sort of the level of that extended lifespan. Are they just hanging in there, these organisms, or are they still strong and vital, right? is the vitality still there. And I think 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.

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Starting point is 00:45:18 Again, that's Roka.com and enter the code Huberman at checkout. Lately, I've been somewhat surprised, although not entirely by some of the data on 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 overlapping distributions, but live longer than non-smokers who don't get sufficient sunlight. Now, getting a lot of sunlight is also correlated with outdoor activity, fresh air,

Starting point is 00:45:53 a number of things. So it's far from perfect study. But, yeah, the interplay between vitality, and I think of sunlight is pro-vitality, and longevity is such an interesting one because the dance that we seem to be playing now with medications and, you know, 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,

Starting point is 00:46:24 much more youthful, skin, hair, even cognition, etc., ability to maintain or put on muscle, lose fat and on and on. But higher IGF1 and growth hormone, broadly speaking, means a shorter life. Yeah, maybe comes at a prize. Yeah. Yeah. So I guess, I mean, that can be determined individually whether or not somebody wants to make that trade off. But what I'm excited about are the things that are possibly in these blood transfusions that come from younger humans, maybe us, but younger humans, you said pooled, 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

Starting point is 00:47:10 impinge on. I probably won't be familiar with the specific molecules, but are they impacting DNA, the epigenome? Are they impacting mitochondrial function? If you would maybe pick your two or three favorite candidates, if you can, I know some of these are still under study. The factors often are growth factors. GDF11 is one of them that has been described, growth and differentiation factor. There is, you know, IGF1 actually also has been described to be in young blood is higher. There are factors that have been identified through an

Starting point is 00:47:48 approach that is similar to transferring young versus old. So what one of my trainees did Solvilade I mean it was graduated soon in my lab. He did these paraviosis experiments. And then his lab and my lab independently did an experiment where we exercised mice, young mice. We took their blood and we injected it in non-exercise mice. And we could show that the beneficial effects of exercise on the brain were transmitted again by blood.

Starting point is 00:48:19 Were you going young to young? We went young to young. Saul went young to old and could show that you can, has a stronger effect on these brains than just young blood. If it's exercised young blood, it's even better. So surprising to me because 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,

Starting point is 00:48:52 brain-derived neurotrophic factor, etc., that are pro-health and vitality, that are not designed to get up in 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.

Starting point is 00:49:19 In our case, we described the protein that's called clustering. It has many different roles. It can bind two lipids. It's also called apolyproprotein J. It's involved in coagulation and complement pathway. Very complicated. We couldn't quite figure out how does it have these effects, but we could show that if we make recombinant synthetic clustering

Starting point is 00:49:44 and injected into mice, we could mimic some of the effects. This is clustering? Yeah. It's in the complement pathway. Yeah. Compliment, initially identified as part of the immune system, coat cells as part of the eat-me signal in the immune system or the eat-me system, but does many other things too, right, involved in synapse formation and remodeling,

Starting point is 00:50:06 and we know from Beth Stevens' work and others. Wild. Wild. Wild. And then Saul found another factor that's called GPLDH, that again, he can clearly show as an effect, but how exactly does that is not clear. Most recently he did another really creative experiment

Starting point is 00:50:27 where he did caloric restriction of mice. And again, that's sort of an accepted, you know, beneficial effect and longevity promoting potentially and takes the plasma from mice, puts it into other mice, and again, can isolate factors that mimic this effect. Because 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 effect. So the exercise effect is not just because you think you're exercising, but there's a lot. But there's a lot. But there's a lot. And then, there actually factors released that seem to benefit your brain.

Starting point is 00:51:23 So interesting. There's this idea that was, at least to me, first put forth in a book called Spark. Do you know John Rady's book? It's, you know, came out some years ago. He's a physician, I believe that trained at Harvard Med. And he talked about the essential requirements for movement in brain plasticity. This was early days of understanding neuroplasticity. but he talked about brain deradnotrophic factor,

Starting point is 00:51:49 other things are liberated by exercise. But he describes some interesting experiments in there of, for instance, there's 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, basically.

Starting point is 00:52:10 And there's been some interesting experiments looking at what happens when you get that organism or other organisms, 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 neuromuscular in origin. It could be hormonal in origin. 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

Starting point is 00:52:43 motor activity, but that the body may supply chemical or other types of feedback to the brain that 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 to the body would signal vitality of the brain aside from hormone-borne 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 clearly the answer. I mean, you look good.

Starting point is 00:53:32 What's, I mean, you're not in your 80s, but do you exercise? Do you exercise? Yeah, that would be impressive. What is your exercise regimen? People want to know. Yeah, I run. I like running outdoors. I like the sun. 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. It's amazing, right? I mean, kids getting cuts and they're just like, what happened? It's 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,

Starting point is 00:54:24 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 possible that 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 know from aging organisms that if you have a cut, there is more of, there's proteins in the extracellular matrix like collagen and things like that that are often overproduced. And they may interfere with a quick healing response.

Starting point is 00:55:06 So I think everything is a little bit out of. of tune, and that might be the reason, 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, 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 that's pro-healing. And I believe people are studying this, but someone's got to figure this out.

