Huberman LabThe Biology of Slowing & Reversing Aging | Dr. David Sinclair
EVERY SPOKEN WORD
150 min read · 30,045 words- 0:00 – 3:30
Dr. David Sinclair, Harvard Medical School
- AHAndrew Huberman
(uptempo music) Welcome to the Huberman Lab Podcast, where 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 Dr. David Sinclair, Professor of Genetics at Harvard Medical School and Co-Director of The Paul F. Glenn Center for the Biology of Aging. Dr. Sinclair's work is focused on why we age and how to slow or reverse the effects of aging by focusing on the cellular and molecular pathways that exist in all cells of the body, and that progress those cells over time from young cells to old cells. By elucidating the biology of cellular maturation and aging, Dr. Sinclair's group has figured out intervention points by which any of us, indeed all of us, can slow or reverse the effects of aging. What is unique about his work is that it focuses on behavioral interventions, nutritional interventions, as well as supplementation and prescription drug interventions that can help us all age more slowly and reverse the effects of aging in all tissues of the body. Dr. Sinclair holds a unique and revolutionary view of the aging process, which is that aging is not the normal and natural consequence that we all will suffer, but rather that aging is a disease that can be slowed or halted. Dr. Sinclair continually publishes original research articles in the most prestigious and competitive scientific journals. In addition to that, he's published a popular book that was a New York Times bestseller. The title of that book is Lifespan: Why We Age and Why We Don't Have To. He is also very active in public-facing efforts to educate people on the biology of aging and slowing the aging process. Dr. Sinclair and I share a mutual interest and excitement in public education about science. And so I'm thrilled to share with you that we've partnered, and Dr. David Sinclair is going to be launching the Lifespan podcast, which is all about the biology of aging and tools to intervene in the aging process. That podcast will launch Wednesday, January 5th. You can find it at the link in the show notes to this episode today. As well, you can subscribe to that podcast on YouTube, Apple, or Spotify, or anywhere that you get your podcasts. Again, the Lifespan podcast featuring Dr. David Sinclair begins Wednesday, January 5th, 2022. Be sure to check it out. You're going to learn a tremendous amount of information and you're going to learn both the mechanistic science behind aging, the mechanistic science behind reversing the aging process, and practical tools that you can apply in your everyday life. In today's episode, Dr. Sinclair and I talk about the biology of aging and tools to intervene in that process. And so you might view today's episode as a primer for the Lifespan podcast, because we delve deep into the behavioral tools, nutritional aspects, supplementation aspects of the biology of aging. We also talk about David's important discoveries of the sirtuins, particular molecular components that influence what is called the epigenome. And if you don't know what the epigenome is, you will soon learn in today's episode. Coming away from today's episode, you will have in-depth knowledge about the biology of aging at the cellular, molecular, and what we call the circuit level, meaning how the different organs and tissues of the bodies age independently and how they influence the aging of each other. Today's episode gets into discussion about many aspects of aging and tools to combat aging that have not been discussed on any other podcasts or in the book Lifespan.
- 3:30 – 7:45
ROKA, InsideTracker, Magic Spoon
- AHAndrew Huberman
Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. I've spent a lifetime working on the visual system and I can tell you that the visual system has to contend with a number of different challenges, such as when you move from a bright area outside to an area where there are shadows, you have to adjust a number of things in your visual system so that you can still see things clearly. One problem with a lot of eyeglasses and sunglasses is they don't take that biological feature into account and you have to take off your glasses and put them back on depending on how bright or dim a given environment is. With ROKA eyeglasses and sunglasses, you always see things with the utmost clarity. In addition, they're very lightweight and they won't slip off your face. In fact, they were designed to be worn while biking or running and in various activities, but they also have a terrific aesthetic, so you could wear them to dinner or work. I wear readers at night and when I drive and I wear the sunglasses for most of the day. If you'd like to try ROKA sunglasses or eyeglasses, you can go to roka.com, that's R-O-K-A .com, and enter the code Huberman to save 20% off your first order. Again, that's ROKA, R-O-K-A .com and enter the code Huberman at checkout. Today's episode is also brought to us by InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done, for the simple reason that many of the factors that impact your immediate and long-term health can only be assessed from a quality blood test. And now with the advent of modern DNA tests, you can also get a clear picture of what your biological age is and compare that to your chronological age. And obviously your biological age is the important one, because it predicts how long you will live and it's the one that you can control. The great thing about InsideTracker is that compared to a lot of other DNA tests and blood tests out there, is that with InsideTracker, you don't just get your numbers back at the levels of various hormones, metabolic factors, blood lipids, et cetera, but it also offers clear directives to lifestyle factors, nutritional factors and supplementation that you can use in order to get the numbers into the ranges that are best for you and for your health. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman to get 25% off any of InsideTracker's plans. Just use the code Huberman at checkout. Again, that's insidetracker.com/huberman to get 25% off any of InsideTracker's plans.Today's episode is also brought to us by Magic Spoon. Magic Spoon is a zero sugar, grain-free, keto-friendly cereal. Now, I don't follow a strictly ketogenic diet. What works best for me is to eat according to my desire to be alert at certain times of day and to be sleepy at other times of day. So for me, that means fasting until about 11:00 AM or 12 noon most days, and then my lunch is typically a low carb, keto-ish lunch, maybe a small piece of grass-fed meat, some salad, something of that sort. And then in the afternoon, I might have a snack that's also keto-ish. And then at night is when I eat my carbohydrates, which for me, helps me with the transition to sleep and allows me to get great deep sleep. That's what works for me. What that means is then in the afternoon, I'm craving a snack, and the snack for me is Magic Spoon. What I do lately is I put in some Bulgarian yogurt, sometimes I just eat it straight. Each serving of Magic Spoon has zero sh- grams of sugar, 13 to 14 grams of protein, and only four grams of carbohydrates in each serving, so it really matches that low carb, keto-ish approach. There's only 140 calories per serving, and they have a variety of flavors, cocoa, fruity, peanut butter, frosted. I particularly like frosted 'cause it tastes like donuts. I try not to eat donuts, but I do love the frosted, and as I mentioned before, I lately mix it with yogurt, put a little cinnamon on there. I'm getting hungry just talking about it now. If you want to try Magic Spoon, you can go to magicspoon.com/huberman to grab a variety pack. Use the promo code Huberman at checkout to get $5 off your order. Again, that's magicspoon.com/huberman and use the code Huberman to get $5 off. And now my conversation with Dr. David Sinclair.
- 7:45 – 10:23
“Aging as a Disease” vs. Longevity & Anti-Aging
- AHAndrew Huberman
Thank you for coming.
- DSDavid Sinclair
Thanks for having me here. (glasses clink) It's good to see you.
- AHAndrew Huberman
All right. This is Mate, by the way, that we're toasting at, uh, 11:00 AM. Uh, unlike other podcasts, we... 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, longevity, lifespan, actionable protocols to increase how long we live, et cetera, and I just want to start off with a very simple question that I'm not even sure there's an answer to, but what is the difference between longevity, anti-aging, and aging as a disease? Because I associate you with this statement, "Aging is a disease."
- DSDavid Sinclair
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 longevity are perfectly valid ways to talk about this subject, uh, so let's talk about aging as a disease. Uh, when I started my research, disease, here at Harvard Medical School, it was considered if, if there's something that's wrong with you, um, and it's a rare thing, has to be less than 50% of the population, that's definitely a disease, and then people work their whole lives to try and cure that condition. And so I looked up what's the definition of aging, and it says, well, it's a deterioration in health and sickness and you can die from it, typically you do, um, so I'm thinking that sounds pretty much like a disease, but the caveat is that if more than half the population gets this condition, aging, uh, it's put in a different bucket, which is first of all, that's outrageous, 'cause it, it's just a, a totally arbitrary cutoff. But think about this, that we're ignoring the major cause of all these diseases. Aging is 80 to 90% the cause of heart disease, Alzheimer's. If we didn't get old and our bodies stayed youthful, we would not get those diseases, and actually what we're showing in my lab is if you turn the clock back in tissues, those diseases go away. So aging is the problem, and instead, through, you know, most of the last 200 years, we've been sticking Band-Aids on diseases that have already occurred because of aging, and then it's too late. Um, so there are a couple of things. One is we want to slow aging down so we don't get those diseases, and when they do occur, don't just stick a Band-Aid on. Reverse the age of the body and then the diseases will go away.
