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
pole. 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.
And 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
Ah, mentation 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.
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 at 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 podcast again. The lifespan podcast featuring. Dr. David Sinclair, begins, Wednesday, January 5th, 2020 to 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.
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 talked 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 talked 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.
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 rokka rokka makes eyeglasses and sunglasses that are the absolute highest quality. I've spent a lifetime working on the visual system. 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
It's activities, but they also have a terrific. Aesthetics, 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 Roca sunglasses or eyeglasses, you can go to Roca.com. That's our okay, a.com and enter the code huberman to save 20% off your first order. Again. That's Roca are ok.com and enter the code huberman at check out. Today's episode is also brought To Us by inside tracker inside tracker 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 accessed from a quality blood test. And now with the Advent of modern DNA test, 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 inside trackers that compared to a lot of other DNA tests and blood tests out. There, is that with inside tracker. You don't just get your numbers back at the levels of various hormones, metabolic factors, blood lipids, Etc. 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 inside tracker, you can go to inside
tracker.com huberman to get 25%
off any of inside trackers plan.
Just use the code huberman at checkout. Again. That's
inside tracker. Dot coms
huberman to get 25% off any of inside. Trackers plans. Today's episode is also brought To Us by Magic spoon. Magic spoon is a zero sugar grained. Freaky, do friendly cereal. 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 a.m. Or 12:00 noon.
Most days. And then my lunch is typically, a low carb, keto ish launch, 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 key do 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 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.
Serving of magic spoon has 0 grams of sugar, 13 to 14
grams of protein, and only four grams of carbohydrates in each serving. So really matches that low carb keto ish approach.
There's only 140 calories per serving and they have a
variety of flavors. Coco fruity. Peanut butter frosted. I particularly like frosted because it tastes like donuts. I try not to eat donuts, but I do love the frost. And as I mentioned before I lately, mix it with yogurt Polo. Cinnamon on there. I'm getting hungry, just talking about it. Now, if
you want to try magic spoon, you can go to magic spoon.
Dot-com huberman to grab a variety pack, use the promo code
huberman at checkout to get $5 off your order. Again.
That's magic spoon.com
huberman and use the code huberman to get five dollars off and now my conversation with dr. David Sinclair. Thank you for coming. Thanks having me here. It's good to see ya. This is mate. By the way that we're toasting 11 a.m. Unlike other podcast. 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 Etc. I just want to start off with a very simple question. 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 the statement aging is a disease,
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 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 is a disease and Longevity are perfectly valid ways to talk about this subject. So let's talk about aging as a disease, when I started my research.
Each disease here. Harvard Medical School. It was considered. If there's something that's wrong with you 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 to deterioration and in health and sickness and you can die from it. Typically you do something that sounds pretty much like a disease, but the caveat is that
More than half the population, gets this condition. Aging it's put in a different bucket, which is first of all, that's outrageous because it's just 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 nobody stayed youthful, we would not get those diseases and actually what we're showing you, my live is if you turn the clock back in tissues those diseases go away. So aging is the
Problem and instead through 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. So there are a couple of things. One is you want to slow aging down so we don't get those diseases and when they do occur, don't you stick a bandaid on reverse the age of the body and then the diseases will go away
that clarifies a lot for me. Thank you. Can we point to one? Specific General phenomenon in the body that underlies aging? Yeah.
Well, that that's contentious because scientists like to come up with new hypotheses is, 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 because causes with was a little bit too strong. But these these eight or nine causes at least for the first time allowed us to come around and talk together and we put them on a pizza. So if I'm got an equal weighting equal slices and but before that
The way we were trying to kill each other in the field. It was horrible.
Interesting that you guys work on aging and trying to kill each other. Yeah, isn't it? Well,
kill each other's careers when 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 1980s and 90s and said free radicals, don't do much. They're 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 and people would shout at each other and backstab was horrible, but then, fortunately, in the 2000, we rallied around this new map of Aging, with these causes or Hallmarks, but I think that there's one slice of the pizza that is way larger than the others and we can get to that. But that's the information in the cell that I call we call the
epigenome.
Well, tell us a little bit more about the epigenome frame it for us, if you will. And and then we'll get into ways that one can adjust the epigenome and positive ways.
Yeah, so in science, what I like to do a reductionist is to boil it down and I actually ended up boiling aging down to an equation, which is the the loss of information due to entropy. It's a hard thing to overcome the second law of Thermodynamics. That's fair. But this equation really represents the fact that
I think aging is a loss of information in the same way that when you Xerox, something a thousand times, you 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 atcg. 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,
T'. And that's the systems that control which genes are switched on and off in what sell at what time in response to what we eat. Etc. And it turns out that 80% of our future longevity and health is controlled by this second part. The epigenetic information, the control systems. I liken the DNA to the music that's on a DVD or compact disc for the younger people used to use these things I recall. 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 overtime, aging is the equivalent of scratching, the CD and the DVD so that you are 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.
Can we go a little deeper into what that these scratches are. Is it the way that the dnar
Packed into a cell. Is it the way that they're spaced? What is, what are the scratches that you're referring to?
So DNA is 6 foot long. So you join the chromosomes together. 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 is wrapped up very carefully in ways that dictates which genes are switched on and off.
And when we're developing in the embryo, the cellmark's, the DNA with chemicals, that says, okay. This Gene is for a nerve cell. You, you sell will stay a nerve cell for the next hundred years. If you're lucky, don't turn into a skin cell. That would be bad and those chemicals. 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 Toto 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 jeans 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 cells type, the cells function, and then the scratches are the disruption of that so genes that were once silent. And
Could say it's a gene that is involved in skin. It's time to come on in the brain, shouldn't be there. But we see this happen and vice versa regime. I 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 and we can measure that. In fact, we can measure it in such a way that we can predict. When somebody's got to die based on the changes in those chemicals,
are these
Has the same sorts of changes that underlie the outward body surface, manifestations of Aging, the most of us are familiar with graying of the hair, wrinkling of the skin drooping of the
of the face
walking around New York lately. It's amazing to me. There are certain people that seem to walk looking down at the sidewalk because their spine is essentially in a c-shape, right? A Hallmark. If you will of Aging that most of us are familiar with are the same.
A DNA scratches associated with that or we talking about people that are potentially are going to look older, but simply live
longer. Well, it's actually you, you are as old as you look, if you want to generalize. So, let's start with centenarian families. These are families attend to live over 100 when they're 70. They still look 50 or less. So, it is a good, a good indicator. It's not perfect. Because you can like me grow up in Australia and accelerate the Aging of your skin, but in
Neural. How you look? 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 a great people. Just came out that said that an AI system looking at the face could very accurately predict. Someone's age. Very interesting.
So, I started off in developmental neurobiology. So one of the things that I learned early on that, I still believe wholeheartedly is that development. Doesn't
Stop at
age, 12 or 15, or even 25 that your entire life is one long developmental Arc. 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.
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 an immense vitality?
The same periods when we're aging faster.
Yes. Yes, and this is something I've never talked about at least not publicly. So this is 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 a, I looked at the faces of those people, they could 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 there are some people that are 10 20 years younger than other people biologically and it turns out if you measure that clock from birth or even before birth, if you look at animals is a massive increase in age on based on that clock early in life. So, you're right that. So that's a really important point that 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 the
we're finding that the genes that get messed up that gets scratched that are leading to eating aging. All 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'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 have an x-ray or a cosmic ray, or even if you go out in the sun and you'll get
Broken chromosomes. That accelerates the unwinding of those beautiful DNA Loops that I mentioned.
We can actually do this to Emmaus. We can accelerate that process and we get an old mouse, 50% older. And it has this been spine kyphosis that has gray hair. It's organs are old. So we now can control aging, the folds Direction. The other thing that accelerates aging is massive cell damage or stress. So we pinched nerves and we saw that. Their aging process was accelerated as
well credible. Yeah, the 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 knee, come back, High School in the u.s. Usually starts eighth or ninth grade or grade 8 or great, 94, your 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, you know, a slow burner, right? They basically acquire the the traits of puberty slowly over many years. Can we make some course prediction? That they are going to live a long time versus a kid that goes home for the summer and comes back 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?
Well,
Yeah, I don't want to scare anybody. Sure? That they're there. 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 taken growth hormone, you know, pay attention. We know that a
look at someone who's taking growth hormone. Yeah. They often won't require these characteristics of Vitality like improved. A smoothness of skin, but
But their whole body shape changes.
Yeah, I'm, 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 are being generated and mutants that have low growth hormone. Not, sometimes these are dwarfs. They live the longest by far a guy in my lab Michael bunk house key. 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 Clark restrictions of fasting combined with one of these dwarf mutations low growth hormone. I think he called it Yoda, but this is, no, you look at who lives the longest. It's the really small people. 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 to into their 90's and Beyond really? Yeah, huh amazing and although there are some Lord Laurent dwarfs as well there.
Red 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. So I having owned a very large dog, breeder bull, dog Mastiff who 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's a direct relationship between body size and Longevity or duration of
Of life. 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 and I wished at the time I did grow, but no matter what size you are. You can have a bigger impact on your life than anything, your jeans give you 80% is epigenetic not.
Attic. So, let's talk about some of the things that people can
do and I've got a batch these into categories rather than just diving right into actionable, protocols. So 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 it's good for us. I know one of the reasons I'm excited to talk to you today is because 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 too 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?