Starting point is 00:55:49 It could be saliva. Wild, right? I mean, the rate of healing, I know there's a lot of blood supply, but there's also a lot of blood supply of the nose and to the hands, and there's scars form on the hands and on the nose. Yeah, it's also scarring in babies, right? may not leave, or a cut in a baby may not leave any trace, but the same type of wound and an older person may leave a scar for the rest of their life.

Starting point is 00:56:18 So how do we move past correlation and to really understand causative 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 describe 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 real pro-laugivity molecule medication treatment?

Starting point is 00:56:45 Or pro-health, 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,

Starting point is 00:57:07 you're cognitively intact, all your organs would still be functioned relatively well, and then you fall asleep, and that's the end of your life. And not necessarily extending lifestyle, as you said, it could be that we extend lifespan and you just have 10 more miserable years. That certainly nobody would want that, right?

Starting point is 00:57:28 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 careful, clinically controlled trial where people are blinded, whether they got the treatment or not, and do a big enough study that we can say,

Starting point is 00:58:08 okay, this truly works, and then we have a drug. How close are we to the clinical trial? There are different molecules. Clotho is actually another one. It's this protein that has been described to have beneficial effects on multiple different organs. The biology, again, not exactly. clear. K-L-O-T-H-O. That's right. Yeah. Yeah. And, you know, there's companies trying to move this into humans,

Starting point is 00:58:43 into human trials. Some of these other factors, I think their companies are trying or inhibiting detrimental factors. And with, you know, individual clinical trials, you could get there in the next five, ten years, there may be something that has an effect. I think we will not have a 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, for this organ, we need this treatment, for this organ, we need that treatment to optimize its function and keep it running at full capacity until you're 100 years old.

Starting point is 00:59:40 I'm not suggesting anyone do this, but I do seem to hear now and again that people are taking clotho already. Not surprising. People will get ahead of the curve, so to speak. Yeah, I also read people taking this GTF 11. I don't know where they get it. I'm guessing it's just Mexico and Central and South America. There are a lot of clinics that do this sort of thing. I will put out a true story, cautionary note, a friend who, whenever people say I have a friend. This is a medical doctor who had a back pain that was 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,

Starting point is 01:00:26 which my neurosurgeon friends tell me is a terrible idea. It turns out the disc cannot accept cellular injections. 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 and got this injection and ended up with an egg-sized infection

Starting point is 01:00:56 that left him paralyzed. He was fortunate enough to be airlifted to a certain clinic in the United States and told he was, that's it, you're done. We're going to have to just sever your spinal cord. He was taken to another clinic

Starting point is 01:01:13 where fortunately they were able to excise 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 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 really can be quite dangerous.

Starting point is 01:01:40 And again, this, you know, is what we discussed earlier, 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 then tested in a blinded fashion ideally so that you know it really works and it's safe. And what you mentioned earlier was 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

Starting point is 01:02:22 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 clinician that you trust. Thank you. By way of contrast, platelet rich 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. I'm not trying to be disparaging of this.

Starting point is 01:02:53 is FDA approved. To my knowledge, platelet-rich 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. What is the deal with platelet-rich plasma? What has it been shown to be actually useful for? 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 plated-rich plasma has, these platelets in there that are full of growth factors. They have these granules that help in wound healing.

Starting point is 01:03:31 It's a primary function. And 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 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.

Starting point is 01:03:53 Yeah, I haven't tried it, but I know people who have and reported some positive effect. I've heard also a lot about exosomes, and there are some clinics, I believe, where I think exosomes are FDA approved as a treatment. What are exosomes and what have they been shown to be useful for in studies and or clinical? I don't know in clinical studies how they're used, but so cells can really sort of little packages of material that is filled with proteins, but there's also RNA molecules in their 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, sort of like little packages, vesicles, we call them, that are filled with, again, all these different molecules. In the blood, you find large numbers of these

Starting point is 01:04:51 exosomes and that's where they're usually purified from. Different cells have different cargo 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 whether they can be used 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, we actually measure what's in the exosomes also. So these exosomes, they float basically, like immune cells, they float in the blood. And we open them up and we measure what's inside. We should probably talk about some of the things that damage vitality and longevity.

Starting point is 01:05:48 accident and injury aside. We know that smoking, especially nicotine, damages DNA, 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 don't actually believe that the low levels of EMFs that are present in most technologies are damaging in the acute 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

Starting point is 01:06:30 a reason the technician runs behind the wall. 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 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.

Starting point is 01:07:07 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 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, 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 I wonder about what's in my environment that I can easily control.

Starting point is 01:07:46 I try not to drink out of plastic. You know, I try and drink out of cans that don't have BPAs and things like that if I can. Yeah, if you go down that route, you know, it raise you crazy and you could, you know, sort of not do anything anymore or not eat anything. Well, it's getting harder nowadays to live a clean life. I mean, how long were you in Switzerland before you came to the States? I was 26. You were weaned in a very clean environment. You know, that's not just a stereotype about the Swiss being.

Starting point is 01:08:22 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, there's still fountains with groundwater 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. And your home is centered around eating mostly whole foods, foods that you cook.

