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Speaker A: Welcome to the Huberman Lab podcast, where. |
Speaker B: We discuss 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. Today, my guest is Doctor David Sinclair, professor of genetics at Harvard Medical School and co director of the Paul F. Glenn center for th... |
Speaker A: Thank you for coming. |
Speaker C: Thanks for having me here. It's good to see you. |
Speaker A: This is mate, by the way, that we're toasting at 11:00 a.m. unlike other podcasts, well, I don't drink alcohol, so I'm boring that way. But truly, thanks for being here. I have a ton of questions for you. We go way back in some sense, but that doesn't mean that I don't have many, many questions about aging, ... |
Speaker C: Right. Well, so longevity is the more academic way we describe what we research. Anti aging is kind of the same thing, but it's got a bad rap because it's been used by a whole bunch of people that don't know what they're talking about. So I really don't like that term, anti aging. But aging as a disease and ... |
Speaker A: That clarifies a lot for me. Thank you. Can we point to one specific general phenomenon in the body that underlies aging? |
Speaker C: Yeah. Well, that's contentious because scientists like to come up with new hypotheses. It's how they build their careers. But fortunately, during the two thousands, we settled on eight or nine major causes of aging. We called them hallmarks because causes was a little bit too strong. But these eight or nine ... |
Speaker A: Interesting that you guys work on aging and trying to kill each other. |
Speaker C: Yeah, isn't it? Well, kill each other's careers. I mean, I like to think I was fairly generous, but I was one of the kids, and the old guard really didn't like the new guard. We just came along in the 1990s and nineties and said, free radicals don't do much. There are actually genes called longevity genes, a... |
Speaker A: Well, tell us a little bit more about the epigenome. Frame it for us, if you will, and then we'll get into ways that one can adjust the epigenome in positive ways. |
Speaker C: Yeah. So, in science, what I like to do, I'm a reductionist, is to boil it down. And I actually ended up boiling aging down to an equation, which is the loss of information due to entropy. It's a hard thing to overcome. The second law of thermodynamics that's there. But this equation really represents the fa... |
Speaker A: Use these things, I recall. |
Speaker C: Yeah. And then the epigenome is the reader that says, okay, in this cell, we need to play that set of songs, and in this other cell, we have to play a different set of songs. But over time, aging is the equivalent of scratching the CD and the DVD so that you're not playing the right songs. And cells, when th... |
Speaker A: Can we go a little deeper into what these scratches are? Is it the way that the DNA are packed into a cell? Is it the way that they're spaced? What are the scratches that you're referring to? |
Speaker C: So DNA is six foot long. So if you join your chromosomes together, you get a six foot per cell. So there's enough to go to the moon and back eight times in your body. And it has to be wrapped up to exist inside us. But it's not just wrapped up willy nilly. It's not just a bundle of string. It's wrapped up ve... |
Speaker A: Are these changes the same sorts of changes that underlie the outward body surface manifestations of aging that most of us are familiar with. Graying of the hair, wrinkling of the skin, drooping of the face. Walking around New York lately, it's amazing to me there are certain people that seem to walk, lookin... |
Speaker C: Well, it's actually, you are as old as you look if you want to generalize. So let's start with centenarian families. These are families that tend to live over 100 when they're 70. They still look 50 or less. So it is a good indicator. It's not perfect, because you can, like me, grow up in Australia and accel... |
Speaker A: Very interesting. I started off in developmental neurobiology. One of the things that I learned early on that I still believe wholeheartedly, is that development doesn't stop at age twelve or 15 or even 25, that your entire life is one long developmental arc. So in thinking about different portions of that d... |
Speaker C: Yes. Yes. And this is something I've never talked about, at least not publicly. So this is a really good question. So those chemicals we can measure, it's also known as the Horvath clock. It's the biological clock. It's separate from your chronological age. So actually, what I didn't mention is that when the... |
Speaker A: Incredible. Yeah. This is more of an anecdotal phenomenon. It is an anecdotal phenomenon, but this experience of in junior high school, going home for a summer, and you come back and high school in the US usually starts 8th or 9th grade or grade eight or grade nine for your Canadians. And then some of the ki... |
Speaker C: Well, yeah, I don't want to scare anybody. |
Speaker A: Sure. |
Speaker C: There are studies that show that the slower you take to develop it also is predictive of having a longer, healthier life. And it may have something to do with growth hormone. We know that growth hormone is pro aging. Anyone who's taking growth hormone, pay attention. |