Well, 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 company selling bars and snacks in between. So the feeling of hunger, almost some people never experienced hunger in their whole lives. It's really, really bad for them. It was based. I believe on the 20th century view that you don't want to stress out the pancreas and you try to keep insulin levels.
Steady and not have this this fluctuation. What we actually found my colleagues and I across this field of longevity is that when you look at first 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. I'm actually was first discovered back in the early 20th century, but people ignored it and there was rediscovered.
Covered in the 1930s. Claude 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 live 30% longer, but then it went away. And then it came back in the 2000's in a big way, when a couple of things happen, one is that 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 a called sirtuins. There's seven of them.
And we show it in 2005 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 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 overtime just to grades quickie.
The clock is ticking Faster by always being fed. Okay, 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 re-establish 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 having low levels of glucose in your body will trigger your
The major muscles in your brain to become more, resilient 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. 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? Yeah, I I do though, you get you
Do the feeling of not eating, so I'm kind of screwed that way. It's like, cold water. You eventually adapt, 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 got this these periods of not being fed and then the body turns on these defensive jeans. There's a really interesting experiment.
Parent that was published maybe a couple of years ago by Rafael De Cobo 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 you also cleverly had a group while two groups one, that was fed all the time or eight 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, because of course, in an hour, they're stuffing.
Faces it turns out, it didn't matter what diet he gave them. It was only the group that eight 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,
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
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. 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, does it matter which meal or they essentially equivalent. 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.
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 Cycle in the same way. So
it's much harder as well for many people. Yeah. Well, I'll tell you what I do. I skip breakfast. I have a tiny bit of yoga 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 feel.
Go with liquids. And so I don't feel hungry.
Beware that the first two to three weeks. When you try that, you will feel hungry and you also have a habit of wanting to 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 and you'll get through it. And I did that most for most of my life, actually, mainly because I didn't, 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
Of the high glucose and the low glucose that anyone who goes on, man, it's 3:00. I'm going to need a sleep. If you do what I do. You will not experience that anymore because what my body does is its 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 even have to think about lunch and just powering through at dinner. 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 mostly vegetables. I can eat some fish, some shrimp. I rarely will eat it. A stake. 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. If I don't eat a steak. I feel terrible. Haha. Well,
we Argentine lineage, but we can talk about that. Some of them.
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'd really a dessert I gave up desert and sugar in my, when I turned 40 and occasionally, I'll steal a bit of dessert because it doesn't hurt if you steal it, right. But other than that, I avoid sugar, which includes simple carbohydrates bread. I try to avoid. I've actually noticed, this is a, just a side note. I used to get buildup of plaque pretty easily. And every time I went to the dentist, they have to scrape it off. And I even bought tools to scrape it off because it was driving me nuts. I don't get plucked anymore.
I think it's because of my diet. I don't have those sugars in my mouth at the bacteria feed on, and then form the biofilm on the teeth, much better Breath. By the way,
all that's a benefit. Should you ever fast longer than this? It sounds like, if you, if you go to bed. We'll use tend to stay up late. I know because I get texts from you at like 2:00 in the morning the my time which means you're out very late and up early as well. But assuming that people go to sleep sometime around.
11:30 or 12:00 plus or minus an hour and wake up sometime around, 7:00 a.m. Plus or minus 90 minutes, you're eating more or less on a, it sounds like a some like 20 hours of fasting for hours of eating, or 16 hours of fasting, eight hours of food intake, Etc. But do you ever do longer fast like 48 hours or 72 hours or we clone fast?
Occasionally, I do. So my typical day. I would only eight within a two-hour window just
Usually I meet it either eating out or I'll see your 20 22. Yeah. Yeah, but I love
well. And if you exercise do you feel like B, then you just power through and maintain that? Fasted State.
Absolutely. I can exercise. And now my body. 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.
To, and actually even better. If you go for three days without eating it kicks in even greater longevity benefits. So, there's a system called the Auto 4G system which digests old and misfolded proteins in the body and there's a natural cleansing, that happens when you're hungry macro autophagy, its name is. But a good friend of mine, Ana Maria, Cuervo at Albert, Einstein College of Medicine, discovered, a deep cleanse called, The Chaperone, mediated, or topology, which kicks in day.
Day 3, which really gets rid of the deep proteins. And what excites me is she just put out a big paper. That said, if you trigger this process in an in an old mouse, it lives 35 percent longer. Yeah, so it's a big deal. If I could go longer, I would, but I just find that with my lifestyle and I'm going, always day, you know, 110%, I need to to eat at least once a day. Unfortunately, one more practical
question than a mechanistic question related to this, the
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 or more
espresso today, which is impressive. But are you also ingesting electrolytes? Like, I know some people get lightheaded, they start to feel shaky when they fast, and that the addition of sodium to their water or potassium, magnesium is something that's becoming a little more in Vogue. Now, is that something that
Do or that you see a need for people to do.
Well, it makes sense, but I haven't had a need to do it. So I don't I just I drank 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, that won't be able to because I don't have a need for it. I don't try it, but it does make sense. Especially if you've had a big night the night before.
Or you probably want to supplement with that. But I think there's a fair amount of good stuff in tea and coffee as it is.
Okay. So then the, the mechanistic question is you've told us that there's ample evidence that keeping your blood sugar low for a period of time. He's 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 gobbling up of
dead cells and things of that sort. How is it that blood glucose triggers these mechanisms? Because we've said ok, remove glucose and things get better. You've talked before maybe we could talk more now about some of the, underlying seller and genetic mechanisms things like the sirtuins, but how our glucose and the sirtuins actually Tethered to one another mechanistically.
There's a really good question.
That proves your scientist old world leading on. 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 genes more important than yours. It was ridiculous, because they're all talking to each other. You pull one labor 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 there's sort of two ins will mainly respond to sugar and insulin and then there's this other system called m.
For 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 Vic the other and vice versa. But together, when you're fasting, you'll get the sirtuin activation, which is good for you. And you'll also through lack of amino acids, particularly three of them. Leucine isoleucine valine, the body will down-regulate mtor and it's that UPS or two and down mtor. That is hugely beneficial in turns on all
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 so these two Pathways I think of the most important for
longevity. So interesting, you mentioned leucine within the resistance training / bodybuilding /. Fitness Community. Leucine gets a lot of attention because there are long-standing debate about how much protein one needs per day and how much you want can assimilate at each meal. It makes for many
Videos and not much else, frankly. However, it's clear that because of Lucien'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 seller growth.
Earth is actually Pro agent in some sense. Is that right?
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 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
I don't burn both candles. I have one end of the candle lit. I'm very careful. I don't blow on it. But I also do enough exercise that I'm building up my muscle. But I'm not huge, anyone who's seen me, you know, knows that I'm not a professional bodybuilder, but I tried to actually here's the key and I haven't said this publicly that I can remember a 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 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 lot of subtlety to it.
Yeah. It sounds like a very rational protocol. Does the name or ehof McClure mean anything to you? No, okay, just briefly I just
Tory Hoff meckler about 15 years ago. He was a in Israeli Special Forces. He's now got to be close to 70, forgive me? Or if that's that, 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, 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 incredible physical stature.
ER he's very lean, very strong and very vital at you. No, no, I wouldn't say an advanced stage, but he's getting up there and he just seems to be getting better and better or ehof McClure was the person who essentially founded if you will, Although our ancestors founded 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 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 want to use that as kind of a segue to 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 have take hormone therapies later in life. You take estrogen, they experience 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
Lower case letters really, there really seems to be something about that. So at a cellular level like we kind of go back to mtor in the sirtuins. How do you think that the cells might be reacting to this kind of lowercased feast
and uppercase famine type protocol? All right. Well, the 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 and 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 their own 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 a fact, 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? Because I didn't read The Warrior Diet, what I found in my research was that if we gave Resveratrol this red wine molecule that became well known in the 2000s. If we gave it to my their whole life span, they were protected against a high fat diet, which we call the Western diet. They have lean organs. They live slightly longer, but not a lot. And if we gave them a high,
I thought without Resveratrol. They actually lived a lot shorter. So it was virtual 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. This is what's not known though. It's in a supplemental data of the paper that nobody ever reads. The mice that were given Resveratrol every second day on a normal diet, live dramatically longer than any other group. So people out there, you know, my critics say our Resveratrol didn't extend.
The lifespan of mice on a normal diet. Therefore, it's not aging. It's just protecting against a high fat diet. Well, look at the supplemental data, please. If you give it to them to the mice, every other day, we had mice, living over three years. Wow. That's a long time for app. I have
got many, many mice, in my owner ownership, at my lab at Stanford, and that's a very long life for a mouse.
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 body and then give it a rest, same with exercise. And I try to time it because 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 and most other countries. You can just get it over the counter and you're protected. It looks like Based on epidemiological data. Cancer, heart disease. Frailty. What else dementia?
So I take metformin
in a dish, you take metformin and you're fasting each day. So when do you take it relative to the fast?
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 pay attention to this, this kind of thing think that they should stop taking metformin because they're never going to get muscle or it's going to affect their ability to build up muscle, but that's not true. What metformin does to it actually just reduces the ability to have stamina because it's inhibiting your body's ability to make energy. And so what happens is when you're on
Foreman 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, but for me, I'm not trying to get giant. I want strong muscles and I want to live longer and healthier. So I just try to
time it so that I get the most reps out of my exercise regime, but sometimes in scientific literature, 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.
