Essentials: The Biology of Slowing & Reversing Aging | Dr. David Sinclair

- Welcome to Huberman Lab Essentials, where we revisit past episodes

for the most potent and actionable science-based tools for mental health,

physical health, and performance. I'm Andrew Huberman, and I'm a professor of

neurobiology and ophthalmology at Stanford School of Medicine. And now, my conversation

with Dr. David Sinclair. Thanks for being here. I have a ton of questions for you

about aging, longevity, lifespan, actionable protocols to increase

how long we live, et cetera. And I just want to start off

with a very simple question: What is the difference between longevity,

anti-aging, and aging as a disease? Because I associate you with

this statement, "Aging is a disease." - Right. Well, so longevity

is the more academic way we describe what were search. Anti-aging is kind of the same thing,

but it's got a bad rap because it's been used by

a whole bunch of people that don't know what they're talking about. So, I really don't like that term,

anti-aging. But aging as a disease

and longevity are perfectly valid ways to

talk about this subject. Now, so, let's talk about

aging as a disease. When I started my research,

disease, here at 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, it's a deterioration

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 if 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 our bodies stayed youthful, we would not get those diseases. And actually,

what we're showing in my lab is if you turn the clock back in tissues,

those diseases go away. So, aging is the problem. And instead, through, you know,

most of the last 200 years, we've been sticking band-aids on diseases that have already occurred

because of aging, and then it's too late. So, there are a couple of things. One is we want to slow aging down,

so we don't get those diseases, and when they do occur,

don't just stick a band-aid on. Reverse the age of the body,

and then the diseases will go away. - That clarifies a lot for me. Thank you. Can we point to one specific general

phenomenon in the body that underlies aging? - Fortunately, during the 2000s, we settled on eight or nine

major causes of aging. These eight or nine causes,

at least for the first time, allowed us to come around

and talk together. We put them on a pizza,

so everyone got equal slices, 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 we call the epigenome. - Well, tell us a little bit more

about the epigenome, and frame it for us, if you will, and then we'll get into ways that one can

adjust the epigenome in positive ways. - Yeah, so in science, what I like to do,

I'm a reductionist, is to boil it down, and I actually ended up boiling

aging down to an equation, which is the loss of information

due to entropy. It's a hard thing to overcome

the second law of thermodynamics, that's 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'll lose that information, or you try to copy a cassette tape, or even if you send information

across the internet, some of it will get lost. That's what I think is aging. And there are two types of

information in the body. There is the genetic information,

which is digital, A, T, C, G,

the chemicalletters of DNA, but there's this other part of

the information in the body that's just as important,

it's essential, in fact, and that's the systems that control

which genes are switched on and off, in what cell, at what time,

in response to what we eat, et cetera. And it turns out that 80%

of our future longevity and health is controlled by this second part, the epigenetic information,

the control systems. I liken the DNA to the music that's on a

DVD or a compact disc, for the younger people, who 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 over time, aging is the equivalent of

scratching the CD and the DVD so that you're not playing

the right songs, and cells, when 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. - What are the scratches

that you're referring to? - So, DNA is six foot long, so if you join your chromosomes together,

you get a six foot per cell, so there's enough to go to the moon

and back eight times in your body. And it has to be wrapped up

to exist inside us, but it's not just wrapped up willy-nilly,

it's not just a bundle of string. It's wrapped up very carefully

in ways that dictates which genes are switched on and off. And when we're developing in the embryo, the cell marks the DNA with chemicals

that says, "Okay, this gene is for a nerve cell. You, cell will stay a nerve cell

for the next 100 years, if you're lucky. Don't turn into a skin cell.

That would be bad." 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 total, what we're saying is that the body controls the genome

through the ability to mark the DNA and then compact some parts of it, silence those genes,

don't read those genes, and open others, keep others open,

that should stay open. And that pattern of genes that are

silent and open, silent, open, is what dictates the cell's type,

the cell's function. And then the scratches are

the disruption of that, so genes that were once silent, and you could say it's a gene

that is involved in skin, it's starting to come on in the brain,

shouldn't be there but we see this happen, and vice versa, the gene might get

shut off over time during aging. Cells, over time, lose these structures,

lose their identity, they forget what they're supposed to do,

and we get diseases. We call that aging,

and we can measure that. In fact, we can measure it in such a way that we can predict

when somebody's going to die based on the changes

in those chemicals. - Are these changes the same sorts of

changes that underlie the outward body surface

manifestations of aging that most of us are familiar with, graying of the hair, wrinkling of

the skin, drooping of the face? Or are we talking about people that potentially are going to look older

but simply live longer? - Well, it's actually, you are as old

as you look, if you want to generalize. So, let's start with centenarian families. These are families that

tend to live over 100. When they're 70,

they still look 50, or less. So, it is a good indicator, it's not perfect because you can, like me,

grow up in Australia and accelerate the aging of your skin,

but in general, 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. - 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 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 immense vitality the same periods when we're aging faster? - Yes. 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. 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, there's a massive increase in age

based on that clock early in life. So, you're right.