Starting point is 01:08:55 Fresh fruits and vegetables are freshly prepared, right? Even desserts that are prepared, right, as opposed to a lot of packaged foods. It seems 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 dies as the thing. And there's no smoking gun data on any of those. But yeah, I think the cumulative effects of things are

Starting point is 01:09:23 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. a luxury, of course, for a lot of people. But as you said, you can, you know, you can also buy fresh fruit. It's more work, right? It's more work than just buying a ready-made food. But you know what you're cooking and what's in there. I'm fascinated these days by the data on organic versus non-organic fruits and vegetables. I spend the extra money on organic, but the more

Starting point is 01:10:05 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 friend, actually, he'll just, he will be okay with me saying this. He's a physician, Dr. Teo Solomani, he's a derm oncologist whose son ran an experiment for his school project looking at the differences between organic and non-organic fruits and vegetables in terms of what contaminants and things are on them, pesticides, et cetera, and found, this is one kid's study, but, um, uh, you know, essentially no significant differences in that particular 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

Starting point is 01:10:54 afford organic will probably be doing about as well as people who can. But I think if you can grow your own 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 shot 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 spraying crops, cancer risk, endocrine disruption. It's very serious. Also association with Parkinson's and cussies.

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Starting point is 01:13:07 but they're offering early access to Huberman podcast listeners. Again, that's functionhealth.com slash 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 subcholaric intake for long periods of time or perhaps intermittent fasting, we can talk about how we define that can extend life.

Starting point is 01:13:36 How is that thought to work? Is it the reduction in this mTOR, mammalian target of rapamycin? Is it reduction in inflammation? Is it clearing of senesin cells? Give us the overview and any specifics about intermittent fasting and perhaps start by saying how you define intermittent fasting. Is it daily or is it two, three days? I think just to answer that there is no definition.

Starting point is 01:14:02 There is no definition. And the whole field is also a mess. You know, it's again taking studies in mice, for example, and then translating them to humans. You know, the lifespan, their whole rhythm, their environment is so different from our environment, right? To translate these is always a stretch. And there's no clinical studies that show.

Starting point is 01:14:32 a clear benefit of fasting in humans. And some studies in monkeys actually suggest that it's detrimental for monkeys to fast, for example. They had more, I think, worse kidney function and things like that. So overall, from animal studies, it's very clear that you activate sort of beneficial pathways. very diverse. Again, we can now use unbiased assessment of many different cell types in an organism, 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.

Starting point is 01:15:21 They're in part reduced inflammation. Other cells, you get benefits on their energy metabolism, protein turnover, how they handle sort of what we call the garbage that accumulates in cells. Overall, from these animal studies clearly benefits from reducing calorie intake, also less what we call oxidative damage. So it's like you burn a fire, right? And 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.

Starting point is 01:16:05 You like breakfast. I tried, you know, Longo's diet a few times where I reduce calorie Walter Longo. I'm familiar with him. What's the contour of the diet? So it's mostly you switch to a ketogenic diet, so a fat-rich diet. So your metabolism changes basically from a regular sort of glucose-driven. diet to burning fat. And you feel that when you start to starve, that somehow it's almost like your body changes a little bit in, you get a bit more alert almost. And in a way that makes sense,

Starting point is 01:16:45 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 I imagine the catacolamines, dopamine or epinephrine, an epinectrine increase. Yeah. So you get more alert. You're a little hangary. Yeah, hangary, exactly. But I'm not sure how long that lasts and how beneficial this is in the long run.

Starting point is 01:17:12 But, yeah, I've done it a few times. You know, you do one week. You lower your calories, I think, down to a thousand per day. So it's pretty brutal. But only for five days and then we go back to normal. I know of a few people who've done long-term fast, 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

Starting point is 01:17:43 the types of foods they were hungry for. And that's thought to be an effect on the gut microbiome, which then impacts the brain. So there may be a place for those longer fasts, what do they call them, medically supervised fast. I generally just like caffeine electrolytes and water until about 10 or 11 a.m. And then I like to eat no later than, no later than nowadays at 7 p.m. because I go to bed a little earlier.

Starting point is 01:18:10 So is that intermittent fasting or is that just being a busy person who wants to still sleep well and exercise? Yeah, it is sort of a fast, right? I mean, in English you call it a break fast. 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.

Starting point is 01:18:36 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 evolved, right? 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 a fair statement. It can handle it.

Starting point is 01:19:00 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

Starting point is 01:19:15 in the public health discussion over the last, let's say, 10 years. And we can really, truly thank the great Matt Walker for this, 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. 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

Starting point is 01:19:46 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 the best science. The other would be the importance of exercise, both cardiovascular and resistance training. But during sleep, we know that there's this so-called glimphatic clearance, the clearance of junk from all the tissues, but in particular from the brain that's facilitated by the glia, hence glimphatic.

Starting point is 01:20:16 Have you guys looked at lymph between young and old animals. I'm fascinated by lymph. 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 extra cellar space that doesn't get picked up by the blood. I mean, it's essentially 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 animals.

Starting point is 01:20:44 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 young CSF from animals, from mice. Yeah. Wow. And then infuse it via a pump over a month into old animals.

Starting point is 01:21:11 And she could show that you can regenerate the brain, improve cognitive function in these mice. and all the good endrocytes, these cells that wrap the connections between neurons, it's like they produce the plastic around the wire, if you will. They were the strongest target if we looked in an unbiased way. 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 has beneficial factors that benefit the old brain.