And, you know, now it's become a myth that metformin greatly inhibits, your ability to exercise which is not true. But in an abundance of caution, I I skip my metformin on days. I'm going to exercise and not only that. I'm one of the twenty percent of people that has a stomach sensitivity to it. So if I'm not feeling great that day, I don't take
it either. You mentioned, metformin is available only by prescription from a doctor at least in the u.s. Berberine. Is this substance that comes from tree bark. Oh, I also learned about many years ago from or
Re he said if ever, I'm going to overeat like a Thanksgiving meal or something, I take berberine. This was hit. Those were his words and I tried it and what's remarkable about berberine is that 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 metformin. Works on the am PK pathway, the mtor pathway etcetera.
That if I didn't ingest food in particular carbohydrates, I would feel a little dizzy and kind of get a headache. Like almost hypoglycemic. What are your thoughts on berberine as an alternative to metformin? And are there any cautionary notes? I mean, obviously people should talk to their doctor before adding or subtracting anything from their life, including
breath, or anything
that want that comes up. But with all that a set aside, what are your thoughts about berberine and timing of
Low blood sugar and these sorts of things,
right? Well before I had access to metformin, I was taking berberine. It's often known as the poor man's metformin, but he just called me, poor, women can take it to. So the the thing with berberine and we started it in my lab. It is effective at boosting energetics in the body, just like a and PK and metformin does and we've actually given it to rats and mice and see that they are very healthy, especially on a high fat diet.
So I think it's likely to be good. There are some human studies that exist clinical trials showing that it increases insulin. Sensitivity have to take high
doses, which is a good thing. Right? Yeah. I think when people hear insulin sensitivity, sometimes, people think, oh, well, that's bad right now, but you want yourselves to be insulin sensitive. You don't want a lot of blood sugar floating around. They
can't be sequestered into cells. Exactly. So this is anti type 2 diabetes. And so that 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 cable lines, lab published that berberine reduce the lifespan of worms, but I'm not sure. Worms, Trump human clinical trials at this point. So I'm not saying not in my opinion. I wouldn't still just
respect to my C elegans colleagues, or my rather, my colleagues that work on CL.
Yeah. Well, that 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 date, I wouldn't panic.
Just yet. I think berberine has been shown to be really safe in
humans. You mentioned Resveratrol. 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 rest of your troll. They
even you can try, you need to drink about 200 glasses a day. So I got it's been tried. There are some
Um 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 selling Resveratrol if it's not light, gray or white in color, throw it away. The brown stuff has gone bad or is contaminated and the contaminated stuff. Be worried look.
Diarrhea, but regular Resveratrol should not do that. So 1,000 milligrams per day is what you do. Yeah, and I had a great for about 15 years now and you ingest that with
some fatty substance like olive oil or yogurt. Is that
right? Yeah, you have to. And other supplements, course, certain curcumin. These are crunchy things. There's not going to get through your gut and I'm not just making this up. I always based my statements on human studies. So we've done a lot of studies on Reservoir.
Troll as of others since and we know that from we found out early, I was one of the first people to take a high dose for his virtual and when we included it with food, the levels in my blood, when I fold. 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.
So you are you taking this all at once in the morning and chasing it with some olive oil, or you dissolving it in yogurt?
What's that? What's the specific
protocol? Yeah, I been improving. Perfecting. What I do for about 10 years. I would take some Greek, yogurt, a couple of spoonfuls. Put the Resveratrol on their 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 is also an activator of the sirtuin defenses. So I'm trying to
ingest more oleic acid. So I switch 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 course, see, Christina similar molecule. Make sure it's dissolved. I put a little bit of vinegar, and if I have a Basil Leaf, I'll put that in. And it's like, drinking some salad dressing, and it's very delicious.
That raises a question that I want to ask before we get to nmn.
And then are in 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 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.
This 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 a.m. 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 and PKM tour Etc.
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 I not everybody can manage on just water or just t or we should say. Not everybody is willing to manage on just water just tea for certain part of the day.
Well, my first answer is not scientific. Its philosophical if you don't enjoy life, what's the point? And so I'd like,
A cup of coffee in the morning, little bit of milk spoonful of yogurt. It'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 those longevity Pathways negatively. But without that first of all, I wouldn't enjoy my life as much SEC. Well, the olive oil is not as great as the yogurt, but 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'm with you. I don't believe that taking a couple of spoonfuls of something unless it's high fructose corn syrup is going to hurt you. Because I've now got the rest of the day till about 8:00 9:00 p.m. Of not eating anything and that I forgive myself for that and that there's a really good point here you and I were discussing this earlier the point about doing this is that you try to do your best if you go from
You're 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 which your body has to get used all sorts of habits and its social, its physical putting stuff in your mouth chewing. Not just the low blood sugar levels and your brain will fight it. Your limbic system is going to go. Hey do it, do it, do it and you're gonna have to fight it once you. But once you get through it, you'll be better, but you do it in stages.
Do breakfast first, then do small lunch, then eventually cut lunch out. Don't go cold turkey because 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.
No, I think that captures the essence of fasting rationally and no rational approach to it to supplementation very well.
Along the lines of supplementation. What about NM n? NR. + 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 pathways that control aging or rates of Aging in the epigenome.
How do they do that? And how does one incorporate that into it, supplementation protocol? Should they choose to do
that? All right. Well, disclaimer is a I don't recommend anything but I talk about what I do. So bit of scientific background these sirtuin genes that we discovered first in yeast cells when I was at MIT. And then in animals, as I moved to Harvard in the 2000s and one of my, one of my first post docs actually, literally my first post doc, I'm Cohen published a great paper, just a couple of months ago.
And found it turning on the sirtuin 16-member. The seven number 16 is very potent. It extended the Life Span dramatically of my study engineered both males and females, which is great. So what you want to do is so naturally boost the activity of these sort of two ins, they are jeans, but they also make proteins. That's what genes typically make 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 jeans 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 sort of tools 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 in the dish and then we gave it to little organisms worms and then flies and mice eventually.
Ends 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 molecule little chemical in the body that we need 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, if you don't ever get hungry 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 Burdon over at UCSF showed choose up. Always now the buck Institute in California. Choose up NAD as you get older, so it's a double whammy don't make as much chew it up.
Which is really bad because what we've shown in my lab and so of others is that NAD levels are really important for keeping those sort to and defenses at a youthful level and you can give a lot of Resveratrol but if you don't have the fuel, your only 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 cold nmn and the body uses that to make
the NAD molecule in one step.
And so I know from measuring dozens of human.
Means that if you take n MN 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. There are other ways to increase energy levels in someone like me who's getting older 52. Know you can take n r, which is used to make any men, which is used to make.
In Ed and both animate and are sold by companies in the us and our is lacks. The phosphate. Phosphate small chemical. The body needs probably heard of the atom phosphorus. Let's go back. One step. How do you make an R & R gets made? From vitamin B3 often. 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 that NAD 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. It's got the Nick, the vitamin be 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 an ed. 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, body needs it for DNA, needs it for bones. So high doses of something that requires additional phosphate makes me a little concerned, and we have compared to n and n are head-to-head in mouth.
Studies for instance and Andaman. We've shown in a cell pay-per-view years ago, makes mice run further, old mice can run 50% further because they better blood flow, better energy and are the same dose did not do that. In fact, it had no effect. I see,
dosage wise, if I were elected to take an omen 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
some worse.
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 and a man every day.
So it's a gram of Resveratrol and a gram and a man,
right? Okay, 1000 milligrams. Now another, another important point which is I'm not the same as everybody else have a different microbiome age sex, right? And so I've been measuring myself. 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 people to be aware that what I do may not perfectly or work at all for others, but I have studied, as I said, dozens of people who take NM n, @a g, sometimes 2 G and I know by looking at all those people that without any exceptions, but if you do what I do, your NAD levels, go up by about to fold or more and so I do that every day, the thousand milligrams.
Now people sell it. Now. 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 should say, I do want to say I am working on a solution for people to know what 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.
As GM P which is good manufacturing practices. 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. But so that that's the that's all I can say. Right now. I'm certain that. Something is can be much more helpful, but overall make sure it's white crystalline in a men and that it to me, it tastes like burnt popcorn.
You crack open the capsules and you'll take a look.
A sample to make sure it tastes like burnt popcorn. Well, when I, when I'm making my capsules, I'll taste it. And I do a lot of quality control on the stuff that I take.
Do you take that g all at once with the Resveratrol or do you take it spread throughout the day?
It's all in the morning for the for those things. So, it's if I take metformin, it's Anna man and the Resveratrol together 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.
The, our bodies actually have a cycle of NAD. It's not steady. It's circadian. It's akkadian. In fact, NAD controls your clock. This was shown by Shin Mi and colleagues, and US 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 these, the nmn late at night, for example, you can disrupt your circadian rhythms. Interesting.
Sleep. 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. Does this
protocol for you? Does it produce an any immediate effects of increased energy? Etc. You mentioned that one would if it's right for them 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 could one.
Possibly expect an increase in overall energy, Focus etcetera and I realized 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 died at age, blank or blank, plus 20, and of course, once they're, you know, once you're dead you can't really know if you would have lived longer if you've done something differently and vice versa.
