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

- Welcome to the Huberman Lab podcast,

where we discuss science and science-based tools

for everyday life.

I'm Andrew Huberman,

and I'm a professor of neurobiology and ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr. David Sinclair,

professor of genetics at Harvard Medical School

and co-director of the Paul F. Glenn Center

for the Biology of Aging.

Dr. Sinclair's work is focused on why we age

and how to slow or reverse the effects of aging

by focusing on the cellular and molecular pathways

that exist in all cells of the body and that progress

those cells over time from young cells to old cells.

By elucidating the biology of cellular maturation and aging,

Dr. Sinclair's group has figured out intervention points

by which any of us indeed, all of us,

can slow or reverse the effects of aging.

What is unique about his work

is that it focuses on behavioral interventions,

nutritional interventions, as well as supplementation

and prescription drug interventions that can help us all

age more slowly and reverse the effects of aging

in all tissues of the body.

Dr. Sinclair holds a unique and revolutionary view

of the aging process, which is that aging

is not the normal and natural consequence

that we all will suffer.

But rather that aging is a disease

that can be slowed or halted.

Dr. Sinclair continually publishes

original research articles in the most prestigious

and competitive scientific journals.

In addition to that, he's published a popular book

that was a New York Times bestseller.

The title of that book, is 'Lifespan:

Why We Age And Why We Don't Have To.'

He is also very active in public facing efforts

to educate people on the biology of aging

and slowing the aging process.

Dr. Sinclair, and I share a mutual interest

and excitement in public education about science.

And so I'm thrilled to share with you that we've partnered.

And Dr. David Sinclair is going to be launching

the lifespan podcast,

which is all about the biology of aging and tools

to intervene in the aging process.

That podcast will launch Wednesday, January 5th.

You can find it at the link in the show notes

to this episode today as well.

You can subscribe to that podcast on YouTube, Apple,

or Spotify, or anywhere that you get your podcasts.

Again, the lifespan podcast featuring Dr. David Sinclair,

Claire begins Wednesday, January 5th, 2022,

be sure to check it out.

You're going to learn a tremendous amount of information,

and you're going to learn both the mechanistic science

behind aging, the mechanistic science behind

reversing the aging process and practical tools

that you can apply in your everyday life.

In today's episode, Dr. Sinclair

and I talk about the biology of aging

and tools to intervene in that process.

And so you might view today's episode

as a primer for the lifespan podcast,

because we delve deep into the behavioral tools,

nutritional aspects, supplementation aspects

of the biology of aging.

We also talk about David's important discoveries

of the sirtuins, particular 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.

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Now I don't follow a strictly ketogenic diet.

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So for me, that means fasting until about 11:00 AM

or 12 noon most days.

And then my lunch is typically a low carb, ketoish lunch,

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And now my conversation with Dr. David Sinclair.

Thank you for coming.

- Thanks for having me here.

It's good to see you.

- This is mate by the way, that we're toasting at 11:00 AM.

Unlike other podcasts, we, well, I don't drink alcohol,

so I'm boring that way.

But truly, thanks for being here,

I have a ton of questions for you.

We go way back in some sense,

but that doesn't mean that I don't have

many, many questions about aging, longevity, lifespan,

actionable protocols to increase

how long we live, et cetera.

And I just want to start off with a very simple question.

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 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 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,

disease here at Harvard Medical School,

it was considered,

if there's something that's wrong with you.

and it's a rare thing,

it 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,

'cause 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,

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 take 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's contentious

because scientists like to come up with new hypothesis.

It's how they build their careers.

But fortunately during the two thousands,

we settled on eight or nine major causes of aging.

We call them hallmarks

'cause causes was a little bit too strong,

but 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 everyone got an equal weighting, equal slices.

But before that, by the way,

we were trying to kill each other in the field,

that was horrible.

- Interesting that you guys work on aging

and you're trying to kill each other.

- Yeah, isn't it?

Well kill each other's careers.

Well I like to think I was fairly generous,

but I was one of the kids

and the old guard really didn't like the new guard.

We just came along in the 1990s

and 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.

I would go to meetings and people would shout at each other

and backstab, it was horrible.

But then unfortunately in the two thousands,

we rallied around this new map of aging

with these causes of 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 we call the epigenome.

- Well tell us a little bit more about the epigenome,

frame it for us if you will, and then we'll get into ways

that one can adjust the epigenome in positive ways.

- 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 loss of information due to entropy.

It's a hard thing to overcome, 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 were 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,

and that's the systems that control which genes

are switched on and off in what cell at what time

in response to what we eat, et cetera.

And it turns out that 80% of our future longevity and health

is controlled by the second part,

the epigenetic information, the control systems.

I liken the DNA to the music that's on a DVD

or a compact disc for the younger people.

We 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,

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.

- Can we go a little deeper

into what that these scratches are.

Is it the way that the DNA are packed into a cell?

Is it the way that they're spaced?

What are the scratches that you're referring to?

- So DNA is six foot long.

So if you join your chromosomes together,

you get a six foot post-sale.

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.

Your cell will stay a nerve cell

for the next a 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 menthols will mark which songs get played

for the rest of your life.

And there are other 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 cells type

the cells 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 is 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.

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 sorts of DNA scratches associated with that?

Or are we talking about people

that are potentially are going to look older,

but simply live longer?

- 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 a hundred.

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 growing up in Australia

and accelerate the aging of your skin.

But in general, how you look,

and 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.

A great paper 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 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, yes.

And this is something I've never talked about,

at least not publicly.

So this is a really good question.

So those chemicals we can measure,

it's also known as the Horvath's clock.

It's the biological clock,

it's separate from your chronological age.

So actually what I didn't mention

is that when the AI looked at the faces of those people,

they could 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,

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 towards the rest of your life.

But there's another interesting thing that 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, 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, this is more of an anecdotal phenomenon.