Starting point is 01:21:52 And so I wouldn't be surprised that there could be beneficial factor in the glimph or the lymphatics that might benefit an old organism. We thought about it, but I think in mice it's extremely difficult. There's also the interstitial fluid itself that people have collected. But they usually collected by infusing artificial spinal fluid and then 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 protein deposits in the brain.

Starting point is 01:22:34 Why not just go straight to humans? I mean, I feel like now that's not what you would have to do. I've worked on so many different species, including humans. But it seems like given the relatively equal. equal expense of doing exploratory science and 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... Oh, yeah, that's what we have done. Oh, okay.

Starting point is 01:22:56 CSF is no problem. Yeah. Okay. 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 comprehensive. unbiased way, you find proteins that go up and go down together with cognition, so that positively or negatively correlate. And almost all the top proteins are synaptic proteins.

Starting point is 01:23:30 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 for cognitive resilience or or decline. And what's scary is that ratio continues to change from early adulthood. So you get a continuous, basically, degradation of that signal. And we get a very prominent risk 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.

Starting point is 01:24:13 So we also had people with 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. 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 anytime I see a study that looks in a correlative way at, you know, like which athletes live the longest?

Starting point is 01:24:55 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 it's the pole vaulters. I'm 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,

Starting point is 01:25:22 you know, five to eight years on average, more than their age match cohorts, even compared to other highly trained athletes. So I see a result like that. And then, of course, the reductionist scientist in me says, okay, so is it the running? Is it the jumping? Is it? Then you think like, oh, using the white,

Starting point is 01:25:41 query 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 feet, I wonder whether the feedback signals from the body. There's some feedback signal in the form of a chemical that says, okay, this body is moving fast, jumping and doing explosive activity essentially on a regular basis that supplies the brain with a cocktail of things, presumably, that keeps neurons healthy, keeps them, you know, keeps the oligodendosites proliferating, right? That make sure that, you know, you've got plenty of myelin for those fast transmission

Starting point is 01:26:27 signals. And to me, that's where I, like the field of health span and lifespan, but especially health spending really needs to go. Because otherwise, it's just like, pick the exercise you're going to do regular. That's great. That's a great first step. Then ultimately, it really does become about quality of life. And if, so the importance of doing these kinds of studies to me is immense because otherwise, it's just sort of like, well, you do a little cardio, do all this, do a little that. And 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 can from in person. It's two totally different landscapes. So, 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 are probably molecules associated with certain forms of exercise that are much more potent in terms of brain

Starting point is 01:27:27 function. Yeah, that's very interesting. So John Long at Stanford has a lab, and he looked at metabolites in the blood of dogs, sprinter dogs, horses that do races, and then also human sprinters. And he found this interesting modified amino acid that is conjugated to lactate, lack fee it's called. And that compound seems to spike with these extreme bursts of muscle activity. And he could then show in animals that it's actually beneficial

Starting point is 01:28:04 and mediate some of the beneficial effects. He identified the receptor. So it's a really very exciting direction of research. But 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.

Starting point is 01:28:27 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? Well, if it buys you life, or anyway, I'm fortunate that I've always loved exercise. I've always loved it.

Starting point is 01:29:07 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 feels that way. Get that reward, right? Our colleague Robert Sapolsky told me about a study where they have rodents run on a wheel regularly.

Starting point is 01:29:24 And rodents love to run on wheels, as you know. And they of course experience reductions in blood pressure, blood lipids, improve, et cetera, 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, it's sort of like your paribiosis experiment,

Starting point is 01:29:48 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,

Starting point is 01:30:07 your markers of stress and deficits in memory associated with hippocampal, not damage, but rewiring. So you realize that the choice is big in all of this. That's for me running on a treadmill in every 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 are colleague Joe Parvizi. Neurosurgeon did this amazing experiment where he stimulates for other reasons. He landed in the anterior mid-singulate cortex,

Starting point is 01:30:36 and when he stimulates there, people feel as if there's some impending pressure on them, like they're driving into a storm, and they feel motivated. They feel subjectively tenacity. And it turns out that the anterior cingulate cortex grows in people who successfully diet, who push through challenges and exercise and cognitive things.

Starting point is 01:30:57 So pushing ourselves, you can tell your friends that if you enjoy doing something, you actually get less benefit. Yeah, maybe. If you hate it, you get more benefit, but not if you're forced to do it. So, electing to do things that you hate and doing them anyway is where the real, where you get the double benefit. So in any case, this is the brain structure associated with superagers.

Starting point is 01:31:21 If you motivate yourself to do a marathon, right, and you go through the torture. That's right. I think I'll sprint instead. I now do this thing where I hop on the airdine bike, the one of the handles, and I'll go warm up a minute, and I'll go hard for 20, 30 seconds and then rest 10 seconds and just repeat. And it's over in like seven minutes. But it's amazing where the brain goes. You're like, I hate this.

Starting point is 01:31:41 I want to get off this thing. But afterwards, it feels pretty great. Well, I would love for you guys to look at CSF or other factors in, let's just call it, high intensity versus long endurance type exercise. It's also hard to do in animals, but you can do it very easily in humans. I mean, I'm trying to think about the ways that we can use lifestyle interventions until you come up with the magic pill. Yeah.