Speaker A: We know just look at someone who's taking growth hormone. They often will acquire these characteristics of vitality, like improved smoothness of skin, but their whole body shape changes. |
Speaker C: Yeah, I mean, you'll feel better, feel better for a short amount of time, you'll build up muscle, you feel great, but it's like burning your candle at both ends. Ultimately, if you want to live longer, you want less of that. And the animals that have been generated and mutants that have low growth hormone, s... |
Speaker A: Really? Yeah. Huh. Amazing. |
Speaker C: And, oh, there are some Laron dwarfs as well. There are dwarf mutations in South America, and they seem to be protected against many of the diseases of aging. You barely ever see heart disease or cancer in these families. |
Speaker A: So I, having owned a very large dog breed, a bulldog mastiff who lived a long life for a bulldog. Eleven years. But there are many dogs that will live 1216 years that are smaller dogs. Can we say that there's a direct relationship between body size and longevity or duration of life? |
Speaker C: Well, there is, but that doesn't mean that you're a slave to your early epigenome, nor to your genome. The good news is that the epigenome can change. Those loops and structures can be modified by how you live your life. And so if you're born tall and I wasn't a. And I wished at the time I did grow, but no m... |
Speaker A: So let's talk about some of the things that people can do. And I've kind of batched these into categories, rather than just diving right into actionable protocols. The first one relates to food, blood sugar, insulin. This is something I hear a lot about, that fasting is good for us, but rarely do I hear why ... |
Speaker C: Well, let's start with what I think was a big mistake was the idea that people should never be hungry. We live in a world now where there's at least three meals a day, and then we've got companies selling bars and snacks in between. So the feeling of hunger, some people never experience hunger in their whole... |
Speaker A: So hunger of course, is associated with low blood glucose and low insulin. Do you think there's anything about the subjective experience of hunger itself that could be beneficial for longevity? |
Speaker C: Yeah, I do, though. You get used to the feeling of not eating, so I'm kind of screwed that way. |
Speaker A: It's like cold water. You eventually adapt. |
Speaker C: You get used to it, unfortunately. But there are some studies that are being done at the National Institutes of Health that are able to simulate the effect of hunger but still provide the calories. And it's looking like there's a small component that's due to hunger, but most of it actually is because you've... |
Speaker A: What is the protocol that people can extrapolate from that? Or maybe I should just ask you, what is your protocol for when to eat and when to avoid food? Do you fast? Do you ever fast longer than 24 hours? What do you do, and what do you think is a good jumping off place if people want to explore this as a p... |
Speaker C: Well, if there's one thing I could say, if I would say definitely try to skip a meal a day, that's the best thing. |
Speaker A: Does it matter which meal? Are they essentially equivalent? |
Speaker C: Well, as long as it's at the end or the beginning of the day, because then you add that to the sleep period, where you're hopefully not eating. |
Speaker A: I think that's an excellent point. I realize it's a simple one, but I think it's an excellent one, because I think one of the things that people struggle with the most is knowing when and how to initiate this so called intermittent fasting. And the middle of the day, obviously, is not tacked to the sleep cyc... |
Speaker C: Yeah. Well, I'll tell you what I do. I skip breakfast. I have a tiny bit of yogurt or olive oil because the supplements I have need to be dissolved in it. And then I go throughout the whole day, as I'm doing right now here with this glass of water here. I'm just keeping myself filled with liquids, and so I d... |
Speaker A: I'll feel terrible if I don't eat a steak. I feel terrible. Argentine lineage. But we can talk about that some other time. |
Speaker C: Well, everybody's different. I mean, that's the other thing. What works for me may not be perfect for you. And we do have to measure things to know what's working. I rarely eat dessert. I gave up dessert and sugar when I turned 40. And occasionally I'll steal a bit of dessert because it doesn't hurt if you s... |
Speaker A: That's a benefit. So do you ever fast longer than this? It sounds like if you go to bed, well, you tend to stay up late. I know, because I get texts from you at like two in the morning, my time, which means you're up very late and up early as well. But assuming that people go to sleep sometime around 1130 or... |
Speaker C: Occasionally I do. So my typical day, I would only eat within a two hour window. Just usually I'm either eating out or. |
Speaker A: So you're 22 too? |
Speaker C: Yeah, yeah. But I love. |
Speaker A: Well, and if you exercise, do you feel like then you just power through and maintain that fasted state? |