It is an anecdotal phenomenon,

but at this experience of in junior high school,

going home for a summer and you come back

and then high school in the US

usually starts eighth or ninth grade,

or grade eight or grade nine for you Canadians.

And then some of the kids,

like they grew beards over the summer,

or they completely matured quickly over the summer.

Do you think there's any reason to believe

that rates of entry into and through puberty

can predict overall rates of aging?

In other words, if a kid is a slow burner, right?

They basically acquire 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 a 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 there are studies that show

that the slower you take to develop it also is predictive

of having a longer, healthier life.

And it may have something to do with growth hormone.

We know that growth hormone is pro-aging.

Anyone who's taking growth hormone, pay attention.

- Just look at someone who's taking growth hormone.

- Yeah.

- They often will acquire these characteristics of vitality,

like improved a smoothness of skin,

but their whole body shape changes often.

- Yeah, I mean you'll feel better

for a short amount of time.

You'll build up muscle, you feel great,

but it's like burning your candle at both ends.

Ultimately, if you want to live longer,

you want less of that.

And the animals that have been generated

and mutants that have low growth hormone,

or sometimes these are dwarfs, they live the longest by far.

A guy in my lab, Michael Bankowski,

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 chloric restriction, so fasting,

combined with one of these dwarf mutations,

low growth hormone, I think he called it Yoda.

You look at who lives the longest,

it's the really small people.

This is a bit anecdotal,

but it 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

into their nineties and beyond.

- Really?

- Yeah.

- Huh, amazing.

- And are there are some Lauren dwarfs as well?

There are dwarf mutations in South America

and they seem to be protected

against many of the diseases of aging.

You barely ever see heart disease

or cancer in these families.

- So I having owned a very large dog breed,

a bulldog 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 life?

- Well, there is, but that doesn't mean that you're a slave

to your early epigenome nor have 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 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 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.

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 to fast,

I think should be dictated by someone 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.

We live in a world now

where there's at least three meals a day,

and then we've got companies selling bars and snacks

in between.

So the feeling of hunger,

some people never 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 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 was first discovered back

in the early 20th century, but people ignored it.

And then it was rediscovered in the 1930s,

Claude McKay did Clark 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 2000's in a big way,

when a couple of things happened,

one is that my lab and others showed

that there were 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 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.

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 quick.

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 two 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 do,

though you get used to 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 these periods

of not being fed and then the body

turns on these defensive genes.

There's a really interesting experiment

that was published maybe a couple of years ago

by Rafael de Cabo down at the NIH.

What he did was he took over 10,000 mice

and gave them different combinations

of fat, carbohydrate, protein.

And he was trying to figure out

what was the best combination.

And then you also cleverly had a group.

Well, two groups, one that was fed all the time

or ate as much as they wanted

and the other group was only given food for an hour a day.

And it turns out they ate

roughly the same amount of calories,

'cause of course in an hour they're stuffing their faces.

It turns out it didn't matter what diet he gave them,

it was only the group that ate within that window

that lived longer and dramatically longer.

So my conclusion is,

and mice are very similar to us, metabolically,

I think that tells us that it's not as important,

what you eat, it's when you eat during the day.

- What is the protocol

that people can extrapolate from that?

Or maybe I should just ask you,

what is your protocol for when to eat

and when to avoid food?

Do you fast, do you ever fast, longer than 24 hours?

What do you do?

And what do you think is a good jumping off place

if people want to explore this as a protocol?

- 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 they're 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 that's an excellent point.

I realized it's a simple one,

but I think it's an excellent one

'cause I think one of the things that people

struggle with the most is knowing when and how

to initiate this so-called intermittent and 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 yogurt or olive oil

because the supplements I have need to be dissolved in it.

And then I go throughout the whole day,

as I'm doing right now, here with this glass of water here,

I'm just keeping myself filled with liquids.

And so I don't feel hungry,

be aware that the first two to three weeks,

when you try that you will feel hungry

and you also have a habit of wanting

just to chew on something

that 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 wasn't hungry in the morning.

Some people are very hungry in the morning

and they may want to consider skipping dinner instead,

but I will go throughout the whole day.

I don't get the crashes of the high glucose

and the low glucose that anyone who goes,

oh man, it's three O'clock, 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 it regulates blood sugar levels naturally.

My liver is putting out glucose when it needs to,

and it's very steady and gives me pure focus

throughout the day.

And I don't have to even have to think about lunch,

I'm just powering through.

At dinner, I mean, I love food as much as anybody.

So I will eat a regular, pretty healthy meal.

I'll try to eat mostly vegetables, I can eat some fish,

some shrimp, I rarely will eat a steak.

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.

[David laughs]

- Argentine lineage, but we can talk about that

some other time.

- Well, everybody's different, that's the other thing.

What works for me may not be perfect for you

and we do have to measure things to know what's working.

I rarely eat dessert, I gave up dessert and sugar

when I turned 40 and occasionally

I'll steal a bit of dessert

'cause 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 just a side note.

I used to get buildup of plaque pretty easily

and every time I went to the dentist,

they'd have to scrape it off.

And I even bought tools to scrape it off.

'cause it was driving me nuts.

I don't get pluck anymore

and I think it's because of my diet.

I don't have those sugars in my mouth

that the bacteria feed on

and then form the biofilm on the teeth.

Much better breath, by the way.

- That's a benefit.

Should you ever fast longer than this.

It sounds if you go to bed,

well, you used to tend to stay up late.

I know because I get texts from you

at like two in the morning my time,

which means you're out very late and up early as well.

But assuming that people go to sleep

sometime around 1130 or 12, plus or minus an hour

and wake up sometime around 7:00 AM

plus or minus 90 minutes, you're eating more or less on.

