2022-01-26 - Podcast Dr. David Sinclair - NMN, NR, Resveratrol, Metformin & Other Longevity Molecules
- https://www.youtube.com/watch?v=bRWT7hVgwuM&ab_channel=DavidSinclair
- In this week’s episode, Dr. David Sinclair and co-host Matthew LaPlante zero in on drugs and supplements that have been reported to combat aspects of aging. They share the latest experimental and clinical data for NAD boosters (these being NR, NMN, NAD IV drips and shots), resveratrol, fisetin, quercetin, rapamycin, spermidine, metformin, and berberine. Given the abundance of data available, a special focus is placed on the NAD precursors nicotinamide riboside and nicotinamide mononucleotide. Known mechanisms, limitations, and/or side effects associated with these molecules are additionally highlighted.
Transcript
- Welcome to the Lifespan podcast,
where we discuss the science of aging
and how to be healthier
at any stage of life.
I'm David Sinclair.
I'm a professor at Harvard Medical School
and Co-director of the Paul F. Glenn
Center for Aging Research.
And I'm joined today
by my lovely co-author
and cohost, Matthew LaPlante.
- Hey, how are we doing?
- [David] Hey, welcome.
- Feeling good today.
- [Matthew] Back at it again.
- We are.
We're here today to talk about
how to live longer and better.
- As part of this podcast series,
this deep dive into things that you can do
to slow, stop, and reverse aging.
- That is true and today is going
to be a really interesting one.
- This is going to be
the one that everybody,
I mean, this is the one that
everybody's been begging for.
- That is true.
We've been monitoring
the responses to tweets
and Instagram posts, and most of them are,
David, just tell us what to take.
- [Matthew] The nice ones.
- Yeah.
- Some of those aren't very nice either,
but yeah, please, please, please.
Should I take NR? Should I take NMN?
What should I do with Metformin?
We're going to be talking
about all of that today.
- We are, and our research team has
been spending weeks on
this, and if you can't see,
I'm actually sitting in front
of many pages of notes here.
We're going to go deep dive into what
is fact and what is not fact.
What is known, what is not known,
because there's so much
misinformation out there,
especially with supplements.
- Yeah.
We do need to say we usually take a moment
to thank our sponsors, we're
going to do that of course,
but we also have to take a moment to say
we are not medical doctors.
We are not medical doctors.
We are not medical doctors.
- What he said. I'm a
PhD, I'm a researcher.
I can read the literature.
I've been doing it for the last 30 years.
I distill that for everybody.
But of course,
if you want to try supplement
or even change your diet radically,
please talk to your physician
before you change anything.
Because some of the things
we'll talk about today
can affect your body in,
hopefully, many good ways,
but sometimes can be dangerous
depending on the person.
And everybody's different.
- And what we want to do is give people
the ability to have a more intelligent
and informed conversation
with their physician.
- Exactly.
- Okay, with that out of the way,
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Okay, Matt, let's dive in.
There's a lot to get through today
and I know everyone's waiting to hear
what we have to say today.
- In the last episode, David,
we talked about adversity mimetics.
These are the things that we
can do in our modern lives
to mirror the sorts of stresses
we faced across our evolutionary history.
But even if you're engaged
in doing these things
like we've talked about already,
fasting and getting lots of exercise,
getting out of your comfort zone,
our modern lives are still
designed around comfort
and sedentariness, is that a word?
- Sedentary lifestyles?
- [Matthew] Sedentary lifestyles.
And that's not to mention the fact
that even before modern
times we aged, right?
So if we're going to combat aging
we may need an additional boost.
Do you believe we may
need an additional boost?
- Well I do and I've been doing this
since my early thirties.
We'll talk about my program
at the end of this episode,
but really what we want to do today
is to talk about some
of the major supplements
and medicines that are
thought and have the greatest
scientific evidence to be able to give you
wellness now as well as
long-term health in the future.
- Supplements and medicines,
drugs and supplements,
molecules and drugs.
There are a lot of different terms
that we're probably going to throw around
and we're going to use
them fairly synonymously.
But in fairness, let's define
drug versus supplement, at least.
- Right, first of all, most
drugs are chemicals, okay?
But some are naturally occurring
and some are freely available
over the counter, OTC.