- AHAndrew Huberman
That clarifies a lot for me. Thank you.
- 10:23 – 15:53
What Causes Aging? The Epigenome
- AHAndrew Huberman
Can we point to one specific general phenomenon in the body that underlies aging?
- DSDavid Sinclair
Yeah. Well, th- that's contentious, because, you know, scientists like to come up with new hypotheses, as, um, it's how they build their careers, but fortunately during the 2000s, we settled on eight or nine major causes of aging. We call them hallmarks 'cause causes was a, was a little bit too strong, but these, these eight or nine causes, uh, at least for the first time allowed us to come around and talk together, and we put, put them on a, on a pizza so everyone got an equal weighting, equal slices, um, and, but before that, by the way, we were trying to kill each other in the field. It was horrible. Um-
- AHAndrew Huberman
Interesting that you guys work on aging and trying to kill each other.
- DSDavid Sinclair
Yeah, isn't it?
- AHAndrew Huberman
Uh, yeah.
- DSDavid Sinclair
Well, k- 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, we just came along in the 1990s and 90s and said, "Free radicals don't do much." There, there are actually genes called longevity genes, and that caused a whole ruckus, and there was this competition for what never happened, which was a Nobel Prize for this, and it just led to a lot of competition. You... I would go to meetings, uh, and people would shout at each other and backstab. It was horrible. Um, but then fortunately in the 2000s, we rallied around this new map of aging with these causes or hallmarks, um, but I, but I think that there's one slice of the pizza that is way larger than the others, uh, and we can get to that, but that's the information in the cell that I call, we call the epigenome.
- AHAndrew Huberman
I think, well, well tell us a little bit more about the epigenome. Uh, frame it for us, um, if, if you will, and, um, and then we'll get into ways that one can, uh, adjust the epigenome in positive ways.
- DSDavid Sinclair
Yeah. So in science, what, what I like to do, I'm a reductionist, is to boil it down, um, and I actually ended up boiling aging down to an equation.... which is the, the loss of information due to entropy. I know it's, it's a hard thing to overcome, second law of thermodynamics. That's, that's fair. But this equation, um, really represents the fact that I think aging is a loss of information in the same way that when you Xerox something a me- a thousand times, you'll lose that information, or you try to copy a cassette tape, or even if you send information across the internet, some of it will get lost. That's what I think is aging. And there are two types of information in the body. There is the genetic information which is digital, A, T, C, G, the chemical letters of DNA, but there's this other part of the information in the body that's just as important, it's essential in fact, and that's the systems that control which genes are switched on and off, in what cell, at what time in response to what we eat, et cetera. And it turns out that 80% of our future longevity and health is controlled by the second part, the epigenetic information, the control systems. Uh, I liken the DNA to the, the music that's on a DVD or compact disc, for the younger people-
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
... we used to use these things.
- AHAndrew Huberman
I re- I recall.
- DSDavid Sinclair
Yeah.
- AHAndrew Huberman
Yeah.
- DSDavid Sinclair
Uh, 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, you're not playing the right songs, and cells, when they don't hear the right songs, they get messed up and they don't function well, and that is what I'm saying is the main driver of aging, and these other hallmarks are largely manifestations of that process.
- AHAndrew Huberman
Can we go a little deeper into what the, these scratches are? Uh, is it the way that the DNA are packed into a cell? Is it the way that, uh, they're spaced? Uh, what is, what are the scratches that you're referring to?
- DSDavid Sinclair
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 in- inside us. But it's not just wrapped up willy-nilly, it's not just a bundle of string. It's wrapped up very carefully in ways that dictates which genes are switched on and off. And when we're developing in the embryo, the cell marks the DNA with chemicals that says, "Okay, this gene is for a nerve cell. You, you cell will stay a nerve cell for the next 100 years if you're lucky. Don't turn into a skin cell. That would be bad." Uh, and those chemicals, uh, s- there are many different types of chemicals, but one's called methylation. Those little methyls will mark which songs get played for the rest of your life. And there are other marks that change daily, but in total what we're saying is that the body controls the genome through the ability to mark the DNA and then compact some parts of it, silence those genes, don't read those genes, and open others, keep others open that should stay open. And that pattern of genes that are silent and open, silent, open is what dictates the cell's type, the cell's function, and then the scratches are the disruption of that. So genes that were once silent, and you could say it's a gene that is involved in skin, it's starting to come on in the brain, shouldn't be there, but we see this happen, and vice versa, the gene might get shut off over time during aging. Cells over time lose these structures, lose their identity, they forget what they're supposed to do, and we get diseases. We call that aging. Uh, and we can measure that. In fact, we can measure it in such a way that we can predict when somebody's going to die based on the changes in those chemicals.
- 15:53 – 17:15
Cosmetic Aging
- DSDavid Sinclair
- AHAndrew Huberman
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, uh, of the face. Um, uh, I'm walking around New York lately, it's, uh, amazing to me there are certain people that seem to walk looking down at the sidewalk because their, their spine is essentially in a C shape, right? Um, a hallmark, if you will, of aging that most of us are familiar with. Are these same sorts of DNA scratches associated with that, or are we talking about people that are potentially are going to look older but simply live longer?
- DSDavid Sinclair
Uh, well, it's actually, uh, you, you are as old as you look, if you want to generalize. Um, 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, it is a good ex- good indicator. It's not perfect, because you can, like me, grow up in Australia and accelerate the aging of your skin, uh, but in general how you look. Uh, no one's ever died from gray hair, but overall you can get a sense just from the ability of skin to hold itself up, how thin it is, the number of wrinkles. That is actually j- it was, uh, a great paper just came out that said that an AI system looking at the face could very accurately predict someone's age.
- AHAndrew Huberman
Very interesting. So I started
- 17:15 – 20:12
Development Never Stops, Horvath Clock
- AHAndrew Huberman
off in developmental neurobiology, so one of the things that I learned early on that I still believe, uh, wholeheartedly is that development doesn't stop at age 12 or 15 or even 25, that your entire life is one d- long developmental arc. Right? So in thinking about different portions of that developmental arc, the early portion of infancy and especially puberty seem like especially rapid stages of aging. And I know we normally look at babies and children and kids in puberty and we think, "Oh, they're so vital. They're so young." And yet the way you describe these changes in the epigenome and the way you have framed aging as a disease leads me to ask, are periods of in- of immense vitality the same periods when we're aging faster?
- DSDavid Sinclair
Yes. Yes, and this is something I've never talked about, uh, at least not publicly, so this is a really good question.So those chemicals we can measure. Uh, it's, 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 AI looked at the faces of those people, they could pre- predict their biological age, their internal age. So your skin represents the age of your organs as well. And the people that look after themselves, we can talk about how to do that later, but th- there are some people that are 10, 20 years younger than other people, um, biologically. And it turns out if you measure that clock from birth or even before birth, if you look at animals, there's a massive increase in age on, based on that clock early in life.
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
So you're right, that, so that's a really important point, that you, you have accelerated aging during the first few years of life and then it goes linear towards the rest of your life. But there's another interesting thing you brought up, which is that we're finding that the genes that get messed up, that get scratched, that are leading to ating- aging, are those early developmental genes. They come on late in life and just mess up the system, and they seem to be particularly susceptible to those scratches. So what a- what's causing the scratches? Well, we know of a couple of things in my lab, we figured out. One is broken chromosomes, DNA damage, particularly cuts to the DNA breaks. So if you, if you have an X-ray or a cosmic ray or even if you go out in the sun and you'll get your broken chromosomes, that ex- accelerates the unwinding of those beautiful DNA loops that I mentioned. Um, we can actually do this to a mouse. We can accelerate that process, and we get an old mouse, 50% older, and it has this bent spine kyphosis, it has gray hair, its organs are old. So we now can control aging in the forwards direction. The other thing that accelerates aging is massive cell damage or stress. So we pinched nerves, uh, and we saw that their aging process was accelerated as well.