It sounds something like a 20 hours of fasting,

four hours of eating or 16 hours of fasting

and eight hours of food intake, et cetera.

But do you ever do longer fast,

like 48 hours or 72 hours a week long, fast?

- Occasionally I do.

So my typical day I would only eat within a two hour window.

Just usually I'm either eating out or.

- 'Cause you're 22 too.

- Yeah, but I love well.

- And if you exercise, do you feel like you,

then you just power through and maintain that fasted state?

- Absolutely, I can exercise

and now I've already so used to it.

I don't feel like I need food after exercising, I used to.

But have I gone longer?

Yes, but not very often.

I find it quite difficult to go more than 24 hours.

But when I do it, maybe it's once a month,

I'll go for two days after two and actually 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 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 autophagy,

which kicks in day two, day three,

which really gets rid of the deep proteins.

And what excites me is you just put out a big paper

that said, if you trigger this process in an old mouse,

it lives 35% longer.

- [Andrew] Wow.

- 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, 110% I need to eat

at least once a day unfortunately.

- One more practical question then a mechanistic question

related to this, the practical question

is when you are fasting, regardless of how long,

I know you're ingesting fluids like water

and presumably some caffeine I heard you had several

or more espresso today, which is impressive,

but are you also 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 invoke 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 and I don't get the shakes.

So 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 wont.

But yeah, 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,

you'd probably want to supplement with that.

But I think there's fair amount of good stuff

in tea and coffee as it is.

- Okay, so then the mechanistic question is,

you've told us that there's ample evidence

that keeping your blood sugar low for a period of time

is 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 cellar and genetic mechanisms,

things like this are sirtuins,

but how our glucose in the sirtuins

actually tethered to one another mechanistically.

- There's a really good question,

that proves you're a scientist or a world-leading one.

So 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 is more important than yours.

It was ridiculous.

'Cause they're all talking to each other,

you pull one lever and the other one moves.

And the way to think of it is that there are systems set up

to detect what you're eating.

So the sirtuins will mainly respond to sugar and insulin.

And then there's this other system called mTOR,

which is sensing how much protein or amino acids

are coming into your body.

And they talk to each other,

we can pull one and affect the other and vice versa.

But together when you're fasting,

you'll get the sirtuin activation, which is good for you.

And you'll also through lack of amino acids,

particularly three of them, leucine, lysine and valine.

The body will down-regulate mTOR and it's that up sirtuin,

down MTOR that is hugely beneficial

and turns on all of the body's defenses,

the pro chewing up the old proteins,

improving insulin sensitivity, giving us more energy,

repairing cells, all of that.

And so these two pathways, I think,

are the most important for longevity.

- So interesting, you mentioned leucine,

within the resistance training slash body building slash

fitness community.

Leucine gets a lot of attention

because there are long-standing debates

about how much protein one needs per day

and how much you want and can assimilate at each meal.

It makes for many YouTube videos and not much else, frankly.

However, it's clear that because of leucine's effects

on the mTOR pathway, that there are many people,

not just people in these particular fitness communities

that are actively trying to ingest more leucine

on a regular basis in order to maximize their wellness

and fitness and in some cases muscle growth

but also just wellness.

But what I interpret your last statement to mean

is that leucine, because it triggers seller growth

is actually pro aging in some sense, is that right?

- Well, it could be that's what the evidence suggests.

And again it goes back to the debate.

Should you supplement with growth hormone or testosterone?

All of these activities will give you immediate benefits.

You'll bulk up more.

You'll feel better immediately,

but based on the research,

it's at the expense 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 tried 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.

- Yeah, it sounds like a very rational protocol.

Does the name Ori Hofmekler mean anything to you?

- No.

- Okay, just briefly, I discovered Ori Hofmekler

about 15 years ago, he was a in Israeli special forces.

He's now got to be close to 70.

Forgive me Ori, if that number is inflated.

He wrote a book called 'The Warrior Diet',

which got very little attention at the time.

But what he said was when he was in Israeli 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, he's very lean, very strong

and very vital at, I wouldn't say an advanced age,

but he's getting up there

and he just seems to be getting better and better.

Ori Hofmekler was the person who essentially founded,

if you will, although our ancestors 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, I actually went to his home

and sat down with him and he said, fasting is wonderful

but these pulses where you nourish the body

or even slightly over nourish the body

provided they aren't too frequent,

have a tremendous effect on vitality.

And so I 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 growth hormone will make you feel better and younger

taking testosterone or estrogen, we should probably say.

There are women who take hormone therapies later in life

who take estrogen,

they experience a strong increase in vitality

if it's done correctly, but there is an effect of aging,

the body more rapidly,

it's sort of a second puberty if you will,

but this idea of restriction and then pulsing,

not necessarily feast and famine,

but certainly famine and feast in lowercase letters,

there really seems to be something about that.

So at a cellular level,

we'd kind of go back to mTOR and the sirtuins.

How do you think that the cells might be reacting

to this kind of lowercased feast and upper case famine

type protocol?

- Right, well, the pulsing, I think is what you want to do

is to get the cells to be perceiving adversity.

Okay, 'cause our modern life we're sitting around,

we're eating 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, first of all, let's get to,

why did I even think that might be possible?

'Cause I didn't read the warrior diet.

What I found in my research was that

if we gave resveratrol on this red wine molecule,

that became well known in the 2000's.

If we gave it to mice, their whole lifespan,

they were protected against a high-fat diet,

which we call the Western diet.

They had lean organs.

They live slightly longer, but not a lot.

And if we gave them a high-fat diet without resveratrol,

they actually lived a lot shorter.

So it resveratrol protected them against the high-fat diet.

We gave it to them on a normal diet,

they just ate it when they wanted,

and there wasn't much effect.

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.

- [Andrew] Interesting.

- So people out there, my critics say, 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 the mice every other day,

we had mice living over three years.