Sure. Well, there was a study Again by Shana my, my good friend at Washington University in st. Louis that
I showed that improves, remember this insulin sensitivity, 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 own. You have one on right now. No. No, I used to I learned a lot. Last
time I saw you. You had this thing. It like it looks like a like a small leech, not a large
leech. And it and it was measuring your blood glucose. They're very informative because you learn what your body reacts to and grapes were really bad. Rhonda, Patrick agrees with that but
The issue was was what where we enter,
the issue is whether or not, you can expect any immediate effects, on energy, Vitality Focus, any just even subject is, what do you feel? Is
the question and anecdotally? Because I've been taking this for a long time. If I don't take it, I start to feel 50 years old, it's horrible. I can't think straight. It may be Placebo, but who knows. But what we're doing now are very careful clinical trials. We've done the safety for two years, and we're now creating
Elderly patients at Harvard Medical School with some wonderful colleagues and those people are actually going to be and currently in MRIs. So you can measure the energetics and the NAD levels in their legs as they exercise in real time. And that will tell us if what we see in the mice, this increased endurance actually works. In the meantime. It's fun to talk about anecdotes. I have a number of athlete friends, some of which have increased their lowered their time.
In marathons, for example, there's a good friend of ours in our Circle that is winning marathons at age 50. Now any attributes that to the protocol, that he's on there
saying I haven't started taking an amend but I'm planning to do that. When my next birthday arrives, which is in a couple months, but I do experiments on my sister and have for years. I have a sister who's three years older than I am. Who is very enthusiastic about these protocols. And I'll tell you that after reading your book, I started.
Thing for her and giving her an MN supplement and she claims. And I believe her, she has a quite sensitive system and she's ready, tuned into it. She feels Far and Away better when she takes it as opposed to when she doesn't and I've done the
control experiment of removing her her Supply and then giving it back to her in this kind
of thing. So, um, that's my other laboratory. This is what younger brothers do. Two older sisters. I have a question about something that if it has no relevance we can just treat as a speed bump.
And then move right on and artificial sweeteners, these things that were should say, non glucose increasing sweetener. So you've got Stevia, which is a plant basically. And then you got sucralose and aspartame in all these things. There are, there is some evidence that I know we're both aware of, they've been publishing quite reputable Journal showing that they can disrupt the gut microbiome. In certain cases in particular saccharin. The one that basically nobody uses anymore, and it's question.
Well as to whether or not Stevia has the same negative effects, Etc. That's not what this is about. But in terms of the sensation of the perception of sweet taste is that itself a possible detriment to these prolonged? Eva? T. Forgive me for using the term. The pathways, you know, 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.
Well, then maybe small effects. I don't think
Worth worrying about Joe Rogan laughed at me because I was drinking a diet coke. During the first interview I did with him. I will drink diet coke, I've read the scientific literature. And again, it's this 5% thing that I think is blown out of proportion. If I was to put 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, that's a 10 out of 10.
Bad for you. A Diet Coke, might be a one and if I'm you know, which am I going to do? I could have a 10 or a 1 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, but you can't say that sucralose is equivalent to drinking a sugary soda. There's just no comparison and I think, soup, what is it Stevie. Oh, I do use Stevia whenever I can because it's it's a naturally sourced.
Product. And I haven't seen any good evidence yet that it's bad for you. But I think a lot of this is overblown and a lot of its the, the media, trying to give equal weight to stories. As, you know, as a scientist, it can be frustrating. When something's attend and something's A1 and their equated.
How do I say this? Respectfully, I think if science journalists were required to post their credentials. Alongside their name. People would take the Articles into
Whether additional grain of salt, right, I mean in other words, that I think that most of the science media is mainly generated around to specific goals. One is to make people very very afraid or get people. Very, very excited. And oftentimes the get people excited part is sponsored content and I think that's overlooked in any case, thank you for that. I want to talk about iron and iron load. We were talking earlier about ferritin and of course women menstruate. And so,
Their iron needs are greater than people men that don't menstruate or women that don't menstruate, how? I don't think we can get right down into how much iron somebody needs because it will vary person to person but I was surprised to learn. That iron is actually going to accelerate the aging process in various contexts. Hmm. Well, this is
new. Finding. I knew finding out of Spain. When will Serranos love has found that
Excess iron will increase the number of senescent cells in the body and senescent cells of the zombie Souls that accumulate as you get older and they sit there and they cause inflammation mainly and also can cause cancer. And it's found that if you get rid of these cells or never accumulate them, you stay younger in animals and there's some really interesting studies out of Mayo Clinic in humans as well. So iron is a pro senescent.
Metal. And so, what I think is that if you're taking excess iron as a supplement your probably accelerating your aging process. The other thing that I found really interesting is I've looked at hundreds of thousands of people's metabolism and their blood biomarkers. I was one of the first people in inside tracker as a board member and I mean, it's still a scientific lead guy so 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. Some of them marathon runners. Some of them 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 because a lot of my best friends are MD's. No 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 fairly vegetarian, but not strict, still have
Slightly low hemoglobin levels, slightly low iron slightly low ferritin, but we have super amounts of energy. We're not in humic and we're getting along with great in life. But 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 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 them for them and not just work towards the average human, but work towards. What's up.
Over human.
I love that answer. You mentioned tracking and tracking over time. And this is a really interesting area that I know you 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 got interested in supplementation and exercise because it made me feel better. But I also want to know what was going on under the hood. So you get numbers back, you get this hormone that hormone this blood glucose measure, Etc.
How do you make sense of the data? I mean, what inside tracker 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? The you think are particularly interesting for people?
Just take note of, I mean, we're not asking you to go against anybody's physician, but 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? You know,
wow, there's a lot there. The first is that you should be tracking things 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 important informative as you know,
Well, no, as you know, so that the physician interestingly, my physician. Let's take him as an example. So
he sees me. He says,
how you feeling. 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. Let
me educate you. That's what David tells us position. I imagine that they're like 12 year old David Sinclair says to his position. Listen, let's have a different discussion. Is that how it worked?
Is he?
He finds me pretty annoying as does my dentist. But so I stopped, hang on. I've got this data. I've got the inside track of data. So pull that up on the screen and he's I'm sure it's showing him my the changes in my cholesterol in my CRP, which is inflammatory markers, you know, and we're going through it. 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 than what he would do, of course, but what was funny is that he says, this is great.
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 not super expensive. I would say if you save a bit of money, on on a coffee, you can afford this kind of stuff. But the main point is the doctors do like this data. It's just that then unable to spend the money on every one of their
patients to get it. Is there a code word that someone can use with their physician that will trigger a comprehensive blood?
Just I keep trying to figure out what's the code that one needs to ask or tell their doctor? Like I'm feeling blank so that they get a full blood panel. What?
Well, you have to be hemorrhaging from the, from the gut or something. Well, I usually use the WTH method which is what the hell and then he and he says, okay, we'll do it
because 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
Is that 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, and that you don't have to feign illness in order to do it.
Right? Yeah, and a lot of people do, so I would say, if you can't afford these tests, there are an increasing number of companies that offer these tests inside tractor. He's one of them and you just do it. A couple of times a year at a minimum and then you can share that with your doctor. If you can't afford that.
Then I would say to your doctor. Here are the main ones that Andrew and David do. Yeah, we must. And there's
an email that is something like 55 or a phone number rather. It's 555-5555. I think, if they have any complaints, they can just call that number David will pick up on the East Coast time, business hours and I'll
pick you up outside of those hours. But there are some main ones I would say, you blood sugar levels, you want to do your hba1c, which is your average glucose levels over the month. There's CR.
Which I mentioned for inflammation.
Let's talk about C-reactive protein for a second because I think it's been shown to be an early marker of macular degeneration of heart disease of a variety of different things. CRP is something that we don't hear enough about. I think, maybe what do you know about CRP that I don't, I'm guessing a lot, but
all it was originally picked up as something that was associated with heart disease in the Framingham study. I believe it is a the best marker for cardiovascular.
Nation and is also we use it as a predictor of longevity, and it's levels, go up with mortality. And so this is an association but there's enough data that I would say, if you have high levels of CRP, you need to get your levels down quickly and the levels, usually go up with age and with levels of information. So the ways to get it down, would be to switch the diet. Eat less try to eat more vegetables. You'll find it will come down. There are also drugs that can do it.
Anti-inflammatories can do it as well. But CRP is it's actually H CR P. There's a high sensitive, rhs CRP. Your doctor will know get one of those readings, because if you've got a normal blood sugar levels, your doctor or fasting, blood sugar levels, your doctor might say you're fine. But a lot of people have normal blood sugar but have high CRP, which is just as bad for you long term and can predict a future heart
attack. All Eyes of heart attack. I want your thoughts.
On cholesterol
and serum cholesterol and dietary cholesterol, I can not for the life of me, get my arms around this literature and even if I ignore all the essentially nonsense that's out there in various social media groups as saying cholesterol is, that is the worst thing in the world or cholesterol is not or dietary. Cholesterol has nothing to do with serum cholesterol and nothing to do with longevity. I can't seem to sort through the
a basic data. That essentially ask is having high levels of LDL going to kill me earlier. Should I be striving to always reduce LDL and increase HDL, is that a reasonable goal? And if so is dietary cholesterol the primary determinant of that and just as a final point about this, I am aware of quite good data that shows that anorexics people that essentially eat no food unless you force them to
Can often have very high LDL so their dietary cholesterol is essentially zero and so they're manufacturing a lot of their own. So realize this isn't your primary area of expertise, but you're a smart guy. You think about this kind of stuff a lot. What do you think is going on with the cholesterol literature? And will we ever get to the bottom of this as a scientific and medical community? Because to me, it is rather perplexing
it is. But you can, you can get through the politics.