- AHAndrew Huberman
Incredible. Yeah, the,
- 20:12 – 23:00
Puberty Rate as a Determinant of Aging Rate
- AHAndrew Huberman
this is more of an anecdotal, uh, phenomenon. It is an anecdotal phenomenon, but this experience of in junior high school, you know, going home for a summer and you come back, and high school in the US usually starts eighth or ninth grade or grade eight or great nine for you Canadians, and then some of the kids, like, they grew beards over the summer or they completely matured quickly over the summer. Do you think there's any reason to believe that rates of entry into and through puberty have, can predict overall rates of aging? In other words, if a kid is a, uh, you know, a slow burner, right? They, they basically acquire the, the traits of puberty slowly over many years. Can we make some coarse prediction that they are going to live a long time versus a kid that goes home for the summer and comes back a c- completely different organism or appearing to be a completely different organism? Like, they basically age very quickly in the summer. Does that mean they're aging very quickly overall?
- DSDavid Sinclair
Well, yeah, I don't want to scare anybody.
- AHAndrew Huberman
Sure.
- DSDavid Sinclair
Uh, there, there, uh, there are studies that show that the slower you take to develop, it also is predictive of having a longer, healthier life. Um, and it may have something to do with growth hormone. We know that growth hormone is pro-aging. S- you know, anyone who's taking growth hormone, you know, pay attention. We know that-
- AHAndrew Huberman
Just look at someone who's taking growth hormone.
- DSDavid Sinclair
Yeah.
- AHAndrew Huberman
They, they often will acquire these, um, characteristics of vitality, like improved, uh, smoothness of skin, but-
- DSDavid Sinclair
Yeah, sure.
- AHAndrew Huberman
... but their whole body shape changes often.
- DSDavid Sinclair
Yeah. I mean, you'll feel bet- feel better for a short amount of time. You'll build up muscle, you'll feel great, but it's like burning your candle at both ends. Uh, ultimately, if you want to live longer, you want less of that, and the animals that, that have been generated, um, and mutants that have low growth hormone, sometimes these are dwarfs, um, they live the longest by far. Uh, a guy in my lab, Michael Bonkowski, he had the longest lived mouse. A mouse typically lives about two and a bit years. He had a mouse that lived five years, and he gave it caloric restriction, so fasting, combined with one of these dwarf mutations, low growth hormone. Uh, I think he called it Yoda. But the- this is, you know, you look at who, who lives the longest, it's the really small people. Um, this is a bit anecdotal, but it sounds, sounds like it might be true, is that the people who played the munchkins in The Wizard of Oz, many of them went on to live t- into their 90s and beyond.
- AHAndrew Huberman
Really?
- DSDavid Sinclair
Yeah.
- AHAndrew Huberman
Huh. Amazing.
- DSDavid Sinclair
And, uh, there are some Laron, Laron dwarfs as well. There are dwarf, um, mutations, uh, 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.
- AHAndrew Huberman
So I, having owned a very large dog breed, a bulldog mastiff, who
- 23:00 – 32:44
Fasting, Hunger & Food Choices
- AHAndrew Huberman
lived a long life for a bulldog, 11 years, but there are many dogs that will live 12, 16 years that are smaller dogs. Can we say that there is a direct relationship between body size and longevity or duration of, of, of life?
- DSDavid Sinclair
Well, th- there is, uh, 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, if you're born tall, and I wasn't, and I wished at the time I, I did grow, um, but no matter what size you are, you can have a bigger impact on your life than anything your genes give you. 80% is epigenetic, not genetic.
- AHAndrew Huberman
So let's talk about some of the things that people can do, and, uh, I've kind of batched these into categories, um, rather than just diving right into actionable protocols. So th- the f- 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 it's good for us, and kind of, um, one of the reasons I'm excited to talk to you today, is because, uh, I want to drill into the details of this, because I think understanding the mechanism will allow people to make better choices and not...... simply to just decide whether or not they're going to fast or not fast, or how long they're going to fast, I think should be dictated by some understanding of the mechanism. So, why is it that having elevated blood sugar, glucose, and insulin ages us more quickly, and/or why is it that having periods of time each day, or perhaps longer, can extend our lifespan?
- DSDavid Sinclair
Well, le- let's start with, 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, uh, snacks in between. So the feeling of hunger alm- ... Some people never experience hunger in their whole lives. It's really, really bad for them. Um, it was based, I believe, on the 20th century view that you don't want to stress out the pancreas, uh, and you try to keep insulin levels pretty steady, um, and not have this, this fluctuation. What we actually found, uh, my colleagues and I, uh, across this field of longevity, is that when you look at, first of all, animals, whether it's a dog or a mouse or a monkey, the ones that live the longest, by far, 30% longer, and stay healthy, are the ones that don't eat all the time. Um, actually it was first discovered back in the early 20th century but people ignored it, and then it was rediscovered in, uh, the 1930s. Clive McKay did caloric restriction. He put cellulose in the food of rats so they couldn't get as many calories even though they ate, and those rats lived 30% longer. But then it, it went away, and then it came back in the 2000s in a big way when a couple of things happened. One is that, uh, my lab and others showed that there are longevity genes in the body that come on and protect us from aging and disease. The group of genes that I work on are called sirtuins. There's seven of them. And we showed in 2005, uh, in a science paper, that if you have low levels of insulin and another molecule called insulin-like growth factor, those low levels turn on the longevity genes. One of them that's really important is called SIRT1. And, b- but by having high levels of insulin all day, being fed means your longevity genes are not switched on. So you're falling apart, your epigenome, your information that keeps your cells functioning over time just degrades quicker. Your, your clock is ticking faster by always being fed. Okay? Um, the other thing that I think might be happening by always having food around is that it's not allowing the cell to have periods of rest and, and reestablish the epigenome, and so it also is accelerating in that direction. There's plenty of other reasons as well that are not as profound such as, um, having low levels of glucose in your body will trigger your major muscles and your brain to become more resi- uh, sensitive to insulin and suck the glucose out of your bloodstream which is very good. You don't want to have glucose flowing around too much. And that will ward off type 2 diabetes.
- AHAndrew Huberman
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?
- DSDavid Sinclair
Yeah, I, I do. Um, though you get used to the feeling of not eating, so I'm kind of screwed that way.
- AHAndrew Huberman
It's like cold water. You eventually adapt.
- DSDavid Sinclair
Ye- you get used to it un- unf- unfortunately. But there, 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 s- a small component that's due to hunger. But most of it actually is because you've got this, these periods of not being fed and then the body turns on these defensive genes. Um, there's a really interesting experiment that was published maybe a couple of years ago by Raphael de Cabo down at the NIH. What he did was he took over 10,000 mice and gave them different combinations of fat, carbohydrate, protein, and he was trying to figure out what was the best combination. And then he also cleverly had a group, well, two groups, one that was fed all the time, or a- ate as much as they wanted, and the other group was only given food for an hour a day. And it turns out they ate roughly the same amount of calories, 'cause of course in an hour, they're stuffing their faces. Uh, it turns out it didn't matter what diet he gave them. It was only the group that ate within that window that lived longer, and dramatically longer. So my conclusion is, and mice are very similar to us metabolically, I think that tells us that it's not as important what you eat, it's when you eat during the day.
- AHAndrew Huberman
What is the protocol that people can extrapolate from that? Um, 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 protocol?
- DSDavid Sinclair
Well, if there's one thing I, I could say, if, I would say definitely try to skip a meal a day. That's the best thing.
- AHAndrew Huberman
Does it matter which meal? Or are they essentially equivalent?
- DSDavid Sinclair
Well, as long as it's at the end or the beginning of the day, because then you, you add that to the sleep period where you're hopefully not eating.
- AHAndrew Huberman
I think that, that's an excellent point. I realize it's a s- it's a simple one, but I think it's an excellent one 'cause I think one of the things that people struggle with the most is knowing h- when and how to initiate this so-called intermittent fasting. And the middle of the day obviously is not tacked to the sleep cycle in the same way. So it's much harder, uh, as well for many people.
- DSDavid Sinclair
Yeah.
- AHAndrew Huberman
Yeah.