Speaker C: Absolutely. I can exercise. And now my body's so used to it, I don't feel like I need food after exercising. I used to, but have I gone longer? Yes, but not very often. I find it quite difficult to go more than 24 hours. But when I do it, maybe it's once a month, I'll go for two days after two. And actually ... |
Speaker A: One more practical question than a mechanistic question related to this. The practical question is when you are fasting, regardless of how long I know you're ingesting fluids like water and presumably some caffeine. I heard you had several or more espresso today, which is impressive. But are you also ingesti... |
Speaker C: Well, it makes sense, but I haven't had a need to do it, so I don't. I just. I drink tea during the day and coffee when I'm first awake, and I don't get the shakes. So, you know, I don't fix what's not broken. And I do add things to my protocol that I think will improve me and avoid those things. Of course t... |
Speaker A: Okay, so then the mechanistic question is, you've told us that there's ample evidence that keeping your blood sugar low for a period of time, each 24 hours, can help trigger some of these pro longevity anti aging mechanisms, and that extending them out two or three days can trigger yet additional mechanisms ... |
Speaker C: Yeah, there's a really good question that proves you're a scientist or world leading one. So what we now know is that these longevity pathways, we call them, these longevity genes, talk to each other. And we used to say, oh, my longevity gene's more important than yours. It was ridiculous, because they're al... |
Speaker A: So, interesting. You mentioned leucine. Within the resistance training bodybuilding fitness community, leucine gets a lot of attention because there are longstanding debates about how much protein one needs per day and how much one can assimilate at each meal. It makes for many YouTube videos and not much el... |
Speaker C: Well, it could be. That's what the evidence suggests. And again, it goes back to the debate. Should you supplement with growth hormone or testosterone? All of these activities will give you immediate benefits. You'll bulk up more, you'll feel better immediately. But based on the research, it's at the expense... |
Speaker A: Yeah, it sounds like a very rational protocol. Does the name Ori Hofmekler mean anything to you? |
Speaker C: No. |
Speaker A: Okay, just briefly, I discovered Ori Hofmekler about 15 years ago. He was in israeli special forces. He's now got to be close to 70. Forgive me, Ori, if that number is inflated. He wrote a book called the Warrior Diet, which got very little attention at the time. But what he said was, when he was in israeli ... |
Speaker C: Well, the pulsing, I think, is what you want to do, is to get the cells to be perceiving adversity, because our modern life, we're sitting around, we're eating too much, we're not exercising, our cells respond, they go, hey, everything's cool, no problem. And they become relaxed and they don't turn on their ... |
Speaker A: Wow, that's a long time. I have got many, many mice in my ownership in my lab at Stanford, and that's a very long life for a mouse. |
Speaker C: It was by far. And so it was a long lifespan extension. And what that told me is that probably you don't want to be taking a supplement every day. You can take it either every other day or give your body a rest. And I do the same with my meals. I rest during the day and then I give a nutritious dinner to my ... |
Speaker A: You take metformin and you're fasting each day. So when do you take it relative to the fasting? |
Speaker C: Yeah, I always take metformin in the morning along with the resveratrol, because for a number of reasons, but mainly because my body responds better. And I've been measuring my body for 1213 years. But here's the thing. If I'm going to exercise that day, I will skip the metformin. And a lot of people who do ... |
Speaker A: You mentioned metformin is available only by prescription from a doctor, at least in the US. Berberine is this substance that comes from tree bark, who I also learned about many years ago from Orey. He said, if ever I'm going to overeat, like a Thanksgiving meal or something, I take Berberine. Those were his... |
Speaker C: Well, before I had access to metformin, I was taking berberine. It's often known as the poor man's metformin. He just called me poor women can take it, too. So the thing with Berberine, and we've studied it in my lab, it is effective at boosting energetics in the body, just like Ampk and metformin does. And ... |
Speaker A: Is a good thing, right? |
Speaker C: Yeah. |
Speaker A: I think when people hear insulin sensitivity, sometimes people think, oh, well, that's bad, right? No, but you want your cells to be insulin sensitive. You don't want a lot of blood sugar floating around that can't be sequestered into cells. |
Speaker C: Exactly. So this is anti type two diabetes. And so this Berberine does have wonderful effects on the metabolism of animals. And in some clinical trials on dozens of people, it's been tested. Now, there's one cautionary tale which just came up. Matt Caberline's lab published that Berberine reduced the lifespa... |
Speaker A: Not in my opinion. I wouldn't say no disrespect to my C. Elegans colleagues, or rather my colleagues that work on C. Elegans. |