I know a fair bit about cholesterol because it's in my family history and I was headed for an early death. My grandmother had a stroke 30. That's how bad I am in terms of my genetics. So I went on a Statin and I know there's a lot of people who say that statins long-term or bad, it might to associated with with Alzheimer's disease.
I-i've been taking a Statin since I was 29 and that's because I forced my same doctor to give me the Statin. The conversation was something like this. You're too young to be on a Statin. So what you want me to have have a heart attack for you. Give me something, give it to me now. So, 29. I've been on a Statin and my cholesterol was way up in Beyond 300, which is a massive massive. Basically, my blood was creamy to look at. So I've now got my cholesterol down to low low levels to, what would it be? I can check on.
Inside track our boat. So my ratio of HDL to LDL which you want to be less than five is now two. And the LDL is blow 100. So it's all good. And my, I've measured my cardiovascular health with an MRI. I got a movie of my heart beating. I've still got a heart of a 20 year old. So that's working. I'm willing to forego the risk that the Statin is causing problems later, because of my family history, but other people, I would say be aware that statins aren't perfect drugs.
There are some interesting new ones. There's one called the PS canine inhibitor, which is a I think fortnightly or every two weeks injection that blocks the release of LDL from the liver and then that seems to be great for lowering cholesterol, but also has other benefits, that might be Pro longevity. And there are some people that I was just talking to her on The Cutting Edge of this, and their doctors are trying them on this drug instead of the Statin. So you could talk to your doctor about
Do you avoid dietary cholesterol for that reason? Also red meat butter and I happen to love butter. I love red, meat who I realize. There's some people who don't my cholesterol is a little bit high, but I'm working to bring that down a bit. Although not by altering my food intake yet. But what do you think is the relationship between dietary, cholesterol and serum cholesterol? And what's what's going on with the liver wire anorexics? Yeah, you know, why is there serum cholesterol?
Also High when they're eating nothing,
yeah, well, they've been in a number of papers over the years that have been ignored and our friend Peter a TIA brought to my attention recently. A new study that I think definitively said that dietary cholesterol has almost zero impact on blood cholesterol levels. Good. Yeah, so I'm annoyed because I've been avoiding eggs and butter for most of my life and I didn't have to. So I had I have eggs plenty of time at least in your case. Yeah. Yeah.
That that's the thing. You can eat these foods that were once banned, because the, it's very difficult to take cholesterol up into the body, from the guard and most of its being synthesized in the
body.
Well, I'm just pausing there for a second because I think that it's what we've been told six meals a day, you know, eat a lot of grains and fruits and this kind of thing.
You know, avoid cholesterol. I mean basically everything we learned in the 80s and 90s and early 2000s is getting flipped on its head now, but and I think this is a very strong caveats. That's important to mention.
Amino, acids in particular, the amino acids that come from animal products, right? Seem to have some Pro aging effect on them. Right. At least the way that I've heard you describe the your diet and now I'm somebody who enjoys meat, I like it. But so I'm by no means a vegan and it all. But I've heard you say you eat mostly plants.
But a little bit of fish or chicken or something of that sort of eggs or but is that specifically to avoid excessive amino acid intake? Or is it something specific about plants that that excites you with respect to that? I mean vegetables are delicious too. But what is it something great about plants or is it something bad about when I think of meat? I guess the biologists and methinks amino acids, right? I don't think top sirloin. I think amino acid, I think top sirloin as I'm eating it. But really what they are, are amino acids.
Including Lucy. Yeah.
Well, there are two good things about plans. And neither of them is taste for me. I would eat steak all the time. If I could, I did. When I was a kid, I'm Australian but plants have two benefits. One is that they're highly nutritious and they'll give you a lot of the vitamins and nutrients that I need. I don't take a multivitamin. I don't want to have the excess iron in my body. So there's that high density nutrition. So those dark leaves
It's a spinach salad. Great. The second is that there is what's called Xeno hermetic molecules in plants that terms in our pharmacist is a term that I came up with with my friend Conrad Howard's, which means stressed plants. Make molecules that benefit your health. I'll break it down. Zeno. It means between species and hormesis is the term whatever doesn't kill. You makes you stronger and live longer.
And the idea is that when plants are stressed out, think of a grapevine that's dried out and they're starting to harvest The Grapes which is typically how it's done. They are full with resveratrol because Resveratrol is a plant defense. Molecule that I think is made to activate those sirtuin genes in a plant. So plants have sirtuins just like we do but by inject purifying or at least concentrating in a lightproof bottle and keeping it out of the air. We stabilize this Zeno hermetic molecule.
It's a cocktail. Not just one. There's others in wine. We then ingest those and get the benefits of activating our own defenses because our food was getting stressed out and buy stressed. I don't mean psychologically, stressed. I mean biologically stress and so I try to eat plants that have gone through a bit of stress. They might be brightly colored. They've had too much sun or got nibbled on by a caterpillar.
So you go to places where it's organic or it's fresh local. And those are the plants that aren't perfect, and they probably have high concentrations of these molecules. And in addition night also, by the supplements, to make sure I'm getting enough of those as well, which supplements, mimic the well, so Resveratrol will, there's another one called Chris certain or Christian, some people call it. Would you find in Trace Amounts and apples and onions. And we also showed back in 2003 that it activates sirtuins as well. But others have 20 years later, found that it
Kill senescent cells or helps kill senescent cells. So it's a double whammy with that
molecule. And are you actively picking out the peaches that look
like they were nibbled on by caterpillar? No, but I don't worry, if they've been banged up a bit.
What's the story with antioxidants? Are they have any value whatsoever? Because the way that you described them at the beginning and what I've heard recently is that they are not all the rage for anti-aging.
What are they doing? That's useful. Should we be seeking out antioxidants? Anyway? For other seller Health purposes. Well,
yeah. Antioxidants and not going to hurt you. Unless you take Mega doses. We do need some oxidants for our immune system. And there's even what's called my toe hormesis, which is your mitochondria power packs need to have a little bit of these free radicals to be able to function so you don't want to overdose on these. Antioxidants vitamin C vitamin E. Don't over do it over, do
it you
Take a multivitamin. Correct? Right. I think I'm going to stop after this conversation because I've always just taken one for the kind of insurance purpose which is a stupid
purpose, not actual insurance,
but just thinking, oh, you know cap, you know, top off on my a CBD buddy and
I'll pee out what I don't need,
right? Yeah, sure. That never bothered me the whole expensive P thing never got. That's a that's a that argument ever got me because I that good vitamin is not that expensive. I just figured better safe than sorry, but it may be
He that it detrimental. Well, it
can in the case of iron as we discussed in the end toxins. So when I came into the Aging field in the early 1990s, it was all about antioxidants. And we thought that enzymes by the name of cattle A's and superoxide dismutase. Whether going to be the key to longevity. It turns out that it's largely been a failure that giving animals and ants. Humans, antioxidants haven't had the longevity benefits that we dreamed of
And the main reason is that there's a lot more going on than just free radical damage. The epigenome gets disrupted. We've got these proteins misfolding and
So the problem really has been that. We didn't realize that you need to turn on the body's natural defenses against that plus a whole host of other things to get the true benefits, but I'm not going to say it's a problem taking it, you know, an antioxidant drink pomegranate juice for one is full of good stuff including Xena hermetic molecules, but Resveratrol is a good case in point, which is when I worked on Resveratrol as a longevity molecule first, we showed it in yeast and worms and flies and mice.
Before that it was thought that was virtual was good for your heart in red wine when you drink red wine because it's an antioxidant. So then we showed that it extended lifespan of yeast cells through this genetic pathway the sort of to ins. And we then tested whether Resveratrol, if we change one atom, to make it not in antioxidant, guess what? It still worked. Fine. So, it wasn't its antioxidant activity that was extending lifespan. It was its ability to turn on the yeasts defenses.
And aging conversely, when we gave the yeast antioxidants, they lived shorter. So yeah, that was the beginning of my transformation into thinking, turn on the body's defenses. Don't give it the
antioxidants. This is a an opportunity for me to see something. I've been wanting to say, for a long time, which is that what's so wonderful about science? Is that because the goal is mechanism. You can really start to understand as you just described, what? Actually mediates a process is very different than, what most
Modulates a process. I mean, it'll fire alarm goes off in the building right now. It's going to modulate our attention. That doesn't mean that it controls are pretension. It's not mechanistically relevant. And so I think this thing about antioxidants is one of these cases. It sounds like we're it's in the right ballpark, but until one really unveils the mechanism as you have, you can be one can or in a field can be badly wrong for a very long period of time. It sounds like the sirtuins. I'm really getting down to the
Of the Machinery of what causes cells to age, is really what it's about zooming, way out. What are the behavioral tools that one can start to think about, in terms of ways to modulate these, you know, basically, the way that DNA is being expressed and functioning. I've heard you talk before about hormesis of other sorts cold exposure. We talked about fasting. We talked about exercise in Broad terms, but what about
Any evidence. If it exists as to, whether or not aerobic training versus weight training, these sorts of things. In other words, what are the sorts of things that people can do to improve the sirtuin pathway? And I realized that there are caveats, we can't go directly from a behavior to sirtuins. But in the general theme, what what can people do? What do you
do? Right? Well, we know that that aerobic exercise in mice and rats raises their energy levels and and their levels of certain, one of the genes goes up.