Starting point is 01:32:01 And, you know, it's interesting that you say that Jill Livingston and others, you know, they have studied sort of how lifestyle influences the development of dementia and Alzheimer's disease. And it's a dramatic component that you can influence easier or not, right? I mean, some of them are very hard to get out of, but, you know, poverty is a risk, of course, childhood obesity. lower education, smoking, excessive alcohol use. Many of these things that we know, you know, they're good or bad. If you have all these, if you optimize everything, your risk for dementia is much lower. I mean, there's now, you know, countless studies that show that. So there are things that you can do, the lifestyle factors, right?

Starting point is 01:32:57 And they're easier to do for some people than for others. but it's clear that there's incredible power in lifestyle and what we do. Are you aware of any correlates to the exercise thing we were just talking about whereby certain cognitive exercises can help us hold on to cognition? For instance, we've heard doing crossword puzzles or reading good books. I mean, I think this is becoming increasingly important because it's so easy to have one's time sucked away on the internet or on social media nowadays, which requires essentially no work.

Starting point is 01:33:37 You just scroll and read. I mean, articles have become very brief. Is there any known benefit of trying to tackle cognitive gymnastics? Is there any data? Not to my knowledge. Unfortunately, you know, the studies that looked in patients who already have cognitive impairment. and you try to give them sort of exercise and mental exercise.

Starting point is 01:34:04 They don't do much, unfortunately. It's probably more complex. And you, of course, also have, again, you know, what we discussed earlier with exercise, right? Some people just love to be stimulated. And, you know, they want to learn something new, you know, want to learn a new language or a new instrument. And their mind is already attuned to that, right?

Starting point is 01:34:26 They crave for this. and for others, that might be much harder and they may not benefit from it. But you're the neuroscientist, you know, what could you get out of something like that? And if somebody is really excited about, you know, doing any of these mental exercises versus, you know, it doesn't speak to them.

Starting point is 01:34:54 Yeah, I think that if we should all find the things that we want to do enough that we would elect to do them, but that are challenging. There are data coming out now showing that handwriting is very important to development of certain brain circuits. It's kind of no surprise, but this is important for the younger generation who's no longer handwriting so much.

Starting point is 01:35:15 The phrase, use it or lose it, makes perfect sense to me. I mean, if you don't walk enough or run enough or cycle enough or do anything with your legs, eventually the neural systems that control your legs will atrophy as will the muscle. We tend to think about the muscles, but we don't think about the neural control over the muscles. So I think, since I'm 50 now, I think, you know, I make it a point to read at least it's going to sound so paltry, but at least one page, and ideally one chapter of a book every day. Sometimes it's just one page, but just with a book, with my phone out of the room, and I do, and I read papers and things like that.

Starting point is 01:35:50 But doing things that feel unnatural, but that I know I will benefit from when they're over. There's such a deep feeling of satisfaction from having done that sort of thing. And for me, the higher intensity cardio is that I'd much rather jog than sprint. So I'd make it a point to sprint. So I think maybe we should think about exercise and cognitive stuff the same way. Who knows? Yeah. I mean, is there anything in Switzerland that they do that they don't do here in terms of food

Starting point is 01:36:16 and exercise and lifestyle? Because the Swiss are very healthy. The Swiss also, as I recall, from something in The Economist a few years ago when I used to, I no longer subscribe to them. But the highest caffeine intake in the world is the Swiss. Really? They drink so much caffeine. Yeah, yeah.

Starting point is 01:36:33 Good chocolate and cheese. And people eat a lot of it. I eat almost every day I eat chocolate. Do you? Yeah. You're making some people very happy. I eat 100% chocolate. It's part of my diet.

Starting point is 01:36:43 When? When do you eat it? Usually after, you know, with a coffee after lunch or so. High in polyphenols. Mm-hmm. Yeah. And taste delicious. Very hot and tasty.

Starting point is 01:36:53 Yeah. Stimulates your brain. It makes you happy. I eat the raw or roasted cacao beans. Yeah. Because I like bitter, bitter things. Those are good, too. Yeah, those are a good punch.

Starting point is 01:37:04 You own a winery. That's right. That runs counter to everything I understand about longevity, but it runs. No, it doesn't. Okay, all right. Here we go. Educate me. Alcohol itself is probably not good for our body, right?

Starting point is 01:37:18 Just pure alcohol. Right. But a lot of drinks are part of a social environment. And I think one of the major benefits that people have attributed to, you know, wine is the social aspects of it. I mean, some people may drink a bottle of wine by themselves. But I think the majority, you know, they have a meal together and you share a bottle of wine. And that's, we talked about this earlier, you know, how you dissociate one thing from another. I think, you know, this is complexity that you see actually in almost all.

Starting point is 01:37:55 studies that look at centenarians, you know, where people live the longest. One of the most common aspects is that they're all very social. They're not left alone when they're old. They have a community and they meet other people, right? And so I think that's part of the wine culture is really being social, being together. Yeah, I mean, the data on social connection and stress reduction, huge. Yeah, I've gone on record saying that the data, say zero alcohol better than any, two drinks per week. It's probably the upper limit for non-alcoholic adult, after which I just say, you know, make sure you're doing other things correctly.