Speaker C: Yeah, well, what I like to do is to give all the information people can decide what they want. But I would say if, based on the worm data, I wouldn't panic just yet. I think Berberine has been shown to be really safe in humans. |
Speaker A: You mentioned resveratrol. I think now would be a great time to talk a little bit about protocols for resveratrol, grapeseed extract, etcetera. Let's start with the obvious one that I know you get a lot, but for the record, can't I just drink red wine and get enough resveratrol? |
Speaker C: David, you can try. You'd need to drink about 200 glasses. |
Speaker A: A day, so I'm sure it's been tried. |
Speaker C: There are some. And I drink a glass of red wine a day if I get the chance, but any more than that, it's a lot of calories and your liver will get fatty and it's all bad. So realistically, you can only get the thousand milligrams that I take a day from a supplement that's pure. Now, there are a lot of people ... |
Speaker A: So a thousand milligrams per day is what you do? |
Speaker C: Yeah, and I have for about 15 years now. |
Speaker A: And you ingest that with some fatty substance like olive oil or yogurt, is that right? |
Speaker C: Yeah, you have to. And other other supplements. Quercetin, curcumin. These are crunchy things, they're not going to get through your gut. And I'm not just making this up. I always base my statements on human studies. So we've done a lot of studies on resveratrol, as have others since, and we know that from. ... |
Speaker A: So are you taking this all at once in the morning and chasing it with some olive oil, or are you dissolving it in yogurt? What's the specific protocol? |
Speaker C: Yeah, I've been improving, perfecting what I do for about ten years. I would take some greek yogurt, a couple of spoonfuls, put the resveratrol on there, mix it around, make sure it's dissolved, and put that in my mouth and swallow that. These days, what I like to do, because I've realized that olive oil and... |
Speaker A: Delicious. That raises a question that I want to ask before we get to nmn and nr and vitamin B three, which is by doing that, do you think that it breaks your fast? And I want to just frame this question of breaking the fast in a more general scientific theme. And I'd love your thoughts on this. One of the q... |
Speaker C: Well, my first answer is not scientific, it's philosophical. If you don't enjoy life, what's the point? And so I'd like a cup of coffee in the morning, a little bit of milk. Spoonful of yogurt's not going to kill me. Olive oil doesn't have protein or carbs in it, not many. And so I'm probably not affecting t... |
Speaker A: I think that captures the essence of fasting rationally and a rational approach to supplementation very well. Along the lines of supplementation. What about NMN, nr and B? Three niacin? I want to know what you do. I also want to know what I should do. I think most people want to know what they should do. I m... |
Speaker C: All right, well, disclaimer is, I don't recommend anything, but I talk about what I do. So a bit of scientific background. These sirtuin genes that we discovered first in yeast cells when I was at mitzvah, and then in animals as I moved to Harvard in the two thousands. And one of my first postdocs, actually,... |
Speaker A: I see. Dosage wise, if I were elect to take NMN in supplement form to increase my NAD levels and presumably slow my aging, how much NMN should I take? What's the protocol that you do? And are the various forms that are out there are some better or some worse? |
Speaker C: Well, I'm always happy to tell you what I do and what my father does. My 82 year old father, we take a gram of NMN every day. |
Speaker A: So it's a gram of resveratrol and a gram of NMN. |
Speaker C: Right? |
Speaker A: Okay. 1000 milligrams. |
Speaker C: Now, another. Another important point, which is I'm not the same as everybody else. I have a different microbiome, age, sex. Right. And so I've been measuring myself. And so I know if something's I. Or I think I know if something's making me better or worse based on measuring 45 different things. So I just w... |
Speaker A: You crack open the capsules and you'll take a little sample to make sure it tastes like burnt popcorn. |
Speaker C: Well, when I'm making my capsules, I'll taste it, and I do a lot of quality control on the stuff that I take. |
Speaker A: Do you take that gram all at once with the resveratrol, or do you take it spread throughout the day? |
Speaker C: It's all in the morning for those things. So it's the. If I take metformin, it's NMN and the resveratrol altogether. And there's a good reason for that. It's all scientific. I try to be. The levels of Nad go up in the morning in our bodies. Naturally, our bodies actually have a cycle of nad. |
Speaker A: It's not steady, it's circadian. |
Speaker C: It's circadian. In fact, Nad controls your clock. This was shown by Shin Emai and colleagues in a nice science paper about a decade ago, that if you disrupt the NAD cycle, which is controlled by the Sirtuin gene that we worked on, that is what's telling your body, oh, it's time to eat, it's time to go to sle... |
Speaker A: Interesting. |
Speaker C: Conversely, when I travel and I want to reset my clock to the time zone, I will take a boost of NMN in the morning, and I feel great. |
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