And that's because they've
been in our food supply before
and the FDA doesn't regulate them.
They fall under what's called generally
recognized as safe, or GRAS.
And that's why you can
pick up whole variety
of molecules from the plant world,
'cause they're already in our food supply.
Therefore the government thinks,
well, they're probably okay,
even if they're a thousand times more
concentrated than what you're eating.
- Which may or may not be the case, right?
- Right, and so that's why
you always have to be careful.
You have to monitor yourself,
like I have been with my blood work
for many years to make sure that
you're not hurting parts of your body.
Your liver particularly could be sensitive
to some of these molecules,
even if they are available freely
at the pharmacy or the vitamin shop.
A different story about drugs.
Drugs are regulated
molecules because they have
the chance to actually cause damage.
And many drugs actually do
have serious side effects
that need to be carefully monitored
and discussed with the doctor.
Even those that are very safe.
Like we'll talk about Metformin.
These are regulated by the government
because they are not in the food supply.
There are artificial molecules that
could theoretically do damage.
- And there are literally
thousands of drugs
and supplements that someone somewhere
will tell you we'll help you
with health spans and lifespans.
We're not going to talk about
thousands of drugs and supplements today.
- No, maybe in future
episodes we'll come back,
but we want to hit the high points today.
- And so that's why today we're going
to move through some of the most popular
and some of the most promising.
These are things that most
people can have access to,
or find a physician who,
if the need exists, will prescribe.
- Right, and I get emails
and I get all sorts of texts
every day, DMs, what should I take?
What about this? What about that?
What's the dose. When should I take it?
What should I take it with?
Is it okay to take this
drug with exercise or not?
That's what we're going to cover today.
Your most pressing questions
answered here today.
- And so we're going to
talk about NAD boosters.
We're going to talk about Metformin,
berberine, rapamycin,
spermidine, resveratrol,
fisetin and quercetin,
and probably a few others.
But those were sort of
the highlight points.
If you're only interested in one of these,
or if you watch this whole
episode need a reminder,
the show notes are going to
be timestamped so that you can
immediately go to berberine
and find it and click on it.
- That's right, included in the show notes
are the scientific references that
we now have in front of us
that we're going to talk about
so that people can do a deep dive,
even deeper than what we're
going to do here today.
- There's one more thing that we'll link
to in the show notes
that's on your website
that I think is valuable
for people to know about.
You're involved in a lot
of different companies.
You're an entrepreneur,
you're a researcher.
You have I don't know how many patents.
There are plenty of people who would say,
oh, this guy's just trying to sell stuff.
If they suspect that you might
have a conflict of interest,
they can go and look at your disclosures.
- I do disclose everything that I do.
My lab has a website. You
can Google Sinclair Lab.
And if you click through my bio,
there's a link to all the work
that I do outside of Harvard,
as well as what we do
at Harvard, of course,
but importantly, I've never
sold any supplement in my life.
- And that's not because
you're a bad salesman.
It's because you haven't
actually tried to sell.
I mean, there's a difference between
having not sold a
supplement and having tried
to sell a supplement and
not sold a supplement.
- Right, I've actively kept myself away
from the supplement industry
because I want to be able
to talk about things without any bias.
- Not for a lack of opportunity though,
there's plenty of people who would
love to put your face on a package.
- Well, and they do,
without my permission.
You can see my face on the internet.
But if you see that, know that
it's not with my permission
and I do actively try to stop that.
- To get into this let's
use some of the same framing
that we've used for
the other conversation.
And that's these three longevity pathways,
three longevity genes that
we've been talking about.
sirtuins, AMPK, and mTOR.
Different drugs and
supplements are thought
to work on these different
pathways in different ways.
And we'll sort of like categorize them
in those three buckets today.
- Exactly, and the thing to also remember
is that these three survival
pathways we've talked about,
and in episode one we talked a lot about,
are responding to our environment.
Whether you're exercising
or fasting they'll turn on,
but also appreciate that
they talk to each other
and some drugs or
supplements will activate
one of these and talk to the other two.
So it's a network and we're still
trying to figure out exactly
what the optimal combination
for each individual might be.
Whether to tweak it with this molecule
and then exercise here
and then fast that day.