So, that's a really important point, that you have accelerated aging

during the first few years of life, and then it goes linear

owards the rest of your life. But there's another interesting thing

you brought up, which is that we're finding that the genes

that get messed up, that get scratched, that are leading to aging

are those early developmental genes. They come on late in life

and just mess up the system, and they seem to be particularly

susceptible to those scratches. So, what'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 your broken chromosomes, that accelerates the unwinding of those

beautiful DNA loops that I mentioned. We can actually do this to a mouse. We can accelerate that process,

and we get an old mouse, 50% older, and it has this bent spine, kyphosis.

It has gray hair. It's organs are old. So, we now can control aging

in the forwards direction. The other thing that accelerates aging

is massive cell damage or stress. So, we pinched nerves, and we saw that their aging process

was accelerated as well. - Incredible. Yeah, this is more of

an anecdotal phenomenon. It is an anecdotal phenomenon. But I had this experience of

in junior high school, you know, going home for a summer

and you come back 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

can predict overall rates of aging? - Well, yeah, I don't want to

scare anybody. - Sure. - 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, because anyone who's taking

growth hormone for a short amount of time, you'll build up muscle, you feel great, but it's like burning your

candle at both ends. Ultimately, if you want to live longer,

you want less of that. And the animals that have been generated, and mutants that have low growth hormone,

sometimes these are dwarfs, they live the longest by far. - Can we say that there's a direct

relationship between body size and longevity

or duration 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. No matter what size you are, you can have a bigger impact on your life

than anything your genes give you. 80% is epigenetic,

not genetic. - So, let's talk about some of the things

that people can do, and I've kind of batched these

into categories, rather than just diving

right into actionable protocols. 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 think understanding the mechanism

will allow people to make better choices, and not simply to just decide whether

or not they're going to fast or not fast, or how long they're going to fast, I think should be dictated by

some understanding of the mechanism. - So, why is it that having

elevated blood sugar, glucose and insulin,

ages us more quickly, and/or why is it that having periods

of time each day, or perhaps longer, can extend our lifespan? - Well, let's start with

what I think was a big mistake, was the idea that

people should never be hungry. Some people never

experience 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 pretty steady, and not have this

fluctuation. What we actually found, my colleagues

and I across this field of longevity, is that when you look at,

first of all, animals, whether it's a dog

or a mouse or a monkey, the ones that live the longest,

by far, 30% longer, and stay healthy, are the ones that don't eat all the time. Actually, it was first discovered

back in the early 20th century, but people ignored it, and then it was rediscovered in the 1930s,

Clive McKay did caloric restriction. He put cellulose in the food of rats, so they couldn't get as many calories

even though they ate, and those rats lived 30% longer. But then it went away, and then it came back in the 2000s in a

big way when a couple of things happened. 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 are

called sirtuins, there's seven of them. And we showed 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. But by having high levels of insulin

all day, being fed, means your longevity genes

are not switched on. So, you're falling apart, your epigenome, your information that

keeps your cells functioning over time just degrades quicker. Your 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

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 major muscles in your

brain to become more 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. - What is the protocol that

people can extrapolate from that? - Well, if there's one thing I could say, I would say definitely try to skip

a meal a day. That's the best thing. - Does it matter which meal,

or are 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. Beware that the first two to three weeks

when you try that, you will feel hungry, and you'll also have a habit of wanting to

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. - Do you ever do longer fasts, like

48 hours or 72 hours or week-long fasts? - Not very often, I find it quite

difficult to go more than 24 hours. But when I do it, maybe it's

once a month I'll go for two days. After two, and actually even better

if you go for three days without eating, it kicks in even greater

longevity benefits. So, there's a system

called the autophagy system, which digests old and

misfolded proteins in the body, and there's a natural cleansing

that happens when you're hungry. Macroautophagy it's 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 autophagy which kicks in day two, day three, 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

old mouse, it lives 35% longer." - When you are fasting,

regardless of how long, I know you're ingesting fluids like water,

and presumably some caffeine, I heard you had several

or more espresso today. Are you also ingesting electrolytes? Like, I know some people get light-headed,