Starting point is 01:38:35 One thing that I want to be really clear on is, since I'm talking to someone from originally from Switzerland, although you're a U.S. citizen now, is that the United States has never had a history of healthy food or drink. drinking habits. You know, if you think about classic American cuisine, it's all unhealthy stuff. Apple pie, French fries, hamburgers, hot dogs, pizza, which was originally not ours, right? And on and on, right? There's been a culture of volume and abundance and kind of amusement park food, frankly. And the same is true for drinking. I mean, certainly not speaking for everybody,

Starting point is 01:39:23 but there's been a culture around alcohol in the United States of drinking a lot of beer or a lot of spirits. Whereas I think in Europe, the food, including the desserts, have a tradition of nourishment, of social connection. And sure, we have bars in the United States and people drink beer while they watch games and things like that. But I think sometimes that gets lost in the conversation that the United States has never been a particularly healthy place

Starting point is 01:39:51 except for its level of engagement in sports and exercise until recently. So I totally agree with what you're saying. If you're getting together with friends and having a couple drinks or something like that, that sounds entirely healthy. But the problem is that that's usually not how it looks. Certainly not on college campuses, but that's another thing. Well, access, right, anything. If you also with food, I mean, I eat any food.

Starting point is 01:40:19 You can eat any food, but you don't want to just eat. one food. I mean, I ate French fries or burger. There's nothing wrong with it. But if that's your only diet, that's not good. If you eat no fruit, that's probably not good. If you have no vegetables in your diet. And the same, I think, with drinks. I mean, I have drinks, but I try to get drunk every day, right? So I think moderation is really, I think, the magic. I'm going to get a little wacky here, not woo wacky. There's some really interesting stories about improving health and vitality, maybe lifespan, with things that adjust blood flow. So for instance, in the literature around chigong breathing, and there's a lot of different forms of this,

Starting point is 01:41:11 but we can distill things down to the fact that inhales, vigorous inhales, increase the heart rate, exhales, deliberate exhales, extended exhales, decrease the heart rate through something called respiratory sinus arrhythmia. So in a number of cultures, they'll do Qigong, Tai Chi, which is deliberate breathing and movement, of course. And the idea is that you're improving circulation, that it feeds the brain, you know, in the language of these things, that it's feeding the brain nutrients. And it all makes perfect sense, given what you're saying. It's also interesting, I've been looking at how patterns of breathing change as people age and talking to people who work in hospitals and with, And there's actually a little bit of data around this. As people get older and their cognitive function goes, they tend to become mouth breathers.

Starting point is 01:41:58 They're having trouble oxygenating their brain. Now, it could be the mouth breathing is the cause or it could be reflective of something else. Kind of interesting to think about because the relationship between breathing and blood flow is an obvious and well-established one. So there are all these things about the young blood versus old blood that might be independent of, pure biochemistry of aging that could be controlled with lifestyle factors. And we say exercise improves health span, but exercise increases breathing rate. So have you, are you at all interested in, I'm trying to get a bunch of studies going here, you can tell, and people that do some sort of deliberate deep breathing.

Starting point is 01:42:39 It doesn't have to be Tai Chi. It would be super interesting, right? Because you're changing the chemistry of the life. I mean, anything, you know, what we discussed earlier is this cause and effect. And really the way to show that something has an effect is you have a study where some people, you take their blood, they do an exercise, and then you take their blood again. And you look, does it change something? Very easy to do. Can we do this experiment? Absolutely.

Starting point is 01:43:06 Because I ran a study with David. It just costs money. Money we can get. Money we can get. I'm not worried about that. David Spiegel and I ran a study on breathwork. But we didn't look at how different patterns of breathing change of blood chemistry. Yeah, that would be super interesting. Absolutely. Because these are things that people can do at any age. Absolutely. And they're zero cost.

Starting point is 01:43:27 But we don't have mechanistic data. We just have, oh, you know, people who do Qigong or Tai Chi live a long time. But then there's so many variables. They're outdoors. They're moving. It's social. And so the thing that concerns me about the health span, longevity space, if you will, is that we keep going around the merry-go-round.

Starting point is 01:43:45 and we keep going, exercise, sleep, nutrition, social connection, sunlight. And don't smoke, drink, in excess, play a contact sport where you hit your, we just keep going around and around, and we need tools. Right. So I think that's exactly what we recognize at Vero, where we want to have tailored interventions that, you know, you give very specific advice based on, you know, if your heart is showing accelerated aging, this is the exact exercise that will help you based on studies that we just discussed, right, where you say, okay, here we had 50 people

Starting point is 01:44:23 who did this exercise and 50 who didn't or something different, and it had a clear benefit and made their heart younger or made their brain younger. That's really what I think we all want, right, rather than these broad sort of, oh, live a healthy life, how is that going to help you? You want really tailored advice and then also validating that it actually does something. And this is not a promotional I just learned about Vero today, really. I'd heard of it, but I'm learning in detail. So it's now a company that anyone can access these tools. We are live.