We don't know all the answers,
but we are going to present the cutting
edge science here today.
- And I think it's been
really interesting.
I've been working with you for, what,
like about four years now.
And in that time a lot of the molecules
that we knew to be working
on one of these pathways,
there's been further
research that has said,
oh, that's not just an AMPK effect.
There's also an mTOR connection there.
- Well they definitely talk to each other.
Because if you're low on immuno acids
and it'll turn on the
mTOR protection pathway,
that will then tell the other survival
pathways to do their thing too.
It's like the Pentagon where
there's centrally coordinated defenses
and basically what we're trying to do
is to make prank phone
call to the Pentagon to say
there's an emergency and
they'll send out the troops
in various ways and protect the body,
even though there's no immediate threat.
- I like that analogy. That's fun.
Let's talk about the class of molecules
that you've worked most
extensively on in your lab.
These are known as NAD boosters.
Talk a little bit about why
NAD is important in our bodies.
It's really important, if it disappears,
we're screwed, right?
- Well, we'd be dead in 30 seconds.
We need it for energy
but it was discovered
about 100 years ago by Germans
who were looking at extracts in yeast.
And there was this component called NAD
that was necessary for chemical reactions.
- We didn't say what
that stands for, that's?
- So NAD stands for nicotinamide,
which is vitamin B3,
and adenine dinucleotide. This
is a sugar and a phosphate.
The important part about
it is that our cells
use NAD to transfer hydrogen atoms
between proteins and even DNA.
That is really important
for life and without it
we can't make chemical energy,
which is in the form of ATP,
which we'll talk about later
because that's important for Metformin.
NAD is found in abundance.
There's many grams of it in the body.
It's probably, with the exception of ATP,
the most abundant molecule
we have in the body.
It helps us make energy but it
also has this other function
that's just as important
that we worked on and just
co-discovered in the 2000s.
It activates the sirtuins
and the sirtuins are these
defensive enzymes that, like the Pentagon,
send out the troops.
The problem is as we get
older we make less NAD
and we also destroy it more for reasons
that we don't fully understand,
but it leads to a decline in our ability
to fight off aging and the
diseases that it causes.
- And this is because NAD
is a sensor for adversity.
- It is, if you exercise, it's known,
and fast, it's known to raise NAD levels.
But even if you exercise and
have the healthiest diet,
you're still going to have
lower NAD levels by the time,
you know, you're in the
latter half of your life.
So that's why these
supplements are thought to help
because they'll boost up
those older levels of NAD
to where they were when you were young.
- Okay. So let's talk about
the first NAD booster.
Probably the most well-known,
it's definitely the most well
studied of the NAD boosters,
and probably the most
taken used. That's NR.
- Which stands for nicotinamide riboside.
So that's the vitamin B3 plus the sugar.
Without the N part, which is a phosphate,
we'll get to the phosphate,
that's important later.
It may make a difference,
but NR has been taken over the counter
or through websites for, what, since 2014,
either solely just as a capsule
or there's some companies that sell it
in combination with other molecules.
- And because it's been
pretty well studied in humans,
there've been plenty of human studies,
at least in the short term that show
little to no side effects.
This is a pretty safe molecule.
- That's for sure.
We know that if you
take it as a supplement
to swallow the pill, either 250 milligrams
per day or a gram, there's
no apparent negative side
effects, and in fact, you will raise
NAD levels in blood tests.
- So I think this is an
important distinction to make,
though, like there's a difference between
safe and effective, right?
Just because we say something as safe,
doesn't mean it's going to work enough.
And in fact sometimes things
that are the most safe
aren't going to work at all.
That's why they're so safe is
they don't have any effect.
But we do know that NR is
largely safe, you know,
millions of people
around the world take it.
NRs have been well studied
in animals as well.
And let's start with that
because we actually know more
about what NR does in
the bodies of animals
than we do in the bodies of humans.
- Well let's start with
yeast. Go even further back.
- Okay, yeah.
- So that's where it was first discovered.
NR was a newly discovered
molecule back in the early 2000s.
It's found a little bit in
milk and other food selves.
And if it was fed to yeast,
they lived longer by turning
on the yeast sirtuin pathway.
- Okay. How much longer
were the yeast living?