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 more in vogue now. Is that something that you 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 drink tea during the day,

and coffee when I'm first awake. - Mm-hmm. - And I don't get the shakes,

so I don't fix what's not broken. - Okay, you've told us that there's ample

evidence that keeping your blood sugar low for a period of time each 24 hours,

can help trigger some of these pro-longevity anti-aging mechanisms, and that extending them out two or three

days can trigger yet additional mechanisms of gobbling up of dead cells

and things of that sort. How is it that blood glucose

triggers these mechanisms? Because we've said, okay,

remove glucose and things get better. You've talked before,

maybe we could talk more now about some of the underlying cellular and

genetic mechanisms, things like the sirtuins, but how are glucose and sirtuins actually

tethered to one another mechanistically? Yeah, there's a really good question. That proves you're a scientist, or a world-leading one. So, what we now know is that

these longevity pathways, we call them these longevity genes,

talk to each other. And we used to say, "Oh, my longevity

gene's more important than yours." It was ridiculous. Because they're all talking to each other. You pull one lever,

and the other one moves. And the way to think of it is that there are systems set up to detect

what you're eating. So, the sirtuins will mainly respond to

sugar and insulin, and then there's this other system

called mTOR, which is sensing how much protein

or amino acids are coming into your body, and they talk to each other, we can pull

one and affect the other, and vice versa. But together, when you're fasting,

you'll get the sirtuin activation, which is good for you, and you'll also, through lack of

amino acids, particularly three of them, leucine, isoleucine, valine,

the body will downregulate mTOR, and it's that up sirtuin, down mTOR that is hugely beneficial and

turns on all of the body's defenses. The chewing up the old proteins,

improving insulin sensitivity, giving us more energy,

repairing cells, all of that, and so these two pathways, I think

are the most important for longevity. - You mentioned leucine. It's clear that because of leucine's

effects on the mTOR pathway, that there are many people not just people

in these particular fitness communities, that are actively trying to ingest

more leucine on a regular basis in order to maximize their

wellness and fitness, and, in some cases, muscle growth,

but also just wellness. But what I interpret your last statement

to mean is that leucine, because it triggers cellar growth,

is actually pro-aging in some sense. Is that right? - 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 knows that

I'm not a professional bodybuilder, but I try to actually... Here's the key, and I haven't said this

publicly that I can remember. I pulse things, so that I get

periods of fasting, and then I eat, then I take a supplement, then I fast, then I exercise, and I'm 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 why it's taken me about

15 years to develop my protocol, and there's a lot of subtlety to it. - Mm-hmm. - What you want to do is to get the cells

to be perceiving adversity, okay? Because our modern life, we're

sitting around, we're eating too much, we're not exercising. Our cells respond; they go,

"Hey, everything's cool, no problem," and they become relaxed, and they don't

turn on their 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. - 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. - Mm-hmm. My sense,

and please tell me if I'm wrong, but my sense is that it depends on the

context of what you did the night before, whether or not you're diabetic,

lots of things. So, for instance, if I eat an

enormous meal at midnight, go to sleep, wake up at 6:00 AM, I could imagine that black coffee, or

coffee with a little bit of cream might "break my fast" but the body doesn't have

a breaking-the-fast switch. The body only speaks in the language of

glucose, AMPK, mTOR, et cetera. So, do you worry that

ingesting these calories is going to "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, not everybody can manage on

just water, or just tea, or we should say,

not everybody is willing to manage on just water, or just tea

for a certain part of the day. - Well, my first answer is not scientific,

it's philosophical, but 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'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. Second 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 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. The point about doing this

is that you try to do your best. If you go from regular living, to don't

eat the whole day, you're going to fail. It's like quitting smoking cold turkey. It's easier to chew gum

and stick the patch on, because your body has to get

used to all sorts of habits, and it's social, it's physical,

putting stuff in your mouth, chewing, not just the low blood sugar levels,

and your brain will fight it. Your limbic system is going to go,

"Hey, do it, do it, do it," and you're going to have to fight it. But once you get through it,

you'll be better, but you do it in stages. 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. - That captures the

essence of fasting rationally and a rational approach to

supplementation very well. Along the lines of supplementation,

what about NMN? How does one incorporate that into

a supplementation protocol? Should they choose to do that? - All right. Well, disclaimer is I don't recommend

anything, but I talk about what I do. So, a bit of scientific background, these sirtuin genes that we discovered