Starting point is 01:45:02 It's currently a small number of clinics that we're working with. And we hope to grow and expand it quickly. Do you measure your steps or make it a point to walk a lot each day or both? I measure my steps. I have a garment. I find it useful. I find also the sleep measurements really useful. Talk about sleep earlier.

Starting point is 01:45:26 You know, it tells me how well I slept, how much deep sleep. Yeah, I think that's useful. Yeah, it's wild. Nowadays, people just accept, oh, yeah, we track our sleep, et cetera. I remember when I was a postdoc at Stanford in 2005 to 2002. 10 people getting into quote unquote wearables. That's what they called in there. They didn't quite work.

Starting point is 01:45:47 Yeah, there was one graduate student in the neuroscience program, this woman, Rachel, who I think went to go work for a wearable company and she had like seven or eight different watches. This is like Mike Snyder. She was, yeah. We had him on here. Yeah. And way ahead of the curve with all these wearables.

Starting point is 01:46:00 And I remember thinking, who's going to wear all those watches? And she said, no, no, eventually it will all be condensed to one watch or maybe even just a small ringer device. And I thought, all right, whatever. I've always been into health and wellness, but sure enough, she was right, but far smarter than me. I think we're going there. I think we're going to a place where soon many, many things will be measured. Like I would love eyeglasses where the frames measure the amount of photons I get during the day to make sure I get sufficient sunlight.

Starting point is 01:46:35 Yeah, that's always something that I don't understand. There's a lot of people in this country who have shades, right? They wear dark glasses all day long. This is so bad for your brain. And for your mental health. We know 80,000-plus subjects in this UK study, the brighter your days, ideally from sunlight, but the brighter your days and the darker your nights, the less susceptible you are to every single mental health condition. And if you have a mental health condition, it gets way better.

Starting point is 01:47:03 So you need bright days and dark nights and artificial lights during the day are not sufficient. and at night, a small amount of artificial height is too much. So these things should be straightforward to measure. Aren't people in the south happier in Europe? If you look, sort of, they enjoy life more. They have more food. They sit together. They have fun.

Starting point is 01:47:25 And the more north you go, the more serious and the more depression you find. I have Danish relatives. I don't want to insult them. And they're very cheerful. But it's interesting. People vary a great deal in their susceptibility to artificial light at night. So I've long said you need to dim the light. Some people should even wear short wavelength blocking glasses, you know, maybe even red light.

Starting point is 01:47:47 Some people, a small amount of artificial light at night increases their cortisol really substantially and could disrupt their sleep. Other people less so. So there seems to be some divergence and it doesn't correlate with light eyes or dark eyes. I am very, very sensitive to light at night. It will really disrupt my sleep. Some people, not so much. But in terms of temperament, I'm going to inspire some family arguments here, but I don't know.

Starting point is 01:48:12 Yeah. Yeah, I mean, even growing up in Switzerland, you know, we had for very short days in the winter and then off and fog, it's hard to get up in the morning. And then coming to California, it's sunny all day, you know, most of the year. It just makes it easier to get your day started. and yeah, I love the sun. Yeah, I think if people don't have access to sunlight, enough sunlight, there are great data that a 10,000 lux artificial light placed in the kitchen or in the bathroom when you wake up in the morning, you don't need a lot of time in front of it.

Starting point is 01:48:48 You don't have to stare at it. That can help offset some seasonal effect depression. And some people just need more photons to get that morning spike in cortisol, which is good to get the catacolamines going dopamine and so on. I mean, the power of light over our mood and metabolism. is huge. Amazing. Yeah. Should do another study on that. I mean, listen, I'm due for a sabbatical. Can I do a sabbatical in your lab? Tell me, is there anything that you're particularly excited about that I did not ask you about? What you've been publishing so well for so long now, and you really put

Starting point is 01:49:21 this whole field of looking at blood-borne and other factors correlated with youth as a therapeutic. You really put that on the map in a serious way. And I really want to I congratulate you for doing that on a backdrop of Dracula stories and kind of sensationalism around that. You're clearly a serious scientist taking things on seriously. And also measuring multiple factors from blood, as you know, has kind of a complicated history. But you've really moved this forward in a very rigorous way. And so that's awesome.

Starting point is 01:49:56 What are you thinking about these days that I wouldn't know about? Thanks for the opportunity. Yeah. So one thing that should later this week actually be publicly available on a preprint server. So we took this idea of looking at organs and getting an estimate of how old is your brain or your heart. We took this to the next level and ask, can we build similar models and estimate how old cells are in your body? So we have many different cell types, right? That's how we have specialized organs.

Starting point is 01:50:33 So we were able to, with the current technology that measures these thousands of proteins, we were able to assign proteins to 40 different cell types. And so we can now make estimates of specific cell types in your body. One of the most striking finding was we looked in people with different neurodegenerative diseases and ask how old are all their different cell types? And we find in this rare disease called amyotrophic lateral sclerosis or ALS, in the U.S., we often call it Lou Gehrick's disease, because Lou Gehrick was this baseball player who got this devastating disease,

Starting point is 01:51:15 it's a muscle weakness that often progresses extremely quickly and people die. And what we found is that these individuals had extremely old. an enrichment in an extremely old muscle cells, skeletal muscle cells in particular, and also heart muscle cells, cardiomyocides. So there was this very strong association. And then we looked in a progressive, in a longitudinal study, cross-sectional, but where we had 20 years follow-up. It's called the UK Biobank.