Our to actually number one, and number three, what we don't know yet is what type of exercise is optimal to get them to change. We will learn, we're doing work. Now. It's revealed that we're doing work with the military in the u.s. To try and understand that kind of thing. And I'll always tell you and the public when I don't know something, I'm not going to extrapolate, but what do I do? I based my exercise on the scientific literature, which has shown that maintaining muscle.
Muscle mass is very important for a number of reasons. The two main ones. Are you want to maintain your hormone levels? I'm an older male losing my testosterone and muscle mass over time and by exercising I will maintain that and have in fact, I've probably haven't had a body like this since I was 20, so that's one of the benefits of having this
lifestyle. Sorry, to interrupt your we did an episode on hormones and there are data in humans that show that there are some
Males in their 80s and 90s where their testosterone is equivalent to the average of 25 and 30 rolls. I can get you that information is really impressive studies. Unfortunately didn't include a lot of information about the lifestyle factors Etc. But this idea that testosterone goes down with age. It might it might be the trend but it's not necessarily a prerequisite,
right? I believe in naturally, increasing and maintaining the
Hormone levels and I've been measuring them for a long time. And I could see for me. My testosterone levels were steadily levels of going down and then you got tenure and they went back up here now, huh? No, I actually became complacent and, and it was the worst actually my age changed in the wrong direction after that, because I was relaxed interests and not worried about the future, but then I got serious. And actually, according to the inside, track rail the algorithm. Got my age down from
He ate 231 in a matter of months. That was a big drop. And I've just, I've been getting steadily younger over the last 10 years. According to that measurement, the blood
test. What about estrogen? Because it women are different in the sense that they do are the number of eggs that they and the ovaries change over time. Right? Do you think that they can maintain estrogen levels at in over longer periods of
time using some of these same protocols? Well, yeah, I get into trouble from certain University when I
Talk about this too much about
estrogen just about
fertility and long story that if I, if I don't want to get too much into the anecdotes be, but I'll tell you the science, which is that if you take a mouse and put it on fasting or caloric, restriction, for up until the point where it should be infertile. So that's about it at a year of a jam else gets in Fertile, female Mouse
due to due to fasting
or do
Simply to agent you'd aging due to aging the fasting. It's not extreme fast. It's just less calorie on it. Then you put them back on a regular food and they become fertile again for many, many months afterwards. So, the effect on slowing down aging is also on the reproductive
system. Interesting.
And so that I wouldn't say to any woman. I wouldn't think that they should become super skinny to try and preserve fertility. That's not what I'm saying, but these Pathways that we work on.
So Tunes are known to delay infertility in female animals case in point. I'm one of the lead authors on a paper where we used nmn. Remember this is the gas, the fuel, the petrol for the sirtuins. We gave old mice. One group of mice was 16 months old. Remember, they became infotile at 12. Gave the man, a man, and think it was only six weeks later. They had offspring.
They became fertile again, which goes against biology at textbook biology, which is that female mammals run out of eggs, turns out that's not true. You can rejuvenate the female reproductive system and even get them to come out of now, suppose as we call it. So that's a whole new paradigm in biology as well. That's
super interesting, uh, sorry to interrupt you, but I'm reminded by a set of a set of studies that were done by your former colleagues as they're no longer there David hubel and Torsten. Wiesel my side.
To be great. Grandparents won the Nobel Prize for discovering, what are called critical periods? This phase of early development when the brain is extremely plastic and a big part of their work was to show that after a certain point, the critical period shuts down. Essentially, the brain can't change or not nearly as as much and then people came along later and showed that you could open up these critical periods again, but very briefly. And it takes a very specific stimulus, essentially High degrees of focus etcetera.
However, there's a well-known phenomenon in this literature, where if you take an animal and to some degree, this has been shown in humans as well and you let them pass through the critical period but then you essentially sensory deprived them. You take away experience, you close both eyes, you essentially reopen, the critical period. So it seems like I couldn't help but mention this that there's this parallel between what we're talking about here with fertility and neuroplasticity where
There's a timer where certain things are available to the organism early in life. And then they tend to taper off. It's not an open and shut but they taper off, but then a deprivation can actually reactivate, the availability of that process, forgive me. I just couldn't help but mention but it to me, they're so both of those things are associated with youth, fertility, and neuroplasticity. And so I think that it'd be so interesting. I'd love to collaborate with you on this, to explore how neuroplasticity might actually be regulated by these.
He's like the sirtuins
right and and the sirtuins do control memory in in neurons as well. So what I think is really interesting, is that what we're learning from work that you and your colleagues have done and in my life as well, is that the body has remarkable powers of healing and recovering from illness and injury. And what we once thought was a one-way Street and you just can't repair. You can't get over these diseases. You can reset the system and the body can really get rid of
An aided in ways that in the future will wonder. Why why do we work on this earlier? I think the future of humanity is more like us walking around like Deadpool will probably be cleaner and we won't smell as badly. But Deadpool, if you don't know, can get injured and just recover. It's very hard to injure this guy and we're going to be the same. There are many species you cut off the limb to limb. Grows back salamanders or yeah, we are now learning how to tap into that system. And in part, what we're doing is reversing.
Passing the age of those cells and telling them how to read the jeans correctly. Again, reversing the age of that epigenome. And we do that the cells, the brain, for instance, the skin. We did the optic nerve that let's talk about those results for a second. Then I want to make sure
that we return to some of these behavioral protocols, you know this amazing paper at the end of last year cover article full article in nature showing that essentially a small menu of transcription factors, which control
Gene expression etcetera, could essentially reverse the age of neurons in the eye and and rescue those cells against damage. Essentially, allow Blind, Mice to see again and offset degeneration of these retinal cells, incredible paper and such a boon to the field. Where is that? Where does that stand now? In terms of human, clinical trials? I mean, how what do you what do you envisioning in terms of the trajectory of those of those data from my sin?
To into human someday, right?
Well, to get to the point immediately we're going to be testing the treatment on monkeys if it's just for safety reasons. Sure. And then the first patient should be done, sometime in 2022, early 2023. And we're going to try to recover blindness in this, involves making an injection
of a virus into the I right right now. There's no way that I am aware of to manipulate these transcription factors through
a pill or some other vets while we were working on in my
At Harvard right now. So it will be based modulation of transcription bubble pop a pill in the whole body gets rejuvenated by twenty years. That's what we're aiming for. Now. We do it with gene therapy in the, I and other places. So, in the eye, yes, it's single injection. The genes go into the retina and we can turn it on with a drug called doxycycline. And we do that in the mice, for four to eight weeks. Then the eye gets younger. We can measure that cause you can measure the clock and then the
Vision comes back in those mice and I don't see any reason why it shouldn't work in people because it's the same structures and mechanisms that are on in the human as well. Now, the only is one injection. It's what I should
imagine injections into the. I obviously nobody should do this outside of a pathology clinic and they're definitely by an ophthalmologist, but the injections into the IR painless if done correctly by the right person, it sounds Dreadful, but it's actually I've seen it done. Hundreds of times. I've done it.
Thousands of times and it's not to myself, but to other creatures and there's a way of doing this is completely painless
to the person, but you are feeling, it's a tiny, tiny needle to. But the great thing about this is that it's a one-time treatment, those genes go into the back of the eye and stay there forever, and you can just turn them on whenever you want. So what we found is you can turn them on in the mice, they get their Vision back and then you turn it off again. And so far many months out the benefit has remained, but if it
This decline would just turn it back on and reset the system, rinse and repeat. So one day, what's exciting is that we could potentially do this across the entire body and just take this antibiotic every five years and go back, time and time again.
In thinking about the body and what's going on under the hood. I'm amazed still. That there isn't a simple affordable technology. That would allow me to just look into my body and see whether or not there any tumors growing anywhere and it's not that hard to look into the body. I mean, that the technology exists, why isn't anybody created an at home or pseudo at Home
Solution like a clinic, where you can go and pay 50 bucks or 100 bucks and see if you have any tumors growing. And yeah, it's still expensive. You can get your doctor to try to get you.
There's some companies that offer blood test. The look at circulating DNA. That will measure it. We're getting there. It's still probably five to ten years away from being really cheap. You can do things like a colon cancer test at home. I think it's 100 something dollars. You you ship off your shit, excuse my language and they measure it and they tell you if you've got colon cancer with high probability. I did that during the pandemic because I didn't want to get a colonoscopy.
Is
it more accurate? Or as accurate as a colonoscopy? I
believe it's close to being as accurate. The downside is that during a colonoscopy? They can pinch off the polyps that are looking dangerous. Whereas this obviously isn't that, but it's certainly easier to do and my father, whose Australian tells me that it's free for Australians. They get this test
routinely interesting. I want to return to the topic that I took us away from. So I apologize, which is behavioral, protocols. You
Regularly do the cold shower thing. Ice baths. Cold water. Swims. Are you into that hole is
ha, ha ha, ha. Well, you do know that I've done it at least once because we did it together. That's
right. Not the same bath just to be very clear. Same sauna different, ice pack the idea of Sinclair and huberman taking an ice bath together is it might warm some people's hearts, but just to be very clear, different. Same ice bath different different times. Yeah. Thank you for
clarifying.
