2021-12-27 - Interview Dr. David Sinclair - Huberman Lab Podcast - The Biology of Slowing & Reversing Aging

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    • https://www.youtube.com/watch?v=n9IxomBusuw&ab_channel=AndrewHuberman
    • Interviewer: Andrew Huberman
    • Length: 2:10:42
    • In this interview, we discuss the cellular and molecular mechanisms of aging and what we all can do to slow or reverse the aging process. We discuss fasting and supplementation with resveratrol, NAD, metformin, and NMN. We also discuss the use of caffeine, exercise, cold exposure, and why excessive iron load is bad for us. We discuss food choices for offsetting aging and promoting autophagy (clearance of dead cells). And we discuss the key blood markers everyone should monitor to determine your biological versus chronological age. We also discuss the future of longevity research and technology. This episode includes lots of basic science and specific, actionable protocols, right down to the details of what to do and when. By the end, you will have in-depth knowledge of the biology of aging and how to offset it.

    Transcript

    - 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.

    Our first sponsor is ROKA.

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    I've spent a lifetime

    working on the visual system.

    And I can tell you that the visual system

    has to contend with a number

    of different challenges,

    such as when you move

    from a bright area outside

    to an area where there are shadows,

    you have to adjust a number of

    things in your visual system

    so that you can still see things clearly.

    One problem with a lot of

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    Today's episode is also

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    InsideTracker is a

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    I've long been a believer in

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    Magic Spoon is a zero sugar, grain-free,

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    Now I don't follow a

    strictly ketogenic diet.

    What works best for me is to eat according

    to my desire to be alert

    at certain times of day

    and to be sleepy at other times of day.

    So for me, that means

    fasting until about 11:00 AM

    or 12 noon most days.

    And then my lunch is typically

    a low carb, ketoish lunch,

    maybe a small piece of grass-fed meat,

    some salad, something of that sort.

    And then in the afternoon,

    I might have a snack

    that's also ketoish.

    And then at night is when

    I eat my carbohydrates,

    which for me helps me with

    the transition to sleep

    and allows me to get great deep sleep.

    That's what works for me.

    What that means is in the

    afternoon I'm craving a snack.

    And the snack for me is Magic Spoon.

    What I do lately is I put

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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.

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