Starting point is 01:51:50 So we had blood samples from people when they entered their study healthy. and then a number of people developed about 250 developed ALS over the course of 15 years. And we found a strongly increased risk to develop the disease if they had these extremely old muscle cells. So here we have now a much finer resolution and granularity where we can get more predictive power, we can get more precise predictions, of what type of disease you might get.

Starting point is 01:52:27 And of course, at the molecular level and the cellular level, we know where the problem might be, right? It's not just the whole organ, but now we know which cell type. Another one was there's these cells we call astrocytes in the brain. We find a very strong association of the age of asteroids and development of Alzheimer's disease, much stronger than just the brain age, so the age of your whole brain,

Starting point is 01:52:54 When we look now at these individual cells, they are a very strong predictor of Alzheimer's disease, especially together with a genetic risk factor. So that's something that we have been developing and really excited about. But my ultimate greatest stimulation right now is to build a map of the human proteome across different genetic diseases. So what I'm trying to do is to ask if somebody has a disease that is caused by a single genetic mutation, and there's about six, seven thousand such, we call them monogenic diseases, where if you have a mutation, you will get a disease, childhood disease or an adult disease. So what I want to do is to look at individuals with these mutations and profile their plasma,

Starting point is 01:53:50 basically measure all the proteins and see, are they different from healthy people? And if you do that across hundreds of diseases, you basically get a picture of how our body responds to the disruption of specific genes. And the idea is that this will allow us to look at any type of disease or we don't know how it's caused and then say, this looks like this genetic disease. Basically what we've been doing in animals with worms, right, where we knock out every gene or in flies. Use the human experiment, if you will. And this may be a bit disparaging. These are obviously people who have diseases. But there are repositories where people volunteer to make these samples available for research.

Starting point is 01:54:43 And so we have had the opportunity already to look at 25 different genetic diseases. and we find these very specific patterns. So that's what I want to build and then make it publicly available so that any researcher can ask how does my protein of interest that I want to study, how does it change in these different genetic diseases and learn about how they're related to each other

Starting point is 01:55:10 and which biological pathways they may change? That's what motivates me the most. I love it. I, it's so clear that you're a driven person and it's learning about what the next vista is, is always exciting. And again, thanks for the incredible work that you've been doing for all these years, you know, bringing a level of rigor and seriousness to something that prior to that was just kind of tossed around as kind of an observation and a, and something to discuss at parties, you know, young blood and this kind of thing. You're clearly shedding light on real mechanistic knowledge.

Starting point is 01:55:50 And the ability to measure aging of different organs now, I think, is a tremendous technology. I'm very curious about that. I know a number of other people will be. We'll put links to the various things in papers, et cetera. And I also want to thank you for coming here, taking time out of your busy schedule, your lab, your family, your vineyards, plural, to educate us on health and on health span and on the relationship. between youthfulness and aging and what we can do to really ameliorate the degradation of health span, you're developing the things that change lives for the better. So thank you so much.

Starting point is 01:56:28 I really appreciate you. Thank you so much for having me. Come back again and tell us about all the other discoveries. And I'll buy a bottle of the wine from your vineyard and I'll gift it to one of the drinkers in my life. Sounds good. All right. Thank you very much. Thank you for joining me for today's discussion with Dr. Tony Weiss-Corey.

Starting point is 01:56:43 To learn more about his work and to find links to the various resources we discussed, please see the show note captions. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please follow the podcast by clicking the follow button on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review. And you can now leave us comments at both Spotify and Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast.

Starting point is 01:57:13 If you have questions for me or comments about the podcasts or guests or topics that you'd like me to consider for the Huberman Lab podcast, please put those in the comments section on YouTube. I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled Protocols, an Operating Manual for the Human Body.

Starting point is 01:57:32 This is a book that I've been working on for more than five years and that's based on more than 30 years of research and experience. And it covers protocols for everything from sleep to exercise, to stress control. protocols related to focus and motivation. And of course, I provide the scientific substantiation for the protocols that are included. The book is now available by presale at protocolsbook.com. There you can find links to various vendors. You can pick the one that you like best. Again, the book is called Protocols, an operating manual for the human body. And if you're not already following me on social

Starting point is 01:58:06 media, I am Huberman Lab on all social media platforms. So that's Instagram, X, threads, Facebook, and LinkedIn. And on all those platforms, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab podcast, but much of which is distinct from the information on the Huberman Lab podcast. Again, it's Huberman Lab on all social media platforms. And if you haven't already subscribed to our neural network newsletter, the neural network newsletter is a zero-cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one-to-three-page PDFs that cover everything from how to optimize your sleep, how to optimize dopamine, deliberate cold exposure. We have a foundational fitness protocol that covers cardiovascular training and resistance training. All of that is available completely zero cost. You simply go to Hubermanlap.com, go to the menu tab in the top right corner, scroll down to newsletter, and enter your email. And I should emphasize that we do not share your email with anybody.

Starting point is 01:59:00 Thank you once again for joining me for today's discussion with Dr. Tony Weiss-Corey. And last, but certainly not least, thank you for your interest in science.

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

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