- DSDavid Sinclair
Well, s- I'll tell you what I do. Um, I, 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, uh, this glass of water here. I'm just keeping myself filled with liquids and so I don't feel hungry. Be aware that the first two to three weeks when you try that, you will feel hungry, and you'll also have a habit of wanting to s- chew on something...... there's a lot of physical parts to it. But try to make it through the first three weeks, and do without breakfast or do without dinner, uh, and I, you'll get through it. And I did that most, for most of my life actually. Uh, mainly because I didn't f- I wasn't hungry in the morning. Some people are very hungry in the morning, and they may want to consider skipping dinner instead. But I will go throughout the whole day. I don't get the crashes of the high glucose and the low glucose that, uh, anyone who goes, "Oh, man. It's 3 o'clock. I'm going to need a sleep." If you do what I do, you, you will not experience that anymore, because what my body does is it's, it regulates blood sugar levels naturally. My liver is putting out glucose when it needs to, and it's very steady and gives me pure focus throughout the day. And I don't have t- even have to think about lunch. I'm just powering through. At dinner, I, I love food as much as anybody, so I will, I will eat a regular pretty healthy meal. I'll eat, I'll try to eat mostly vegetables. I can eat some fish, some shrimp. Um, I rarely will eat a, a steak. Um, in fact, my microbiome is so adapted to my diet now if I eat a steak, it will not get digested very well. I'll feel terrible.
- AHAndrew Huberman
Mm-hmm. If I don't eat a steak, I feel terrible.
- DSDavid Sinclair
(laughs) Well, we-
- AHAndrew Huberman
Argentine lineage, but we can talk about that some other time.
- DSDavid Sinclair
Well, everybody's different. I mean, that's the other thing. What, uh, what works for me may not be perfect for you, and we do have to measure things to know what's working. Um, I rarely eat dessert. I gave up dessert and sugar in my f- when I turned 40, and, um, occasionally I'll steal a bit of dessert 'cause it doesn't hurt if you steal it, right? But other than that, I, I avoid sugar, which includes, uh, simple carbohydrates. Um, bread I try to avoid. I've actually noticed, this is a, uh, just a side note, I used to get buildup of plaque pretty easily, uh, and every time I went to the dentist they'd have to scrape it off, and I even bought tools to scrape it off 'cause it was driving me nuts. I don't get plaque anymore, and I think it's because of my diet. I don't have those sugars in my mouth that the bacteria feed on and then form the biofilm on the teeth.
- AHAndrew Huberman
Interesting.
- DSDavid Sinclair
Much better breath, by the way.
- AHAndrew Huberman
Uh, all, that's a benefit. Uh, so do you ever fast longer than this? It sounds like if you, um, if you go to bed at l- well you tend to stay up late I know because I get texts from you at like 2:00 in the morning, the, um, my time, which means you're up very late and up early as well. But
- 32:44 – 34:50
Fasting Schedules, Long Fasts, (Macro)Autophagy
- AHAndrew Huberman
assuming that people go to sleep sometime around 11:30 or 12:00-
- DSDavid Sinclair
Mm-hmm.
- AHAndrew Huberman
... plus or minus an hour, and wake up sometime around 7:00 AM plus or minus 90 minutes, you're eating more or less on a, it sounds like a, uh, something like a 20 hours of fasting, four hours of eating or 16 hours of fasting and eight hours of, of food intake, et cetera. But do you ever do longer fasts, like 48 hours or 72 hours or week-long fasts?
- DSDavid Sinclair
Occasionally, I do. Um, so my typical day, I, I would only eat within a two-hour window, just usually I'm eating, either eating out or-
- AHAndrew Huberman
So you're 22/2?
- DSDavid Sinclair
Yeah. Yeah, but I, I love, well-
- AHAndrew Huberman
And if you exercise, do you feel like b- then you just power through and maintain that fasted state?
- DSDavid Sinclair
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, um, and, but have I gone longer? Yes, but not very often. I find it qu- quite difficult (laughs) to go more than 24 hours. Uh, but when I do it, maybe it's once a month, I'll go for two days. Um, after two, and actually even better if you go for three days without eating, it kicks in even greater, uh, longevity benefits. Um, so there's a system called the autophagy system, which digests old and misfolded proteins in the body, and there's a natural cleansing that happens when you're hungry. Uh, macroautophagy, its name is. But a good friend of mine, uh, Ana Maria Cuervo at Albert Einstein College of Medicine, discovered a, a deep cleanse called the chaperone-mediated autophagy which kicks in day two, day three, uh, which really gets rid of the, the, the deep proteins. And sh- what, what excites me is she just put out a, a big paper that said if you trigger this process in an, in an old mouse, it lives 35% longer.
- AHAndrew Huberman
Wow.
- DSDavid Sinclair
Yeah. So it, it's a big deal. I, if I could go longer, I would, but I just find that with my lifestyle and I'm going always day, you know, 110%, um, I need to, to eat at least once a day unfortunately.
- AHAndrew Huberman
One more practical question, then a mechanistic question related to this. The practical question is when you are fasting, regardless of how long,
- 34:50 – 35:56
Caffeine, Electrolytes
- AHAndrew Huberman
I know you're ingesting fluids like water and, uh, presumably some caffeine. I heard you had several or more, or more espresso today, um, which is impressive. But are you also ingesting electrolytes? Like I know some people get lightheaded, they start to feel shaky when they fast, um, and that the addition of sodium to their water or potassium, magnesium, uh, is so- something that's becoming a little more in vogue now. Is that something that you do, or that you see a need for people to do?
- DSDavid Sinclair
Well, it makes sense, um, but I haven't had a need to do it, um, so I don't. I just, I drink tea during the day and coffee when I'm first awake-
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
... and I don't get the shakes. So, you know, I, I don't fix what's not broken.
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
Um, and I do add things to my protocol that I think will improve me, um, and avoid those things, of course, that won't. Uh, but yeah, but because I don't have a need for it, I don't try it. But it does make sense, especially, you know, if you've had a big night the night before, you probably want to supplement with that. But, uh, I think there's, there's a fair amount of, uh, good stuff in tea and coffee as it is.
- AHAndrew Huberman
Okay. So then the, the mechanistic
- 35:56 – 37:55
Blood Glucose & the Sirtuins; mTOR
- AHAndrew Huberman
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 of, of eat, gobbling up of, of dead cells and things of that sort. How is it that blood glucose triggers these mechanisms? 'Cause we've said, okay, remove glucose and things get better. Uh, you've...... uh, talked before, maybe we could talk more now about some of the underlying cellular and genetic mechanisms, things like the sirtuins. But how are glucose and the sirtuins actually tethered to one another mechanistically?
- DSDavid Sinclair
Yeah, there's a really good question. That proves you're a scientist, uh, or a world-leading one. So, what we, what we've 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 'cause they're all talking to each other. You pull one lever and the other one moves. And the way to think of it is that there are systems set up to detect what you're eating, so the sirtuins will mainly respond to sugar and insulin, and then there's this other system called mTOR, which is sensing how much protein or amino acids are coming into your body. And they talk to each other. We can pull one and affect the other and vice versa, but together when you're fasting, you'll get the sirtuin activation, which is good for you, and you, you'll also, through lack of amino acids, particularly three of them, leucine, isoleucine, valine, the body will downregulate mTOR. And it's that up sirtuin, down mTOR that is hugely beneficial and turns on all of the body's defenses. The pro- chewing up the old proteins, improving insulin sensitivity, giving us more energy, repairing cells, all of that. And, and so these two pathways, I think, are the most important for longevity.
- 37:55 – 44:35
Amino Acids: Leucine, “Pulsing”
- AHAndrew Huberman
So interesting. You mentioned leucine. Within the resistance training/bodybuilding/fitness community, leucine gets a lot of attention because there are long-standing 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, and not much else, frankly. However, it's clear that because of leucine's effects on the mTOR pathway, that there are many people, not just people in these particular fitness communities, that are actively trying to ingest more leucine on a regular basis in order to maximize their wellness and fitness, and in some cases, muscle growth, but also just wellness. But what I interpret your last statement to mean is that leucine, because it triggers cellular growth, is actually pro-aging in some sense. Is that right?
- DSDavid Sinclair
Well, it could be. That's, 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, you'll bulk up more. You'll feel better immediately. But based on the research, it's at the expense of long-term health. So my view of longevity, the way I treat my body, is, um, I don't burn both candles. I have one end of the candle lit. I, I'm very careful. I don't blow on it. Um, but I also do enough exercise that I'm building up my muscle, but I'm, I'm not huge. Anyone who's seen me, you know, knows that I'm not a, a, a professional bodybuilder. But I try to actually... Here's the key, and I haven't said this publicly that I can remember. I pulse things so that I get periods of fasting, and then I eat, then I take a supplement, then I fast, then I exercise, and I'm, I'm taking the supplements and eating in the right timing to allow me to build up muscle sometimes. Because you can't just expect to take something constantly and do something constantly for it to work. And that's, that's why it's taken me about 15 years to develop my protocol, and there's a, there's a lot of subtlety to it.