- Wow, that's a long time, 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 life span 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 then 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 two diabetics

to bring down their blood sugar levels.

But it's been found that looking at tens of thousands

of veterans and all those,

that those two type two diabetics

live longer than people

that don't even get type two diabetes.

So it's a longevity drug,

right now you have to get it from your doctor in the US,

in most of the countries you can just get it

over the counter and you protected.

It looks like, based on epidemiological data, cancer,

heart disease for LT.

What else?

Dementia.

So I take Metformin.

- In addition,

you take Metformin end fast fasting each day.

So when do you take it relative to the fasting?

- 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 12, 13 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 kind of thing,

think that they should stop taking Metformin

'cause 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 you,

it actually just reduces your ability to have stamina

because it's inhibiting your body's ability to make energy.

And so what happens is when you're on Metformin,

you do fewer reps.

But guess what?

Those muscles that you do build up on Metformin,

have the same strength and have much lower inflammation

and other markers of aging.

You just won't have that extra 5% size of muscles.

So if you want large muscles,

don't take Metformin and you'll be fine

during your exercise.

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% contact 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 now it's become a myth

that Metformin greatly inhibits our ability to exercise,

which is not true, but in an abundance of caution,

I skipped my Metformin on days I'm going exercise.

And not only that,

I'm one of the 20% of people

that has a stomach sensitivity to it.

So if I'm not feeling great that day,

I don't take it either.

- You mentioned Metformin is available

only by prescription from a doctor, at least in the US.

Berberine is a substance that comes from Tree Barco.

I also learned about many years ago from Ori.

He said, if ever, I'm going to overeat

like a Thanksgiving meal or something,

I take berberine, 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 where some of the AMPK pathway

and the mTOR pathway, et cetera,

that if I didn't ingest food in particular carbohydrates,

I would feel a little dizzy and kind of get a headache,

like almost hypoglycemic.

What are your thoughts on berberine

as an alternative to Metformin?

And are there any cautionary notes?

Obviously people should talk to their doctor

before adding or subtracting anything from their life,

including breath order, anything that comes up,

but with all of that 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.

- He just called me poor.

- Women can take it too.

So the thing with berberine and we started it in my lab,

it is effective at boosting energetics in the body,

just like AMPK and Metformin does.

And we've actually given it to rats and mice

and seen 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.

You have to take high doses.

- Which is a good thing, right?

I think when people hear insulin sensitivity,

sometimes people think, oh, well that's bad, right?

No, but you want your cells to be insulin sensitive.

You don't want a lot of blood sugar floating around

that can't be sequestered into cells.

- Exactly, so this is anti type two diabetes.

And so that this berberine does have wonderful effects

on the metabolism of animals and in some clinical trials

on dozens of people that's being tested.

Now, there's one cautionary tale, which just came up,

Caenorhabditis lab published that berberine

reduced the lifespan of worms,

but I'm not sure worms trump human clinical trials

at this point.

- Not in my opinion,

no disrespect to my C. elegans colleagues

or rather my colleagues that work on C.

- Yeah, well, what I like to do

is to give all the information,

people can decide what they want,

but I would say based on the worm data,

I wouldn't panic just yet.

And 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, great seed extract, et cetera.

Let's start with the obvious one that I know you get a lot,

but for the record, can't I just drink red wine

and get enough resveratrol, David.

- You can try, you need to drink about 200 glasses a day.

- I'm sure it's been tried.

- There are some, and I drink a glass of red wine a day

if I get the chance, but any more than that,

it's a lot of calories and your liver will get fatty

and it's all bad.

So, I mean, 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 beware it'll cause diarrhea.

But regular resveratrol should not do that.

- So a thousand milligrams per day is what you do.

- Yeah and I had 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

of course it's in curcumin.

These are crunchy things,

that is not going to get through your gut.

And I'm not just making this up.

I always base my statements on human studies.

So we've done a lot of studies on resveratrol

as have others since, and we know that from,

we found out early, I was one of the first people

to take a high dose for resveratrol.

And when we included it with food,

the levels in my blood went up five 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 are you taking this all at once in the morning

and chasing it with some olive oil

or are you dissolving it in yogurt?

What's the specific protocol?

- Yeah, I've been improving perfecting

what I do for about 10 years

I would take some Greek yogurt,

a couple of spoonfuls, put the resveratrol on there,

mix it around, make sure it's dissolved

and put that in my mouth and swallow that,

these days, what I like to do,

because I've realized that olive oil

and particularly oleic acid, one of the mono unsaturated,

fatty acids is also an activator of the sirtuin defenses.

So I'm trying to ingest more of oleic acid.

So I switched to olive oil.

What I do is I put a couple of teaspoons of olive oil

in a glass mix around the resveratrol,

and maybe some Coresatin a 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 NR and vitamin B3,

which is by doing that,

do you think that it breaks your fast?

And I want to just frame this question of breaking the fast

in a 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?

If I walk in the room and someone else is eating a cracker,

does it break my fast?

People get pretty extreme with 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 6:00 AM.

I could imagine that black coffee

or coffee with a little bit of cream might quote unquote,

break my fast, but the body

doesn't have a breaking the fast switch.

The body only speaks in the language of glucose, AMPK,

mTOR, et cetera.

So do you worry that ingesting these calories

is going to quote unquote break your fast?

And more generally,

how do you think about the issue of whether or not

you're fasting enough to get these positive effects?

Because 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.

If you don't enjoy life, what's the point.

And so I'd like a cup of coffee in the morning,

a little bit of milk, spoonful of yogurt,

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.

Second, well, the olive oil isn't 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

because I've now got the rest of the day

till about eight, 9:00 PM 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 regular living to donate the whole day,

you're going to fail.

It's like quitting smoking, cold turkey.

It's easy 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.

Do breakfast first, then do small lunch

and 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, they'll almost always fail.