first in yeast cells when I was at MIT, and then in animals

as I moved to Harvard in the 2000s. And one of my first postdocs, actually

literally my first postdoc, Chaim Cohen, published a great paper and found that

turning on the Sirtuin 6 gene, remember there's seven,

number six gene is very potent; it extended the lifespan dramatically

of mice that he engineered, both males and females,

which is great. So, what you want to do is naturally

boost the activity of these sirtuins. They are genes,

but they also make proteins, that's what genes

typically make or encode, and then those proteins take care of

the body in many different ways. NAD levels are really important

for keeping those sirtuin defenses at a youthful level. I take a precursor to NAD

called NMN, and the body uses that to make

the NAD molecule in one step. And so, I know from

measuring dozens of human beings, that if you take NMN

for the time period that I do, I've been taking it for years,

but if you take it for about two weeks, you'll double, on average,

double your NAD levels in the blood. So, I just want people to be aware that what I do may not

perfectly work at all for others. But I have studied, as I said,

dozens of people who take NMN at a gram,

sometimes two grams, and I know by looking at all those people,

that without any exceptions, that if you do what I do, your NAD levels

go up by about twofold or more. 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? - Mm-hmm. - But what we're doing now

are very careful clinical trials. - I want to talk about iron and iron load. I don't think we can get right down into

how much iron somebody needs, because it'll vary person to person,

but I was surprised to learn that iron is actually going to accelerate the

aging process in various contexts. - This is a new finding out of Spain,

Manuel Serrano's lab has found that excess iron will increase the

number of senescent cells in the body. And senescent cells are these zombie cells

that accumulate as you get older, and they sit there and they cause

inflammation mainly, and also can cause cancer. 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. 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 anemic, and we're getting along 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, and not just work towards

the average human, but work towards what's optimal for 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 6 months, frankly since I was in college. So I just got, I like data. Are there any things that

you pay attention to, that you think are

particularly interesting for people to 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 look at? - Yeah. The first is that

you should be tracking things, because one measurement isn't enough,

these things vary over time, and if you can have a decade or more of

data it's super informative, as you know. But there are some main ones,

I would say your blood sugar levels, you want to do your HbA1c, which is your

average glucose levels over the month, there's CRP which I mentioned

for inflammation. - Yeah, 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,

a variety of different things. CRP is something that we don't hear

enough about, I think. - It is the best marker for

cardiovascular inflammation, and also, we use it as

a predictor of longevity. And its 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 inflammation. 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,

it's actually hCRP, there's a high sensitivity for hsCRP.

Your doctor will know. Get one of those readings, because

if you've got normal blood sugar levels, 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. - 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? In other words, what are the sorts of

things that people can do to improve the sirtuin pathway? And I realize that there are caveats, we can't go directly from

a behavior to sirtuins, but in the general theme,

what can people do, what do you do? - Well, we know that aerobic exercise in

mice and rats raises their NAD levels, and their levels of sirt,

one of the genes, goes up. Two actually,

number one and number three. I base my exercise on the scientific

literature, which has shown that maintaining 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 probably haven't had

a body like this since I was 20, so that's one of the benefits

of having this lifestyle. - What about estrogen? Because women are different in the sense

that the number of eggs that they... And the ovaries change over time, right? Do you think that they can

maintain estrogen levels over longer periods of time using

some of these same protocols? I don't want to get too much into the

anecdotes, 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 at a year of age,

a mouse gets infertile, a female mouse- - Due to fasting? - No, due to-

- Or due simply to aging? - Due to aging.

- Yeah. - Due to aging. The fasting, it's not an extreme fast,

it's just less calories. - Got 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, I wouldn't say to any woman, I wouldn't think that they should become

super skinny to try & preserve fertility. That's not what I'm saying. But these pathways that we work on,

these sirtuins, 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 infertile at 12. Gave them NMN, and I think it was only six weeks later,

they had offspring. - Mm-hmm. - They became fertile again,

which goes against textbook biology, which is that female mammals

run out of eggs. - Mm-hmm. - Turns out, that's not true. You can rejuvenate the

female reproductive system, and even get them to come out of

mouse-pause, as we call it. - Mm-hmm. - So, that's a whole new paradigm

in biology as well. What I think is

really interesting is that what we're learning from work that

you and your colleagues have done, and in my lab 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 rejuvenated

in ways that, in the future, we'll wonder, "Why didn't we work on this earlier?" - And thank you for talking to us today. I realize that 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, or that's right for them, to how to

think about this whole process that we talk about

when we talk about lifespan. As always, incredibly illuminating.

Thank you, David. - Thanks, Andrew.