- AHAndrew Huberman
Mm-hmm. Yeah, it sounds like a very rational protocol. Does the name Ori Hofmekler mean anything to you?
- DSDavid Sinclair
No.
- AHAndrew Huberman
Okay. Uh, just briefly, uh, I discovered Ori Hofmekler about 15 years ago. He was a, in Israeli Special Forces. He's now gotta be close to 70. Forgive me, Ori, if that's, uh, if that number is inflated. Um, 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 Special Forces, they rarely ate more than once per day, and sometimes once every second or third day. And this is a guy who maintains an incredible physical stature. You know, he's very lean, very strong, and very vital at, you know, not... I wouldn't say an advanced age, but he's getting up there, and he just seems to be getting better and better. Ori Hofmekler was the person who essentially founded, if you will, although our ancestors found it, to be completely fair, the so-called intermittent fasting diet. He called it the warrior diet, and this book didn't get much attention. But one of the things that you just said really reminded me of Ori. I sat down with him, I actually went to his home and sat down with him, and he said, "Fasting is wonderful, but these pulses where you nourish the body, or even slightly over-nourish the body, provided they aren't too frequent, have a tremendous effect on vitality." And so I, I want to use that as kind of a segue to, uh, address this issue of vitality versus longevity, because here you're telling me, and certainly the evidence supports that, you know, growth hormone will make you feel better and younger, taking testosterone or estrogen, we should probably say. There are, right, women who are take hormone therapies later in life, who take estrogen, they experience a, a strong increase in vitality if it's done correctly. But there is a, an effect of aging the body more rapidly. It's sort of a second puberty, if you will. But this idea of restriction and then pulsing, not necessarily feast and famine, but certainly famine and feast in lowercase letters, real- there really seems to be something about that. So at a cellular level, like, we kind of go back to mTOR and the sirtuins. How do you think that the cells might be reacting to this kind of lowercased feast, uh, and ho- uppercase famine-type protocol?
- DSDavid Sinclair
All right. Uh, well, the, the pulsing, I think, is... What you want to do is to get the cells to be...... perceiving adversity, okay? 'Cause our modern life, we're sitting around, we're eating, uh, too much. Uh, 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 defenses, and we age rapidly. We can see it in the clock. People who exercise and eat less have a slower-ticking clock. It's, it's a fact. Uh, but my protocol is different than most people's, because I am pulsing it. Now, there... First of all, let's get to, why did I even think that might be possible? 'Cause I didn't read The Warrior Diet. Um, what I found in my research was that if we gave resveratrol, this red wine molecule that became well-known in the 2000s, uh, if we gave it to mice their whole lifespan, they were protected against a high-fat diet, which we call the Western diet, they had lean organs, they lived slightly longer, but not a lot. And if we gave, uh, them a high-fat diet without resveratrol, they actually, um, lived a lot shorter. So, resveratrol protected them against the high-fat diet. We gave it to them on a normal diet, they just ate it when they wanted, and there wasn't much effect. Uh, this is what's not known, though it's in the supplemental data of the paper that nobody ever reads. The mice that were given resveratrol every second day on a normal diet lived dramatically longer than any other group.
- AHAndrew Huberman
Interesting.
- DSDavid Sinclair
So, people out there... You know, my, my critics say, "Oh, resveratrol didn't extend the lifespan of mice on a normal diet, therefore it's not aging, it's just protecting against the high-fat diet." Well, look at the supplemental data, please. If you give it to the, to the mice every other day, we had mice living over three years.
- AHAndrew Huberman
Wow. That's a long time for a m-
- DSDavid Sinclair
Yeah.
- AHAndrew Huberman
I have got many, many mice in my, um, owner- uh, ownership at, uh, in my lab at Stanford, and that's a very long life for a mouse.
- DSDavid Sinclair
It was, by far. And so it was a long lifespan extension, and what that
- 44:35 – 50:29
Metformin, Berberine
- DSDavid Sinclair
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 body, and then give it a rest. Same with exercise. And then I try to time it, 'cause there are times when I'm taking the drug metformin, which mimics low energy. For those of you who don't know, metformin is a drug given to type 2 diabetics to bring down their blood sugar levels, but it's been found that, looking at tens of thousands of veterans and others, that those two type 2 diabetics live longer than people that don't even get type 2 diabetes. So, it's a longevity drug. Right now, you have to get it from your doctor in the US. In most other countries, you can just get it over the counter. And you're protected, it looks like, based on, uh, e- epidemiological data, uh, cancer, heart disease, frailty, um, what else? Dementia. So, I take metformin.
- AHAndrew Huberman
In addition... You take metformin and you're fasting each day? So, when do you take it relative to the fasting?
- DSDavid Sinclair
Yeah, I, I always take, um, metformin in the morning, uh, along with the resveratrol, uh, because... For a number of reasons, but mainly because, uh, uh, my body responds better, and I've been measuring my body for 12, 13 years. But here's the thing. If I'm going to exercise, uh, that day, I will skip the metformin. And a lot of people who, uh, who do pay attention to this, this kind of thing think that they should stop taking metformin 'cause they're never gonna get muscle or it's gonna affect their ability to build up muscle, but that's not true. What metformin does to you, it actually just reduces the ab- your ability to have stamina, because it's inhibiting your body's ability to make energy. Um, and so what happens is, when you're on metformin, you do fewer reps, but guess what? Those muscles that you do build up on metformin have the same strength and have much lower inflammation and other markers of aging. You just won't have that extra 5% size of muscles. So, if you want large muscles, don't take metformin, and you'll be fine during your exercise. Uh, but for me, I, I'm not trying to get giant. I want strong muscles, and I want to li- live longer and healthier, so I'm, I just try to time it so that I get the most reps out of my exercise regimen. Um, but sometimes, in scientific literature, it, it's worth bringing this up. If there's a 5% difference in a graph, then either the press release or some reporter will say, "Oh, my goodness. Big difference, 5%, can't take metformin during exercise." That's the headline. And then you go in, and it's barely significant, and the graph is distorted because they've changed the axes to make it look bigger. Uh, and, you know, now it's become a myth that metformin greatly inhibits your ability to exercise, which is not true.
- AHAndrew Huberman
Interesting.
- DSDavid Sinclair
But in an abundance of caution, I, I skip my metformin on days I'm gonna exercise. And not only that, I'm one of the 20% of people that has a stomach sensitivity to it. So, if I'm not feeling great that day, I don't take it either.
- AHAndrew Huberman
You mentioned metformin is available only by prescription from a doctor, at least in the US. Um, berberine is this substance that comes from tree bark, uh, I also learned about many years ago from Ori. Um, he said, "If ever I'm going to overeat, like a Thanksgiving meal or something, I take berberine." Uh, this was hi- those were his words, and I tried it. And what's remarkable about berberine is that, um, you can eat enormous quantities of food and not feel as if you've eaten enormous quantities of food. I'm not necessarily recommending people do this, but what I noticed was if I took berberine, which my understanding is it works very similarly to m- to metformin, works on the AMPK pathway and the mTOR pathway, et cetera, that if I didn't ingest food, in particular, carbohydrates, I would feel a little dizzy and kind of get a headache, like ex- uh, almost hypoglycemic.... what are your thoughts on berberine as an alternative to metformin, and are there any cautionary notes? Uh, I mean, obviously people should talk to their doctor before adding or subtracting anything from their life, including, um, uh, breath work or anything that want, that comes up. But with all that as, set aside, what are your thoughts about berberine and, uh, timing of, of low blood sugar and, and these sorts of things?
- DSDavid Sinclair
Right. Well, before I had access to metformin, I was taking berberine. It's, it's often known as the poor man's metformin, though that-
- AHAndrew Huberman
He just called me poor.