- Now, I think that captures the essence

of the fasting rationally and irrational approach

to supplementation very well,

along the lines of supplementation.

What about NMN, NR and B3, niacin?

How does one, I want to know what you do.

I also want to know what I should do,

and I think most people want to know what they should do.

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 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 are two in genes that we discovered

first in yeast cells when I was at MIT

and then in animals as I moved to Harvard in the 2000's

one of my first post-docs,

actually literally my first postdoc Haim Cohen,

published a great paper just a couple of months ago

and found that turning on the sirtuin six gene,

middle of the seven, number six gene is very potent.

It extended the lifespan dramatically of mice

that he engineered both males and females, which is great.

So what you want to do is so naturally boost

the activity of these sirtuins.

They are genes, but they also make proteins.

That's what genes typically make or encode.

And then those proteins take care of the body

in many different ways as we've discussed.

So how do you turn on these genes and make the proteins

they make even more active?

You want to rev up that system.

So exercise will do it, fasting will do it.

What about supplementation?

Well, the first activator of the sirtuins that we discovered

that acts on the enzyme to make it do a better job

of cleaning up the body and protecting 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 humans.

And we saw that it activated that enzyme.

So resveratrol is one way to activate it.

And 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 and is a really small molecule,

little chemical in the body that we need for life.

It's used by the body for chemical reactions,

for a hundred 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's an enzyme called CD38 that Eric Verdin

over at UCSF showed choose up.

Now he's now at the Buck Institute in California,

choose up NAD as you get older.

So it's a double whammy.

You don't make as much and chew it up,

which is really bad because what we've shown in my lab

and so have others is that NAD levels

are really important for keeping those sirtuins and defenses

at a useful level.

And you can give a lot of resveratrol

but if you don't have the fuel,

you're basically accelerating a car

that doesn't have enough gas.

So you want to do both.

And that's what I do.

I take a precursor to NAD called NMN and the body uses that

to make the NAD molecule in one step.

And so I know from measuring dozens of human beings,

that if you take NMN for the time period that I do,

I've been taking it for years.

But if you take it for about two weeks,

you'll double on average,

double your NAD levels in the blood.

Okay, that's not public information.

That's from clinical trials that are not yet published

over the last two years.

There are other ways to increase NAD levels

in someone like me, who's getting older, I'm 52 now.

You can take NR, which is used to make an amend,

which is used to make NAD, and both NMN and NR

are sold by companies in the US.

NR is laxter phosphate,

the phosphate is a small chemical the body needs.

You've probably heard of the atom, phosphorus.

Let's go back one step.

How do you make NR?

NR 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 is that NAD,

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 vitamin B attached.

So you've got all these components that come together

to make this very complicated little molecule called NAD.

When you give NMN, it contains all three components

that the body needs to make NAD.

If you give NR or just vitamin B3,

which is an even smaller molecule,

the body has to find these other components

from somewhere else.

So where do you get phosphate,

well, the body needs it for DNA, it needs it for bones.

So high doses of something

that requires additional phosphate

makes me a little concerned.

And we have compared to NMN and NR head-to-head

in mouse studies, for instance in NMN,

we've shown in a cell paper a few years ago,

makes mice run further, old mice can run 50% further

'cause they had better blood flow, better energy.

NR are at the same dose, did not do that.

In fact, it had no effect.

- I see, dosage wise, if I were elect to take NMN

in supplement form to increase my NAD levels

and presumably slow my aging,

how much NMN should I take?

What's the protocol that you do?

And are the various forms that are out there,

are some better or some worse?

- Well, I'm always happy to tell you what I do

and what my father does, my 82-year-old father,

we take a gram of NMN every day.

- So it's a gram resveratrol and a gram of NMN.

- Right.

- Okay a thousand milligrams.

- Now another important point,

which is, I'm not the same as everybody else.

I have a different microbiome, age, sex, right?

And so I've been measuring myself

and so I know if something's,

or I think I know if something's making me better

or worse based on measuring 45 different things.

So I just want 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 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 two 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'm working on a solution

for people to know what works

and what's real and what isn't, but I'm not there yet.

And in the meantime, I would say,

if you do want to buy this, let's say you want to buy NMN,

look for a company that is well-established

that has high levels of quality control.

Look for three letters, GMP,

which is 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's all I can say right now.

I'm working on something that's going to be much more helpful,

but overall, make sure it's white, crystalline NMN,

and that to me, it tastes like burnt popcorn.

- You crack open the capsules,

and you'll take a little sample

to make sure it tastes like burnt popcorn.

- Well, when I'm making my capsules, I'll taste it

and I do a lot of quality control on the stuff that I take.

- Do you take that gram all at once

with the resveratrol

or do you take it spread throughout the day?

- It's all in the morning for those things.

So if I take Metformin, it's NMN

and the resveratrol altogether.

And there's a good reason for that.

It's all scientific, I try to be.

The levels of NAD go up in the morning

in our bodies naturally.

Our bodies actually have a cycle of NAD, it's not steady.

- It's Arcadian?

- It's Acadian.

In fact, NAD controls your clock.

This was shown by Shin Imai and colleagues

in this 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.

- Conversely, when I travel and I want to reset my clock

to the time zone, I will take a boost of NMN in the morning

and I feel great.

- Does this protocol for you,

does it produce any immediate effects

of increased energy, et cetera?

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 NAD levels increase,

could one possibly expect an increase

in overall energy, focus, et cetera?

I realize we're not making promises here,

but I'm just wondering whether or not the only measure

of whether or not this protocol is working

is whether or not you die at age blank or blank plus 20.

And of course, once you're dead,

you can't really know if you would've lived longer

if you'd done something differently and vice versa.

- Sure, well, there was a study again by Shin Imai

my good friend at Washington University in St. Louis

that showed that improves,

remember this insulin sensitivity, which is a good thing.