- Generally yeast live about 30% longer
when you give them these molecules,
similar to choleric restriction.
And that's what this was doing,
mimicking choleric restriction,
'cause both activate the sirtuins
and give increased genome stability
and epigenome stability
that lengthens their life.
- And those kinds of findings
make you really interested
because you're really interested
the sirtuin activation.
And so you've been part
of a group of scientists
that have been looking at this.
- Yeah, one of the first
things that we discovered,
this is now, we're talking
2002, 2003 in my lab,
is that there's an NAD
synthesis gene called PNC1.
In our body it's called NAMPT.
And it gets activated
by these mild stressors.
In a yeast cell it's low
salt, it's low sugar, heat.
And that turns on the synthesis of NAD
and we found that extended lifespan.
And then a few years later it was shown
you can mimic this effect with this NR.
- How does the NR turn into NAD?
- So NR has to go through
an intermediate molecule.
Let's start with the mouth.
You swallow your NR,
it'll go into the gut.
Some of it will be metabolized
by the gut bacteria,
but most of it will go
into the bloodstream
and then flow around and then get taken up
into your muscle, into
your brain and other cells,
by transport that's called ENTs.
And there it's converted into
NMN by what are called NRKs.
And then you add the phosphate
and you've got this thing, NMN.
What's NMN? Nicotinamide mononucleotide.
And then the cell puts two of
those together to make NAD.
- And when we do this
in laboratory animals,
you mentioned in yeast
it extends life by 30%.
What have we seen in mice,
which are a little closer
to you and I than yeast is?
- Yeah, it's going back
a number of years ago.
It was found that NR, when given to mice,
extends their lifespan by about 9%.
But it was given to them late
in life at about 700 days,
which is a pretty old mouse,
that'd be like a 70 year old
human, but it still worked.
But they're also in
improvements in health,
they had more mitochondria,
which is the energy.
They had more athleticism,
less inflammation.
And so that was the first
real study that said, okay,
maybe supplementing with these molecules
like NR or NMN might have some long-term
health benefits as well in humans.
- Among the other health benefits
that have been seen by researchers
who have given NR to animals
and lab enhanced oxidative metabolism.
Let's talk about that.
- So they burn more fat, they get thinner.
And that also means that
they're burning more oxygen
and that's thought to be really good
at staving off diabetes,
type two diabetes,
as well as improving lifespan.
- Let's carry this now
into the human studies
because what we don't have for reasons
that maybe are obvious, but
I'm going to state it any way,
which is that humans
live a very long life.
And it's really hard to put humans
into a control group and a test group
across a very long time,
then control for every
variable that's possible,
is longitudinal studies
that show increases
in lifespan as a result of taking NR.
But we do have studies that have sought
to show similar health benefits
to what we've seen in rodents.
- Somewhat. I would say, NR,
there've been a few
positive results. Not a lot.
Before we'd get to that I think
it's worth talking about why
can't we just take vitamin B3,
which is a precursor to NR.
You can but it doesn't raise NAD levels
anywhere near the level that NR does.
NR doesn't seem to be as effective as NMN.
So the closer you get to NAD
with your molecule, the better it seems.
And that's probably because you need
to bring in other components.
So if you just take vitamin B3,
you need a sugar and a phosphate.
If you just take NR,
you need the phosphate.
Phosphate is pretty rare in the body.
It's in your bones, it's in your DNA.
And maybe when you take
NR one of the issues
is that you need to find a phosphate
head on there before it becomes active.
- Okay, back to the human studies on NR.
We have sought to see,
by we I mean the research community,
I don't mean necessarily you and me,
we've sought to see the
same sorts of effects
that have been seen in
models, organism studies.
Sometimes that's happened.
Sometimes it's not.
Is that fair to say?
- That's very fair to say.
With NR there've been a handful of studies
in humans showing that low
dose, 250 milligrams per day,
up to a pretty large dose, a gram a day,
does raise NAD levels, but
it takes about 9 to 10 days
to get to those peak levels.
What we've also seen
is, or others have seen,
is lower inflammation as
well as some other markers
such as minor changes in body composition.
But these other things
which are lower blood sugar,
improvements in insulin
sensitivity, increased mitochondria,
those haven't been born out just yet
in these short term studies with NR.