- DSDavid Sinclair
W- w- women can take it too. Uh, so the, the thing with berberine, we've studied it in my lab. It, it is effective at boosting energetics in the body, just like AMPK, uh, and metformin does. Um, and we've actually given it to rats and, and mice and seen that they are very healthy, especially on a high fat diet. Um, so I, I think it's, it's likely to be good. There are some human studies that exist, clinical trials showing that it increases insulin sensitivity. You have to take high doses.
- AHAndrew Huberman
Which is a good thing, right?
- DSDavid Sinclair
Yeah.
- AHAndrew Huberman
I think when people hear insulin sensitivity, sometimes people think, "Oh, well, that, 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.
- DSDavid Sinclair
Exactly, so this is anti-type 2 diabetes. S- and so the, this berberine, uh, 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, there's one cautionary tale which just came up. Matt Kaeberlein's lab published that berberine reduced the lifespan of worms, uh, but I'm not sure worms trump human clinical trials at this point. So I would say that-
- AHAndrew Huberman
Not, not in my opinion.
- DSDavid Sinclair
... I wouldn't start take-
- AHAndrew Huberman
But no disrespect to my C. elegans colleagues, or my, or rather my colleagues that work on C. elegans.
- DSDavid Sinclair
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. Uh, I think berberine has been shown to be really safe in humans.
- 50:29 – 53:20
Resveratrol, Wine
- DSDavid Sinclair
- AHAndrew Huberman
You mentioned resveratrol. I think, uh, now would be a great time to talk a little bit about protocols for resveratrol, grape seed extract, et cetera. Um, let's start with the, the obvious one that, um, I know you get a lot, but, um, for the record, can't I just drink red wine and get enough resveratrol, David?
- DSDavid Sinclair
You can try. You, you'd need to drink about 200 glasses a day. So, uh, I, I don't-
- AHAndrew Huberman
I'm sure it's been tried. (laughs)
- DSDavid Sinclair
There are some. Uh, and I, I drink a, 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, I mean, realistically, you can only get the 1,000 milligrams that I take a day, uh, from a supplement that's pure. Now, there are a lot of people selling resveratrol. If it's not light gray or white in, in color, throw it away. The brown stuff has gone bad or is contaminated. Um, and the contaminated stuff, beware, it'll cause diarrhea. Uh, but re- regular resveratrol should not do that.
- AHAndrew Huberman
So 1,000 milligrams per day is what you do?
- DSDavid Sinclair
Yeah, and I have-
- AHAndrew Huberman
I agree.
- DSDavid Sinclair
... for about 15 years now.
- AHAndrew Huberman
And you ingest that with some fatty substance like olive oil or yogurt, is that right?
- DSDavid Sinclair
Yeah, you have to. And other, other supplements, quercetin, curcumin, these, these are crunchy things. They're not going to get through your gut. And I'm not just making this up. I, 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, we found out early, I was one of the first people to take a high dose resveratrol, uh, and when, when we included it with food, the levels in my blood went up fivefold. Uh, and so you want to have something in there. If you just drink it with water, it's not going to get through, and unfortunately some people have done clinical trials without even thinking that they might need to dissolve it in something.
- AHAndrew Huberman
So you're, are you taking this all at once in the morning and chasing it with some olive oil, or are you, uh, dissolving it in yogurt? What's the, what's the specific protocol?
- DSDavid Sinclair
Yeah, I, I've been improving, perfecting what I do. For about 10 years, I would take some Greek yogurt, 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 particularly oleic acid, one of the monounsaturated fatty acids, uh, is also an activator of the sirtuin defenses. So I'm trying to ingest more o- oleic acid, so I switched to olive oil. What I do is I put a couple of teaspoons of olive oil in a glass, mix around the resveratrol and maybe some corset- quercetin, a similar molecule, make sure it's dissolved. I put a little bit of vinegar, uh, and if I have a basil leaf, I'll put that in, and it's like drinking some, uh, salad dressing, and it's great.
- AHAndrew Huberman
Delicious. Um,
- 53:20 – 56:45
What Breaks a Fast?
- AHAndrew Huberman
that raises a question that I want to ask before we get to NMN and NR and vitamin B3, 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, in a more general scientific theme, and I'd love your thoughts on this. One of the questions I get asked all the time is, does ingesting blank break the fast? Does eating this or drinking this, coffee, you know, if I walk in the room and someone else is eating a cracker, does it break my fast, you know? People get pretty extreme with this.
- DSDavid Sinclair
Mm-hmm.
- AHAndrew Huberman
My sense, and please tell me if I'm wrong, but my sense is that it depends on the context of what you did the night before, whether or not you're diabetic, lots of things. So for instance, if I eat an enormous meal at midnight, go to sleep, wake up at 6:00 AM, I could imagine that black coffee or coffee with a little bit of cream might, quote unquote, break my fast. But the body doesn't have a breaking the fast switch. The body only speaks in the language of glucose, AMPK, mTOR, et cetera. So do you worry that ingesting these calories is going to, quote unquote, break your fast, and more generally, how do you think about the issue of whether or not you're fasting enough to get these positive effects? Because, uh, not everybody c- can manage on just water.... or just tea. Or, uh, we should say not everybody is willing to manage on just water or just tea for a certain part of the day.
- DSDavid Sinclair
Well, the, my first answer is not scientific, it's philosophical. Uh, if you don't enjoy life, what's the point? Um, and so I'd, I'd like a cup of coffee in the morning, little bit of milk, spoonful of yogurt's not going to kill me. Um, olive oil doesn't have protein or carbs in it, not many, and so I'm probably not affecting those longevity pathways negatively. Um, but without that, uh, first of all, I wouldn't enjoy my life as much. Second, well, the olive oil isn't, is not as great as the yogurt, but, uh, I'm trying to optimize and there's no perfect solution to what we're doing. And we're still learning. We don't know what's, what's optimal for me, let alone everybody else. But I, I, I'm with you. I don't believe that taking a couple of spoonfuls of something, unless it's high fructose corn syrup, is gonna hurt you. Because I, I've now got the rest of the day till about 8:00, 9:00 PM of not eating anything, and that, you know, I, I forgive myself for that. And that, there's a really good point here, you and I were discussing this earlier. Um, the point about doing this is that you try to do your best. If, if you go from regular living to don't eat the whole day, you're going to fail. Like quitting smoking cold turkey, it's easier to chew gum and stick the patch on, 'cause your body has to get used to all sorts of habits. And it's social, it's physical, putting stuff in your mouth, chewing. Not just the low blood sugar levels. And your brain will fight it. Your limbic system is gonna go, "Hey, do it, do it, do it." And you're gonna have to fight it. Once y- but once you get through it, you'll be better. But you do it in stages. Do breakfast first, then do small lunch, and then eventually cut lunch out. Don't go cold turkey, 'cause everyone knows, it's a fact that if you try to do a strict diet right out of the gates, you'll almost always fail.
- AHAndrew Huberman
Mm-hmm. No, I think, um, that captures the, the essence of, of fasting rationally and a rational approach to, to supplementation very well.
- 56:45 – 1:09:10
Resveratrol, NAD, NMN, NR; Dosage, Timing
- AHAndrew Huberman
Along the lines of supplementation, what about NMN, NR and B3, niacin? What, how does one... I want to know what you do. I also want to know what I should do. Like, and I think most people want to know what they should do. I mean, these are molecules that impact the sirtuin pathway, impact the, the pathways that control aging or rates of aging in the epigenome. How do they do that, and how does one incorporate that into a, a supplementation protocol, should they choose to do that?