But you can't know your insulin sensitivity

unless you're measuring glucose,

have a glucose monitor on your arm.

- Do you have one on right now?

- No, no, I used to, I learned a lot.

- Yeah, last time I saw you had this thing,

it looks like a small leach,

not a large leach 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 were we, Andrew?

- The issue is whether or not you can expect

any immediate effects on energy, vitality, focus,

just even subject.

- So what do you feel, is the question.

And anecdotally,

'cause 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 treating elderly patients

at Harvard Medical School with some wonderful colleagues.

And those people are actually going

to be an 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

is 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 load,

their time in marathons, for example.

There's a good friend of ours in our circle

that is winning marathons at age 50 now.

And he attributes that to the protocol that he's on.

- Interesting, I haven't started taking NMN,

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 purchasing for her and giving her

an NMN supplement and she claims and I believe her.

She has a quite sensitive system

and she's very 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 supply,

and then giving it back to her in this kind of thing.

So that's my other laboratory.

This is what younger brothers do to their older sisters.

I have a question about something

that if it has no relevance,

we can just treat it as a speed bump and then move right on.

And the artificial sweeteners,

these things that we should say non-glucose,

increasing sweetener.

So you've got Stevia, which is a plant basically.

And then you've got sucralose and aspartame

and all these things.

There is some evidence that I know we're both aware of,

they've been publishing quite reputable journals,

showing that they can disrupt the gut microbiome

in certain cases in particular saccharin,

the one that basically nobody uses anymore.

And it's questionable as to whether or not Stevia

has the same negative effects, et cetera.

That's not what this is about,

but in terms of the sensation of,

or the perception of sweet taste,

is that itself a possible detriment

to these pro-longevity, forgive me for using the term,

the pathways.

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, there may be small effects.

I don't think they're worth worrying about.

Joe Rogan laughed at me 'cause I was drinking a diet coke

during the first interview I did with them.

I will drink diet coke, I've read the scientific literature.

And again, it's this 5% thing

that I think is blowing 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 10 out of 10 bad for you.

A diet coke might be a one.

And if I'm, which am I going to do?

I could have a 10 or a one or go without in my life.

I'll do the one on occasion.

I try to avoid them because I don't like the ones as much.

But you can't say that sucralose

is equivalent to drinking a sugary soda.

There's just no comparison.

And I think suc, what is it?

Stevia, I do use Stevia whenever I can,

because 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 it's the media trying

to give equal weight to stories as you know as a scientist.

It can be frustrating when something's a 10

and something's a one, and they're equated.

- How do I say this respectfully?

I think if science journalists were required

to post their credentials alongside their name, [chuckles]

then people would take the articles into,

with additional grain of salt, right?

I mean, in other words,

that I think that the science media

is mainly generated around two 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.

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.

- Well, 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.

So iron is a pro-senescent metal.

And so what I think

is that if you're taking excess iron as a supplement,

you're probably accelerating your aging process.

The other thing that I found really interesting

is I've looked at hundreds of thousands

of people's metabolism and their blood biomarkers.

I was one of the first people

in InsideTracker as a board member,

and I'm still their 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 are 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

'cause a lot of my best friends are MDs

and I work with them at Harvard Medical School.

The issue though, is that with MD training,

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 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 worked on about every six months

frankly, since I was in college.

I just got, I like data

and I got interested in supplementation and exercise

'cause 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, et cetera.

How do you make sense of the data?

I mean, what InsideTracker is doing aside,

how do you personally make sense of the data

in ways that might differ from the way

that a standard MD might look at one of these charts?

Because the standard practice is to say,

is it red, yellow, or green, right?

Is it basically too high or too low?

Is it somewhere close to the margins or are you okay?

Are you in these ranges?

Are there any things that you pay attention to

that you think are particularly interesting

for people to just take note of?

I mean, 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, well, 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 if you can have a decade or more of data,

it's super important, informative,

as you know, well know, as you know.

So the physician, interestingly,

my physician, let's take him as an example.

So he sees me, he says, "How are 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 his physician.

I imagine that the 12-year-old David Sinclair

says to a physician,

"Listen, let's have a different discussion."

Is that how it works? - It is.

He finds me pretty annoying as does my dentist.

But so I say, so hang on, I've got this data.

I've got the InsideTracker data.

So I pull that up on the screen,

and I'm showing him the changes in my cholesterol

and my CRP, which is inflammatory marker as you know.

And we're going through it,

and you can see things change over time,

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, I love this data.

But I'm not allowed to get this because of course,

the insurance companies won't pay for it.

So again, you can pay out of pocket.

It's not super expensive.

I would say, if you save a bit of money on a coffee,

you can afford this kind of stuff.

But the main point is that doctors do like this data.

It's just that they're unable to spend the money

on every one of their patients to get it.

- Is there a code word

that someone can use with their physician

that will trigger a comprehensive blood test?

I keep trying to figure out what's the code

that one needs to ask or tell their doctor,

I'm feeling blank so that they get a full blood panel.

- Well.

- Do you have to be hemorrhaging from the gut or something?

- Well, I usually use the WTH method,

which is what the hell?

And then he says, "Okay, we'll do it."

- 'Cause I think a lot of people out there are thinking,

look, I'd love to have blood work repeatedly over time,

but that's hard to get for financial reasons,

but also a lot of people just don't know how

to approach the conversation.

And this is one of the things

that I hope that we can educate people on,

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 increasing number of companies

that offer these tests, InsideTracker is 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.

- Yep, and we must.

And there's an email

that is something like 555,

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 business hours

and I'll pick up outside of those hours.

- But there was the 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.

'Cause 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.

- Oh, it was originally picked up

as something that was associated with heart disease

in the Framingham study, I believe.