I don't do them. Regularly. I I do. Try to sleep cool. I sleep better. Anyway, I tried a dress without a lot of warm clothes. I'm here in a t-shirt. It's middle of summer. But in Winter, I'll try to wear a t-shirt to
your challenging your system to thermoregulate. Right,
right. I've got this hypothesis with Ray Cronus. We published What's called the metabolic winter hypothesis, which is a few tens of thousands of years ago. We were either hungry or cold.
To both and we really experience that now. And so we try to give ourselves the metabolic winter and part of the problem. I think with the Obesity epidemic is that we're never called and cold when you're cold. You have to burn energy. It may be only slightly but over the whole night, if you're a little bit cool, you'll actually expend more energy. So I try to do that, but I'm not a big fan of cold showers. The sauna I don't have access to my gym as much as I did. So but I do want to get back into it. I used to do it regularly with my son and I
posted on Instagram once so that he could stay in there for 15 minutes and I could only stay in for about three. Anyway, long story short. I try to compensate with changes in my diet and exercise until I get back into
it. You reminded me of something that I meant asked earlier that obesity reduces NAD levels and accelerates aging.
How I mean, okay. So again, this is the the scientist in us, you know, someone's carrying a lot of excess adipose, tissues, subcutaneous and visceral fat, but why should that reduce NAD in any ways that are independent of effects on glucose and Insulin? If you know, there's something direct about white adipose tissue. And the reason I ask this is not simply to dig into mechanism alone, but I think they're really interesting data.
That fat actually gets neural innervation. I mean, it's kind, it's not just a, it's a it's not just stored fuel. It's stored fuel. That's acting as an endocrine organ essentially. So yeah, why would being fat make people age faster?
Yeah. That's a question. That is so obvious. But so few people ask it that's what makes you a good scientist and so that we don't know but I'll give you my best answer which is that obesity comes along with a
A lot of problems that include a lot of senescent cells. In fact, if you stain old fat for senescent cells, it lights up. And when you kill off those cells, at least in mice and maybe in humans, it looks like the fact is less toxic to the body because those senescent cells in their fat are secreting. These inflammatory molecules that will accelerate aging. As we know know you talk about the sirtuins and NAD. So if we just look
Suffolk lie at why, this would be the sirtuins only like to come on or get activated. When the body needs is our is under adversity. And if a cell is surrounded by fat or contains a lot of fat, it's going to think times a good doesn't need to switch on, so that's the evolutionary argument mechanistically. We don't know, but it could have something to do with the response to glucose which then responds to the sirtuin gene, but that hasn't been worked out very
well.
Well, and there's is there any evidence that leptin this hormone from fat can actually interact with the sirtuin pathway?
I don't recall saying that maybe I could do a sabbatical in your lab and that'd be a fun one. Definitely
your because leptin during development is what triggers the permission for the hypothalamus to enter puberty, right? Yes. Is why kids that eat a lot when they're young and get overweight will also start to go and undergo puberty more quickly. Although they have reproductive issues later.
We yeah, we should start.
The hypothalamus together because the hypothalamus is can control the Aging of the body. The most interesting part of the brain, for sure. Yes. Absolutely. If you turn on the sort one Jane this or two engine that we work on in the hypothalamus that actually will extend lifespan. Also, it's been shown by dong Cheng Chi at Albano Albert, Einstein College of Medicine. That if you inhibit inflammation in the hypothalamus in a mouse, it will increase or maintain the expression of what's called GnRH, which is the hormone.
That he found actually controls longevity in the mouse in part. And so keeping inflammation down in the hypothalamus is sufficient to extend the lifespan of animals and I reviewed that paper for nature or about 7 years ago. And that was the first demonstration that the hypothalamus is one of the leading Regulators of the bodies age and find this fascinating
GnRH. For those of, you don't know, actually comes from neurons in the hypothalamus that then literally reach down into the pituitary and Trigger the release of all the things that control for
Leti, luteinizing hormone, follicle-stimulating hormone Etc, such a powerful set of neurons. And it's never really been clear. What at a behavioral level triggers, the release of GnRH. There's all the stories about pheromones and timers in puberty Etc, but environmental conditions and dietary conditions and behaviors that can control GnRH release. I think, is an incredible area for exploration. I've love to do that. Sabbatical, by the way, have a couple.
Seemingly random questions, but I can't help but ask because I one thing I like to do is forage the internet for practices that at least more than a few people are doing and then wonder whether or not there's any basis for it, you mentioned methylation as a detrimental process, the way it disrupts, the epigenome and the CD reader. So to speak, there are people out there who are ingesting methylene blue. And when I was a kid, I used methylene blue to clean my fish tank and
I
love fish tanks. I know you're into Aquaria also different podcast episode, talk about a query of, but why in the world would people ingest methylene blue? It meaning is their logic correct? And or is that a dangerous practice? I I'm not sure I'd want to ingest methylene blue. Sounds like a bad thing to do.
It stains your body you seen.
Yeah. When we would. Yeah, there was a someone in my lab as opposed to talk was using it to study it.
Completely different process related to the blood-brain barrier and used to inject into animals and they would turn blue. But then again people in jest colloid, silver, you know, they'll put in there. There's this. Please people don't do this or if you do just don't tell me because I won't like it. They people put it in their eyes and some people actually stay in their skin. They actually become kind of a this silver purple, brown color. If they do it excessively. I mean, there's a lot of crazy stuff out there, but what do you think they're thinking with this?
Lean blue thing or should we just get them to a good psychiatrist?
I don't know for sure. I think methylene blue was found to extend the lifespan of some lower organism. And that's where it came from, my recollection with the emphasis on Lower organized. Yes. Smaller organisms. I think doesn't do you remember Andrew, does it in interrupt or interfere with mitochondrial activity? And that aliens might I like doing it. Yeah, we need to look this up and post it. Okay, we'll get to the bottom of this but those methods. Let's talk about those. Yeah, those metals have to be placed on the right.
Part of the genome. They get attached to the right genes and the wrong jeans. And if you have a lot of methylation, it's going to mess up. The epigenome. Smoking will do that lack of exercise, all that good stuff. So what you actually want to do is you want to measure it and make sure what you're doing with your body is working. How do you know that if you do this or that is actually helping and so you can you can test your age. I could take a swab from your mouth and tell you how old you are biologically and then we could work on
Bring that down. And actually there are anecdotes. Now
that people are reversing their age by a
decade or more just by doing some of the things that we've talked about and some other cutting-edge stuff that I'm going to write about. But yeah, but you have to measure stuff that's a didn't want to forget to bring that up. I'm measuring stuff all the time. I have blood tests like you, I've got this monitor that stuck to my chest right now. That's measuring myself a thousand times a second. And I measure
My biological age. What's it measuring 1,000 homes? As usual stuff things. Yeah. So this this little device is stuck here, and it's 42 weeks at you. Just recharge it or send it back, and get a new one. It's got body temperature movement, heart rate, variability. It's an FDA-approved device. It's not a toy. It's not one of these recreational things. It also listens to my voice. Eventually will tell me if I need a psychiatrist or if I'm depressed. It will tell me how I sleep obviously.
But when you put all that data together, and it's individualized and anonymized.
It can now tell my doctor in real time if I've got a cold that needs an antibiotic or it's just a virus if I am suffering from covid-19 or even if I'm gonna have a heart attack next week. And so these little devices are going to be with us all the time instead of going to your doctor once a year, which is ludicrous.
I have to ask you about x-rays because every time I go through the scanner at the airport, I think Sinclair would never do this.
And the argument I heard you
give about this before was a really excellent one, which is that, you know, it's a low-level amount of radiation going through at the airport. But the argument is always, let's just as much as on the plane and your argument your counter argument. I should say was, well, then why would I want to do both right? Why would so, when you go to the airport, assuming you're not running late and you have to go through the standard line, what do you say to them? And you say, I'm David Sinclair.
And then they shuttle you to your own line. What do you say you do? Say, I don't like this thing. Do you have to give them a
reason? No, you don't. You can say, I don't want this end. They'll get annoyed because it's hard for them to pat you down, but you get a pat down and you're done. As long as you're not in a hurry, it's fine.
If you want to pay for the TSA Pre in America, or the way to get around those scanners, you can do that. So, I travel a lot, so it's worth it anyway, but I just go through the metal
detector. I don't get scan and the metal detector doesn't have the same same problem. What about X-rays at the dentist? Yeah.
Well, you know, one x-rays not going to kill you twos. Not going to kill you, but I'd rather kill you. No, I'm just kidding. I try to limit it because it's cumulative. Right? And I went for six years without having a dental x-ray.