- DSDavid Sinclair
All right. Well, disclaimer is that I don't recommend anything, but I talk about what I do. Um, so a bit of scientific background. These sirtuin genes that we discovered first in yeast cells when I was at MIT, and then, uh, in animals as I moved to Harvard in the 2000s, um, and one of m- one of my first post-docs, actually literally my first post-doc, Haim Cohen, published a great paper just a couple of months ago, and found that, uh, turning on the sirtuin-6 gene, remember there's seven, number six gene is very potent. It extended the lifespan dramatically of mice that he engineered, both males and females, which is great. So, what you want to do is, so naturally boost the activity of these sirtuins. They are genes, but they also make proteins. That's what genes typically make, uh, or encode. And then those proteins take care of the body in many different ways, as we've discussed. So, how do you turn on these genes and make the proteins they make even more active? You want to rev up that system. So, exercise will do it. Fasting will do it. What about supplementation? Well, the first activator of the sirtuins that we discovered that acts on the enzyme to make it do a better job of cleaning up the body and protecting, was resveratrol. We looked at thousands of different molecules, eventually tens of thousands, and the one that was the best was resveratrol, uh, in the dish, and then we gave it to little organisms, worms and then, uh, flies and mice, eventually humans. Uh, and we saw that it activated that enzyme. So, resveratrol is one way to activate it. You can think of it as the accelerator pedal on a car, it revs it up. But there's something else that the sirtuins need to work, and that's NAD. NAD is a really small mo- molecule, little chemical in the body that we need f- for life. It's used by the body for chemical reactions, 400 different reactions in the body, and without it you're dead within seconds. You need NAD. The problem that we've seen is that NAD levels decline as you become obese, as you get older, uh, if you don't ever get hungry. Um, and the body not only doesn't make enough of it, it's chewing it up as well. There is an enzyme called CD38 that Eric Verdin, uh, over at, um, UCSF showed chews up, oh, he's now at the Buck Institute in California, chews up NAD as you get older. So, it's a double whammy. You don't make as much, you chew it up. Which is really bad because what we've shown in my lab and so have others, is that NAD levels are really important for keeping those sirtuin defenses at a youthful level. And you can give a lot of resveratrol, but if you don't have the fuel, you're only, you're basically accelerating a car that doesn't have enough gas. So, you want to do both, and that's what I do. I take a precursor to NAD called NMN, and the body uses that to make the NAD molecule in one step. And so I know from measuring dozens of human beings, that if you take NMN for the time period that I do, I've been taking it for years, but if you take it for about two weeks, you'll double, on average double your NAD levels in the blood. Okay, that's not public information. That's from clinical trials that are not yet published over the last two years. Um, there are other ways to increase NAD levels in someone like me who's getting older, I'm 52 now. Um, you can take NR, which is used to make NMN, which is used to make NAD, uh, and both NMN and NR are sold by companies, uh, in the US.Um, NR is s- lacks the phosphate. Uh, phosphate's a small chemical the body needs. You've probably heard of the atom, phosphorus. Um, let's go back one step. How do you make NR? NR gets made from vitamin B3 often. Um, you can also find it in milk and other foods. But sometimes people ask me, "Why don't you just take vitamin B3? And won't that just force the body to make NAD?" And the answer is, no, it doesn't work very well. We know this just by doing the experiment. But the reason, I think is, is that NAD is a, is a... I said it's a small molecule, but relative to vitamin B3, it's big. It's got those phosphates on there, it's got a sugar, um, it's got the nic- the vitamin B attached. So you've got all these components that come together to make this very complicated little molecule called NAD. And you... When you give NMN, it contains all three components that the body needs to make NAD. If you give NR or just vitamin B3, which is an even smaller molecule, the body has to find these other components from somewhere else. So where do you get phosphate? Well, the body needs it for DNA, needs it for bones. So high doses of something that requires additional phosphate, uh, makes me a little concerned. And we have compared NMN and NR head-to-head in mouse studies. Um, for instance, NMN we've shown in a cell paper a few years ago makes mice run further, old mice can run 50% further 'cause they have better blood flow, better energy. NR at the same dose did not do that. In fact, it had no effect.
- AHAndrew Huberman
I see. Uh, dosage-wise, if I were, like, 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? Um, and are the various forms that are out there, are some better or are some worse?
- DSDavid Sinclair
Well, I'm always happy to tell you what I do and what my father does, my 82-year-old father. We, we take a gram of NMN every day.
- AHAndrew Huberman
So it's a gram of resveratrol and a gram of NMN?
- DSDavid Sinclair
Yeah. Right.
- AHAndrew Huberman
Okay, 1,000 milligrams.
- DSDavid Sinclair
Now, m- another, another important point which is, I'm not the same as everybody else. I have a different microbiome, age, sex.
- AHAndrew Huberman
Sure.
- DSDavid Sinclair
Right? And so I've been measuring myself. Um, and so I know if something's, or I think I know if something's making me better or worse based on measuring 45 different things. So I just want to be, uh, people to be aware that what I do may not perfectly w- or work at all for others. But I have studied, as I said, dozens of people who take NMN at a gram, sometimes two grams, and I know by looking at all those people that without any exceptions, that if you do what I do, your NAD levels go up by about twofold or more. Um, and so I do that every day, the 1,000 milligrams. Now people sell it. Now I, I never get into brands and all that. First of all, I don't have the time to measure products I don't know. Though I, I should say, I do want to say, I'm working on a solution for people to know what's, what works and what's real and what isn't. But I'm not there yet. And in the meantime I would say, if you do want to buy this, let's say you want to buy NMN, look for a company that is well-established, that has high levels of quality control. Look for three letters, GMP, which is, um, good manufacturing practices.
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
And so that means they make it under a certain level of quality control. You're not going to find iron filings in there and it probably has the stuff in it that they say it does. Um, but... So that, that's the- that's all I can say right now.
- AHAndrew Huberman
Sure.
- DSDavid Sinclair
I'm working on something that's going to be much more helpful. But o- overall make sure it's white crystalline NMN and that it sh- to me, it tastes like burnt popcorn.
- AHAndrew Huberman
You crack open the capsules and you'll take a little sample to make sure it tastes like burnt popcorn?
- DSDavid Sinclair
Well, when I, when I'm making my capsules I'll taste it, um, and I'll... I do a lot of quality control on the stuff that I take.
- AHAndrew Huberman
Do you take that gram all at once with the resveratrol or do you take it s- spread throughout the day?
- DSDavid Sinclair
It's, uh, all in the morning for th- for those things. So it's the, it's... An- if I take metformin, it's NMN and the resveratrol all together and there's a good reason for that. Uh, it's all scientific. I try, I try to be. Uh, the levels of NAD go up in the morning in our bodies naturally. Our bodies actually have a cycle of NAD, it's not steady.
- AHAndrew Huberman
It's circadian?
- DSDavid Sinclair
It's circadian. In fact, NAD controls your clock. This was shown by Shin Imai and colleagues in a s- 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 sleep." And if you take this, the NMN late at night for example, you can disrupt your circadian rhythms.
- AHAndrew Huberman
Interesting.
- DSDavid Sinclair
Conversely when I travel and I want to reset my clock to the timezone, I will take a boost, uh, of NMN in the morning and I feel great.
- AHAndrew Huberman
Does this protocol for you, um, does it produce m- any immediate effects of increased energy, et cetera? You mentioned y- that, um, one would, if it's right for them, (laughs) would have to take it for at least two weeks to start to see the NAD levels increase. At that point when A- NAD levels increase, um, could one possibly expect an increase in overall energy, focus, et cetera?
- DSDavid Sinclair
Well, sure.
- AHAndrew Huberman
I mean, I realize we're not making promises here, but I'm just wondering whether or not the only measure of whether or not this protocol is working is whether or not you die at age blank or blank plus 20? And of course once you're, uh, you know, once you're dead you, you can't really know if you would have lived longer if you'd done something differently and vice versa. (laughs)
- DSDavid Sinclair
Sure. Well, th- there was a study, again by Shin Imai, my good friend at Washington University in St. Louis, that, um, showed that it improves remittence insulin sensitivity.... uh, which is a good thing. So, but you can't know your insulin sensitivity unless you're measuring glucose, have a glucose monitor on your arm.
- AHAndrew Huberman
Do you have one on right now?
- DSDavid Sinclair
No.
- AHAndrew Huberman
(laughs)
- DSDavid Sinclair
No. I used to. Uh, I learned a lot.
- 1:09:10 – 1:12:04
Are Artificial Sweeteners Bad for Us?
- AHAndrew Huberman
I have a question about something that if it has no relevance, we can just, um, treat it as a speed bump and then move right on. You know, the, the artificial sweeteners, these things that m- or, uh, I should say non, uh, glucose increasing sweeteners. So you've got stevia, which is a, a plant basically, and then you've got, uh, sucralose and aspartame and all these things. There are, there is some evidence that w- w- I know we're both aware of, they've been published in quite reputable journals showing that they can disrupt, uh, the gut microbiome in certain cases. In particular, saccharin, the one that basically nobody uses anymore. Um, and it's questionable as to whether or not stevia has the same negative effects, et cetera. That's not what this is about. But in terms of the sensation of, or the perception of sweet taste-
- DSDavid Sinclair
Mm-hmm.