It is the best marker for cardiovascular inflammation

and is 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,

and there are also drugs that can do it.

Anti-inflammatories can do it as well.

But CRP is, it's actually, hCRP,

there's a high sensitive hCRP, your doctor will know.

Get one of those readings.

'Cause if you've got 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 longterm,

and can predict a future heart attack.

- On the lines of heart attack.

I want your thoughts on cholesterol

and serum cholesterol and dietary cholesterol.

I cannot, 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 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 very 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

and 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 get through the politics.

I know a fair bit about cholesterol

'cause 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 are bad.

It's associated with Alzheimer's disease.

I've been taking a statins since I was 29.

And that's 'cause 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.

And I said, what?

You want me to have a heart attack

before you give me something, give it to me now.

So 29, I'd been on a satin,

and my cholesterol was way up in beyond 300,

which is a massive mess up.

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.

You can check on my InsideTracker,

but so my ratio of HDL to LDL,

which you want to be less than five, is now two,

and the LDL is below a hundred, so it's all good.

And I've measured my cardiovascular health with an MRI.

I've 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 forgo 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 were some interesting new ones.

There's one called the PCSK9 inhibitor,

which is, I think fortnightly, 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 prolongevity.

And there were some people

that I was just talking to 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.

I mean, I have been to love butter.

I love red meat.

I realized 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 going on with the liver?

Why are anorexics?

Why is there a certain cholesterol so high

when they're eating nothing?

- Well, there've been in a number of papers over the years

that have been ignored.

And our friend, Peter Attia,

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 'cause I'd been avoiding eggs

and butter for most of my life and I didn't have to.

So I have eggs-

- Plenty of time, or at least in your case.

- Yeah, yeah.

So that's the thing.

You can eat these foods that were ones banned

because it's very difficult

to take cholesterol up into the body from the gut.

And most of it's 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, eat a lot of grains and fruits

and this kind of thing, 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 caveat

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 your diet.

And I'm somebody who enjoys meat, I like it.

But so I'm by no means, a vegan at 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 excites you with respect to? [chuckles]

I mean, vegetables are delicious too, but what is it?

Is it something great about plants

or is it something bad about when I think of meat,

I guess the biologist in me thinks amino acids, right?

I don't think top sirloin, I think amino acids.

And I think top sirloin as I'm eating it,

but really what they are, are amino acids,

including leucine.

- Yeah, well, there are two good things about plants,

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 an 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 multivitamin,

I don't want to have the excess iron in my body.

So there's that high density nutrition.

So those dark leaves, if it's a spinach salad, great.

The second is that there

is what's called xenohormetic molecules in plants.

That term, xenohormesis is a term

that I came up with with my friend, Conrad.

How it's, which means stressed plants make molecules

that benefit your health.

I'll break it down.

Xeno 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 great vine that's dried out

and then 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 purifying or at least concentrating

in a light-proof bottle and keeping it out of the air,

we stabilize the xenohormetic molecule,

or 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 by stressed, I don't mean psychologically stressed.

I mean, biologically stressed.

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, I also buy the supplements

to make sure I'm getting enough of those as well.

- Which supplements mimic that?

- So resveratrol will,

there's another one called quercetin,

or quercetin, some people call it,

what you find in trace amounts in 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 kills 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 a caterpillar?

- No, but I don't worry if they've been banged up a bit.

- What's the story with antioxidants?

Are they of any value whatsoever,

because the way that you describe 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 are 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 mitohormesis,

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 overdo it.

- You don't take a multivitamin, correct?

- Right.

- I think I'm going to stop after this conversation

'cause I've always just taken one

for the kind of insurance purpose,

which is a stupid purpose.

Not actual insurance, but just thinking,

oh cap top off on my ACBD.

- Right, and I'll pee out what I don't need, right, sure.

- But that never bothered me.

The whole expensive pee thing never got.

That argument never got made because of that.

A good vitamin is not that expensive.

I just figured better safe than sorry,

but it may be that it's detrimental.

- Well, it can in the case of iron

as we discussed and the antioxidants.

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 catalyze

and superoxide dismutase, well,

they're going to be the key to longevity.

It turns out that it's largely been a failure

that giving animals and 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,

an antioxidant drink,

pomegranate juice for one is full of good stuff,

including xenohormetic 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 resveratrol

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 the lifespan

of yeast cells through this genetic pathway, the sirtuins.

And we then tested whether resveratrol,

if we change one atom

to make it not an antioxidant, guess what?

It still worked fine.

So it wasn't its anti-oxidant activity

that was extending lifespan.

It was its ability to turn on

the yeast's defenses against 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 an opportunity for me to say something

that 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 modulates a process.

I mean, if a fire alarm goes off in the building right now,

it's going to modulate our attention.

That doesn't mean that it controls our attention,

it's not mechanistically relevant.

And so I think this thing about antioxidants

is one of these cases,

it sounds like where 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

and really getting down to the guts 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?

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 their sirtuin pathway?

And I realized that there are caveats.

We can't go directly from a behavior dissertations,

but in the general theme,

what can people do, what do you do?

- Right, well, we know that 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.

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 US,

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 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.

- Sorry to interrupt you.

You do know 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-year-olds.

I can get you that information,

is really impressive studies.

Unfortunately, they didn't include a lot of information

about the lifestyle factors, et cetera.

But this idea that testosterone goes down with age,

it might be the trend,

but it's not necessarily a prerequisite.

- Right, I believe in naturally increasing

and maintaining these hormone levels

and I've been measuring them for a long time.

And I could see for me, my testosterone levels

were steadily, levels were going down.

- And then you got tenure and they went back up again.

[both chuckle]

- No, I actually became complacent.

And it was the worst.

Actually my age changed in the wrong direction after that,

'cause I was relaxed.

- Interesting.

- And not worried about the future.

But then I got serious.