And then my last visit I just gave up. I was tired of arguing with my dentist. So they gave me one but they've got LED coats on and they put little over your body. That's telling you something right there. And funnily enough. My teeth hadn't changed. Now, you could balance that by saying, well, one x-ray, 2x 3x raised is worth it. If I had cavities and that's true. You want to know what's in there, but doing it regularly for me. I don't think was worth it because at my teeth,
Perfect health. And I've always been don't have any cavities didn't have braces. They're fine. So stop scanning me. I mean, I know you have to pay for the machine, but, you know, do I have a choice? Yes, so stop. Pressuring
me, you know, who shared your sentiments about X-rays and the dentist in general. My apologies to the dentist's out. There was the great physicist. Richard Feynman. This is a story about him. That's not especially well known, but he had very serious concerns health concerns about x-rays because
cuz he understood the physics. He understood enough biology that he was actually quite vocal about his dislike of dental technology and its dangers. And he talked about some of that people can find that on the internet. If they, like, speaking of people who are like fine men who've been engaged in public discourse about science, one of the things that I appreciate about you. In fact, the way that you and I initially came to know, one another is,
Your public health education efforts. So, obviously, we're doing this podcast. You've done The Joe Rogan podcast, Lex Friedman pot. Friedman's podcast. Scuse me, Lex. I'm still adjusting that Lex Friedman podcast. I'm any other podcasts, you written an amazing book. What are you thinking? These days in terms of what the world needs in terms of?
Education from scientist, education from MDS, education in general, as it relates to these things because you know, I think if nothing else 2020 revealed to us that there's a gap. There's a gap in understanding and that the scientists to are guilty of not knowing what to do with all the information that's out there. On PubMed or elsewhere. I'm just, what do you thinking for yourself and in general? I'd like to just know what do you think the world needs their way? We can recruit some more.
A public Educators.
Yeah. Well, we have gone from a time when you and I were in college and young professors where the only way to get our voice out to the public was either through a newspaper or a very short radio interview, which for me was extremely frustrating. Because particularly the newspapers and my topic every time was twisted into something that was not just embarrassing. But Harvard University used to bring me into the back office and slang.
I resign. How did you say? Such a thing? Roll. Going to live 200. I didn't say that. So we're now also in a world where were overwhelmed with information and most of it is wrong. And anyone can pretend to be an expert. So, we've gone from early days to now the future and we're experiencing it right now. Thanks to guys like you, people like you is that the experts, some experts are very small number who are brilliant and good communicators are
Talking directly to the public. This is never been able to be possible until this time right now. So another five years from now and certainly, by 10 years. I would hope that there are trusted sources of information of people who cannot just communicate the ideas directly, but are able to talk about things that are going on that aren't even published yet to say. Here's what's really going on and this is what the future looks like.
But this is somebody like yourself who spent their whole life studying a particular topic and knows what they're talking about. And this is all this. Also something that I think most people don't know that we scientists if we tell a lie, we burst into flames. We absolutely cannot tell something that's untrue and took the best of our knowledge. We say it as it is because if we don't were beaten up and we all we kicked out of the University. So the people who survived to our age, and I'm a little older than you.
Surviving bit longer, but a lot younger inside. Now, we have to measure you with my yeah, we need to say, we probably need a little help. Hopefully, not too much will measure that and we'll work on your eating. But this is really, really important. Is that finally people like, your are allowed by our universities to talk to the public. I used to do it with a real threat to my survival. People would look at me, always a Salesman. He's promoting this. And that it was seen as a rule -, but finally, I think we're in a world where it's not
- anymore. And the pandemic showed that we need to voices of Reason voice in the voices of fact that you could trust. And you can see the popularity of your podcast shows that the public are desperate for facts, that they can trust because they don't know what to believe anymore.
Well, I'm being completely honest. When I say this that, you know, I followed your lead. I saw you on the Joe Rogan podcast and my jaw dropped. I was like, this is amazing like this because
Get out other good scientists on before, but you're, you know, tenured professor at Harvard genetics, department of genetics. And for those of you don't know, there's the Harvard and of course, Harvard medical school and they're both. Excellent, of course, but is there the top tiers of Academia? And I certainly understand what it takes to get there and survive there and to thrive there. It's like a game of pinball. You never win. Neither. Just, you just get to. If you're doing really well, you get to keep playing, that's the truth. And
Academia, and if you're not, you stop playing basically, but when I saw, you explain what you were doing in a way that was accessible to people and also talking about possible protocols that they might explore for themselves to see if those were right for them. I was just I was just dazzled and excited and I made every effort to get in contact with you and you know, the rest is history, but I think what's really exciting to me these days is because of 2020 and everything.
Happened in the continues to happen. There's a thirst for knowledge. There's also this direct to the public route that you mentioned. And and I think there's also an openness. I'd love your thoughts on this, but it seems to me that there's an openness from the general public about health practices that there are actually things that people can do to control their stress level to control their sleep, to control their cholesterol. If that's what they need to do. Maybe they
They don't and to even control their lifespan, which I think is remarkable. And you know, I know I speak on behalf of so many people, when I just want to say thank you. You've truly changed the course of my life. I would not be sitting here doing this. We're not for your example and I always say Sinclair, many people have written books, many academics have written books as you have but in terms of doing podcasts and really getting out there with your message in a way that I have to assume raised your cortisol level and heart rate.
The little bit, but you did it in on the less, you know, you were truly first man in and that, that deserves a nod and a great debt of gratitude to you for that. So, thank you so
much. Thanks, Andrew, your, you become a good friend and I'm super proud of what you've done and what, you know, what you will
do. So in addition to your book and your presence on social media, Instagram and Twitter and appearances on podcast recently. I've noticed that you've opened up a
a sort of email / website that people can ask access scuse me to get some information about their own health and rates of Aging. Tell us about that and what's being measured and what is this test that you've been working on secretly and now soon, not so secretly. Yeah. Well,
what I want is is a credit score for the body to make it easy for people to follow their health. And there is a number, there's a biological age that you can measure. Unfortunately, the
As many hundreds of dollars right now, but in my lab we've been able to bring that down a lot. And so I want to democratize this test so that everybody has access to a score for their health that can predict their not just their future health and time of death, but to change it. And I'm building a system that will Point people in the right direction and give them discounts for certain things that will improve not, just their health now, but 10, 20, 30 years into the future and we can measure that and very cheaply.
Keep measuring it to know that you're on the right track because if you don't measure something you can't optimize it. And so this is the biological age test. We've developed it. It's a simple mouth swab. We're rolling it out. We're building the system right now, and there is a sign-up sheet because a lot of people want to get in line, go to dr. Sinclair.com, you can get on that and you'll be one of the first people in the world to get this test and see what we're doing. A fantastic.
Will people be celebrating
their biological age birthday.
In other words, if I'm - like if I can imagine. So I'm 45 right now soon to be 46. But if my if I were to be so lucky as to get my biological age 235
within 12
months, maybe can help me do that. Do I get to
celebrate a - birthday? Absolutely. And my plan is that those people who take their age back a year or more? We think we can go back 20 years. Eventually, they'll get a birthday card from me and it's a - birthday card.
I love it and probably
Very little actual birthday cake being ingested, but who cares? Because you're living that much longer till it's full of stevia. That'll be fine. And thank you for talking to us today. I realized, I took us down deep into the guts of mechanism. And as well, talking about global protocols, everything from what one can do and take if they choose? That's right for them to how to think about this whole process that we talk about when we talk about life span, as as
Is an incredibly Illuminating. Thank you. David. Thanks Andrew. Thank you for joining me for my conversation with dr. David Sinclair. If you're enjoying end or learning from this podcast, please subscribe to our YouTube channel. In addition, please subscribe on Apple and or Spotify and on YouTube you can leave us comments and you can leave us suggestions for future podcasts guests, that you would like us to feature. In addition on Apple. You can leave us up to a five star review and you can leave us a comment, please. Also check out the sponsors mentioned at the beginning.
Inning of this episode. That's the best way to support this podcast. Also, I teach science and science related tools on Instagram. It's huberman lab on Instagram. I also have a Twitter which is also huberman lab, so be sure to check those out. A lot of the material covers things similar to the podcast, but oftentimes, I'll cover a unique material not featured at all on the podcast. So that's huberman. Lab on Instagram. And on Twitter, in addition. We have a patreon. It's patreon.com slash Andrew huberman. And there, you can support the podcast at any level that you like.
Today and in many other previous episodes of the huberman. Last podcast, we discussed
supplements. Well
supplements aren't necessary or right for everybody, many people drive tremendous benefit from supplements. For that reason. We partnered with Thorn, th OU are any because Thorn supplements are the absolute highest quality and the absolute highest Precision. Meaning, what you see listed on the bottle is, what's actually in the bottle, which is not the case for many supplement, companies out there. Thorn is one of the partners of the Mayo Clinic and all the major sports teams and
Really are very trusted, very highest quality. If you want to see the supplements that I personally take, you can go to Thorn.com / the letter U / huberman and there you'll see the supplements that I take, you can get 20% off any of those supplements. And if you navigate deeper into the thorn site through that portal, you'll also get 20% off any of the other supplements that thorn makes. So again, it's Thorn th orn e.com/live/android, you / huberman to get 20% off any of the supplements that thorn makes also take note that the lifespan.
Cast, featuring. Dr. Davidson Claire is a host launches, Wednesday, January 5th. You can find the first episode here on the huberman Lab podcast Channel. They also have their own independent Channel. You can find the link to that channel in the show notes. So please go there, subscribe on YouTube. Also on Apple and Spotify. I've seen these episodes. They are phenomenal and you're going to learn a tremendous amount about aging and how to slow and reverse aging from the world expert himself, dr. Davidson Claire. And last, but certainly not least. Thank you for your interest in science.