- AHAndrew Huberman
... is, is that itself a possible detriment to these, um, pro-longevity, forgive me for using the term, the, um, uh, pathways? You know, if, if I were to drink a diet Coke during a fast, am I somehow disrupting this? And I'm asking this question because I get asked this question a lot.
- DSDavid Sinclair
Mm-hmm. Well, th- there may be small effects. Uh, uh, I don't think they're worth worrying about. Um, Joe Rogan laughed at me 'cause I was drinking a diet Coke during the first interview I did with him. Uh, I will drink diet Coke. Um, I've read the scientific literature, and again, it's this 5% thing that I think is blown out of proportion.
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
If I was to put a, a number on it, I would say if eating a high sugary meal or drinking a sugar-filled soda, what is that? 30 grams of sugar. Let's say that's a s- that's a 10 out of 10 bad for you. Uh, a diet Coke might be a one.
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
Um, and if I'm, you know, which am I going to do? I could have a, a 10 or a one or go without in my life. I'll do the one on occasion. I try to avoid them because I don't like the ones as much. Um, but, uh, you can't say that sucralose is equivalent to drinking a sugary soda. There's just no comparison. Um, and I think suc- what is it? Stevia. I do use stevia whenever I can because it's, it's a, a naturally sourced product and I haven't seen any good evidence yet that it's bad for you. Uh, but I think a l- a lot of this is, is overblown and a lot of it's the, the media trying to give equal weight to stories, as you know, as a scientist-
- AHAndrew Huberman
Mm-hmm.
- DSDavid Sinclair
... it can be frustrating when something's a 10 and something's a one and they're equated.
- AHAndrew Huberman
Uh, how do I say this respectfully? I think if science journalists were, uh, required to post their credentials, uh, alongside their, their name, (laughs) then people would take the articles into, with a additional grain of salt, right? I mean, in other words that I think that most the science media is mainly generate around two specific goals. One is to make people very, very afraid or get people very, very excited. And oftentimes the, the get people excited part is sponsored content, and I think that's overlooked. In any case, um, thank you for that.
- 1:12:04 – 1:15:05
Iron Load & Aging
- AHAndrew Huberman
I want to talk about iron and iron load. We were talking earlier about ferritin and of course women menstruate. Um, and so they, their iron needs are greater than people, men that don't menstruate, uh, or women that don't menstruate. How, I don't think we can get right down into how much iron somebody needs because it'll vary person to person, but I was surprised to learn that iron is actually going to accelerate the aging process, uh, in various contexts.
- DSDavid Sinclair
Mm-hmm. Well, th- this is new finding, a, a new finding out of Spain. Manuel Serrano's lab has found that, uh, excess iron will increase the number of senescent cells in the body. Uh, and senescent cells are these zombie cells that-... accumulate as you get older, and they sit there, and they cause inflammation mainly and also can cause cancer. Uh, and it's found that if you get rid of these cells or never accumulate them, um, you stay younger, uh, in, in animals and there's a s- some really interesting studies out of Mayo Clinic in humans as well. So iron is a pro-senescence, um, metal. And so what I think is that if you're taking excess iron as a supplement, you're probably accelerating your aging process. The other thing that I found really interesting is I've, I've looked at hundreds of thousands of people's metabolism and their blood biomarkers. Um, I was one of the first people in InsideTracker as a board member, and I'm th- still their scientific, um, lead guy. So I, I can look anonymously at hundreds of thousands of people's blood work and we also know how fit they are, how old they are. Um, some of them are marathon runners, some of them are, are CrossFit. And there's a signature of health that actually is different than your average person. Now, I'm not going to say bad things about MDs 'cause a lot of my f- best friends are MDs and I work with them at Harvard Medical School. The issue though is that with MD training, it's, there's a scale of what's normal, and if you're out of that normal range, something must be wrong. That's the paradigm that they work under, but first of all, everybody's different, and you want to know their baseline and track people over years to know what's normal for them. And what I find, for example, is people who are really healthy and live the way I do and have a diet that's, um, fairly vegetarian but not strict, uh, still have slightly low hemoglobin levels, slightly low iron, slightly low ferritin, but we have super amounts of energy, we're not anemic, and we're getting along with great in life. But a, a doctor who just looks at that might say, "Oh, we need to give you more iron." All right, so what I'm getting at is an, an example of we need to personalize medicine and look at people over the long run to know what works for them and what's healthy for th- for them, and not just work towards the average human but work towards what's optimal for human.
- AHAndrew Huberman
I love
- 1:15:05 – 1:19:37
Blood Work Analysis
- AHAndrew Huberman
that answer. I, you mentioned tracking and tracking over time, and this is a really interesting area that I know you h- have been focused on for a long time. I've been getting blood work done about every six months since I've, frankly since I was in college. I just got, I like data, and I, uh, got interested in supplementation and exercise 'cause it made me feel better, but I also wanted to know what was going on under the hood. So, you get numbers back, you get this hormone, that hormone, this blood glucose measure, et cetera. How do you make sense of the data? I mean, uh, what InsideTracker is doing aside, how do you personally make sense of the data in ways that might differ from the way that a standard MD might look at one of these charts? Because the standard practice is to say is it red, yellow, or green, right? Is it basically too high or too low? Is it somewhere close to the margins or are you okay? Are you in these ranges? Are there any things that you pay attention to that you think are particularly interesting for people to just take note of? I mean that, we're not asking you to go against anybody's physician.
- DSDavid Sinclair
No.
- AHAndrew Huberman
Um, but w- what sorts of things should people start to educate themselves about in terms of what these molecules are on their charts if they choose to get them and what do you, what do you look at?
- DSDavid Sinclair
Yeah. Wow, there's a lot there. Um, the first is that you should be tracking things, um, because one measurement isn't enough. These things vary and over time and you, if you can have a decade or more of data, it's super impo- informative, as you know well know, um, as you know. So the, the physician interestingly, my physician, let's take him as an example, uh, so he sees me, he says, "How are you feeling?" Uh, "I'm feeling great." "Okay, see you next year." That's craziness. Anyway, so I say, "Okay, stop. Let's talk a little bit about..."
- AHAndrew Huberman
Let me educate you (laughs) . That's what David tells his physician. I imagine the, the like 12-year-old David Sinclair says to his physician, "Listen, let- let's have a different discussion." Is that how it works?
- DSDavid Sinclair
It is. He, he finds me pretty annoying, as do- does my dentist. But, uh, so I say, "Stop, hang on. I've got this data, uh, I've got the InsideTracker data." So I pull that up on the screen and he, I'm sh- showing him my, the changes in my cholesterol, in my, uh, CRP which is an inflammatory marker as you know, and we're going through it and you can see things change over time and, and I've corrected them as they go slightly out of the optimal range for me, which is different th- than what he would do of course. But what was funny is that he says, "This is great. I love this data, but I'm not allowed to get this because of course the insurance companies won't pay for it." So again, you can pay out of pocket, it's, it's not super expensive. I would say if you, you know, save a bit of money on, on a, on a coffee, uh, you can afford this kind of stuff. But the, the main point is that doctors do like this data, it's just that they're unable to spend the money on every one of their patients to get it.
- AHAndrew Huberman
Is there a code word that someone can use with their physician that will trigger a c- a comprehensive blood test? I keep trying to figure out what's the code, uh, that one needs to ask or, or tell their doctor, like, "I'm feeling blank," so that they get a full blood panel? What do...
- DSDavid Sinclair
Well-
- AHAndrew Huberman
Do you have to be hemorrhaging from the, from the gut or something?
- DSDavid Sinclair
Well, I usually use the, uh, WTH method, which is what the hell? And then he, and he says, "Okay, we'll do it." Um...
- AHAndrew Huberman
Interesting. 'Cause I think a lot of people out there are thinking, look, I'd love to have blood work repeatedly over time, but that's hard to get for financial reasons but also a lot of people just don't know how to approach the conversation, and this is one of the things that I, I hope that we can educate people on, you know, that they deserve to know what's going on inside their body, and that it makes a doctor's visit worthwhile.
Episode duration: 2:10:42
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