And I actually, according to the InsideTracker algorithm,

got my age down from 58 to 31 in a matter of months.

So that was a big drop.

And I've been getting steadily younger

over the last 10 years,

according to that measurement, the blood test.

- What about estrogen?

Because women are different in the sense

that they do the number of eggs that they,

and the ovaries change over time, right?

Do you think that they can maintain estrogen levels

in over longer periods of time

using some of these same protocols?

- Well, yeah, I get into trouble from a certain university

when I talk about this too much.

- About estrogen?

- Just about fertility and long story.

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 in fertile,

so that's about at a year of age,

a mouse gets infertile, female mouse.

- Due to fasting or due to simply to aging?

- Due to aging, due to aging.

The fasting, it's not extreme fast,

it's just less calories.

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 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.

They became fertile again,

which goes against biology, the 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 mouseopause

as we call it.

So that's a whole new paradigm in biology as well.

- That's super interesting.

Sorry to interrupt you,

but I'm reminded by a set of studies

that were done by your former colleagues

'cause they're no longer there,

David Hubel and Torsten Wiesel,

my scientific 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 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, et cetera.

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 deprive 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 yes,

there is 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 him mention it,

but to me,

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 things like the sirtuins.

- Right, and the sirtuins do control memory

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 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,

or 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 will wonder,

why didn't we work on this earlier?

The future of humanity

is more like us walking around like Deadpool.

We'll 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,

the 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 the age of those cells,

and telling them how to read the genes correctly again,

reversing the age of that epigenome.

And when you do that, the cells,

the brain, for instance, the skin.

We did the optic nerve.

- 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 have 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, et cetera,

could essentially reverse the age of neurons in the eye

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 boom to the field.

Where does that stand now in terms of human clinical trials?

I mean, how do, what are you envisioning

in terms of the trajectory of those data

from mice into human someday?

- Right, well, to get to the point immediately,

we're going to be testing the treatment on monkeys,

just for safety reasons.

And then the first patient should be done sometime in 2022,

early 2023, and we're going to try to recover blindness.

- This involves making an injection

of a virus into the eye, right?

Right now, there's no way that I am aware of

to manipulate these transcription factors

through a pill or some other?

- And that's why, we working on in my lab

at Harvard right now.

So it will be-

- It will base moderation of-

- Well you pop a pill in the whole body

gets rejuvenated by 20 years.

That's what we're aiming for.

Now we do it with gene therapy in the eye and other places.

So in the IES, 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 these-

- And it's one injection.

- It's one.

- I should mention injections into the eye

obviously nobody should do this

outside of a ophthalmology clinic.

And there definitely by an ophthalmologist but,

the injections into the eye are 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

as completely painless to the person-

- Oh you don't feel it.

It's a tiny, tiny needle too.

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 does decline,

we'll 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.

- And thinking about the body

and what's going on under the head 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 are any tumors growing anywhere.

I mean, it's not that hard to look into the body.

I mean that the technology exists.

why hasn't anybody created an at home

or pseudo at home solution, like a clinic where you can go

and pay 50 bucks or a hundred bucks

and see if you have any tumors growing anymore.

- Yeah, it's still expensive.

You can get your doctor to try to get you in,

there's some companies that offer blood tests

that look at circulating DNA,

that'll measure it.

We're getting there.

It's still probably five to 10 years away

from being really cheap.

You can do things like a colon cancer test at home.

I think it's a hundred and something dollars.

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.

- Mhmh, 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 who's Australian tells me that

it's free for Australians.

They get this test routinely.

- Mhmh, interesting.

I want to return to the topic that I took us away from.

So I apologize, which is behavioral protocols.

Do you regularly do the cold shower thing?

Ice baths, cold water swims, are you into that whole biz?

[David chuckles]

- Well, you do know that I've done it at least once

'cause we did it together.

- That's right.

Not the same bath, just to be very clear,

same sauna, different ice baths,

[David chuckles]

the idea of Sinclair

and Huberman taking an ice bath together it's a,

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.

- [Andrew] Yeah.

I don't do them regularly.

I do try to sleep cool.

I sleep better anyway.

I try to dress without a lot of warm clothes.

I'm here in a T-shirt and it's middle of summer,

but in winter, I'll try to wear a T-shirt too.

- So you're challenging your system to thermoregulate?

- Right, right.

I've got this,

hypothesis with Ray Cronise.

We published what's called The Metabolic Winter Hypothesis,

which is, few tens of thousands of years ago,

we were either hungry or cold or 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 cold 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

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 to ask earlier

that obesity reduces NAD levels and accelerates aging.

How?

I mean, okay.

So again, this is the,

the scientist in the us,

so 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 it, you know,

is 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 there are really interesting data now

that fat actually gets neural innervation.

I mean,

it's not just a,

it's not just stored fuel.

It's stored fuel,

that's acting as an endocrine organ, essentially.

So,

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 lot of problems that,

include a lot of senescent cells in fat,

if you stain old fat for senescent cells, it lights up.

- Mhmh.

And when you kill off those cells,

at least in mice, and maybe in humans,

it looks like the fat is less toxic to the body.

'Cause those senescent cells in their fat are secreting

these inflammatory molecules

that will accelerate aging as we now know.

We talk about the sirtuins in NAD.

So if we,

if we just look philosophically,

at why this would be the sirtuins only,

like to come on or get activated when the body needs,

is on the right adversity.

And if a cell is surrounded by fat or contains a lot of fat,

it's going to think times a good,

it 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.

- And is there any evidence that leptin,

this hormone from fat can actually,

interact with the sirtuin pathway?

- I don't recall seeing that-

- Maybe I could do a sabbatical in your lab

and that'd be a fun one.

- Definitely-

- Because leptin during development is what triggers,

the permission for the hypothalamus to enter puberty, right?

- Yeah.