- Sorry, so these are the
things that were present
in the mice who also lived longer.
- Right, yeah.
Now it could be that you need a longer
term exposure of these people.
These have been fairly short-term studies.
Or that humans are not the same as mice.
- So would you say, I mean,
if somebody tells you, oh, David,
I've been taking NR for so many times,
you're not rolling your eyes,
but you're not convinced at this point.
The jury's still out.
- Well, it depends what you're asking.
If it's to lower inflammation,
yeah, it probably works.
There's also a study that
was put out by a group
that combined NR with [indistinct],
which is a resveratrol-like molecule,
We'll talk about resveratrol next,
that found that in ALS
patients, Lou Gehrig's disease,
there was an improvement
in their daily function.
So that is somewhat promising.
I think that of course
we need more studies.
That's what we really need here to be able
to make any sort of conclusion
about what the long-term effects
of taking this supplement are.
- It's fair to say that in the sirtuin
activated compound research community,
there's kind of team NR
and then there's team NMN.
Your lab really focuses on NMN
and I think if people were
sort of like following
what you said earlier about
how NR turns into NAD,
they might go, oh,
well, NR turns into NMN,
NMN turns into NAD, so why don't we just
take NMN to begin with anyway.
And you had mentioned earlier phosphate,
and that's an important
component of this question.
- Well, it is.
NR is more popular because
it's cheaper to make.
It doesn't have that phosphate
which can be expensive
to put on the molecule through chemistry.
And that's why most people
started using NR first
in humans and in mouse experiments.
I didn't have a horse in the
race. I didn't care which one.
In fact, I'd prefer if
both worked according to,
you know, my theories,
but what we found through
empirical studies, basically,
we're looking at which ones
work better, my lab and others,
including Matt [indistinct],
who's at Wash U,
who treated a mitochondrial disorder
and we were treating
regular mice on treadmills.
We found that NMN just worked
better at the same dose.
We don't actually
understand why it could be
that this phosphate addition
is one of the reasons,
but, you know, just based on observations
in our hands and in others,
NMN works better than NR.
- When we supplement with NMN,
when NMN is given to organisms
in the lab, what's happening?
- Well, it's a little different,
there's been an argument in the literature
that NMN doesn't get into cells.
And similarly, NAD is
really a big molecule
because it's got multiple components.
And that also has a real
struggle to get it into cells.
Neurons take it up but other cells
typically need to break it down
into its various components
and then re-uptake it.
And that's important because some people
actually are giving themselves
NAD through the IV route.
When it comes to NMN what happens
is it was recently discovered
by Shin Imai at Wash U,
his team discovered that
there's a specific transporter
that takes NMN out of the
liquid outside the cells
inside the cell and its name is SLC128A.
Still debated, a lot of
things to figure out.
But I think it's just best to say, okay,
we know what's happening
when you give it to animals,
we are starting to learn
what happens to people.
We of course want to
understand how it's working,
but the fact that it does work
is the most important point.
- So when it comes to NMN,
there's been a number of
animals studies showing,
for instance, similar to
NR, restores NAD levels,
it enhances insulin sensitivity.
One of the things that
was surprising to me
is that we don't have a study that shows
NMNs effect across analysis
entire lifespan yet.
- Well, we have half a life span.
Shin Imai showed that it
actually was pretty good
at slowing down the effects of aging,
but he stopped the experiment
because he ran out of NMN.
It used to be rare stuff.
Now you can buy it.
But we took up the challenge
and we've been doing these
studies for the last few years in my lab.
Now, preliminarily, these
mice have less frailty.
We've reported that out in
the scientific community.
They seem to be younger,
having better activity,
better mitochondrial
function. They run further.
The lifespan looks promising.
We've done it once and
they do live longer on NMN.
The doses are out 400mgs per kg.
- How much longer?
- At this point by recollections,
about 10 to 15%, but
particularly strong in females.
- Okay, so not particularly, like,
wholly different than what we saw
in the NR cases with the mice.
- Right, a little bit better than that,
but certainly those mice are healthier
and more active and are more youthful.
- And you said it was more
pronounced in the females,
or at least according to
the first phase of this
it's more pronounced in the females.
- Right, well we had fewer females
so we have to repeat that.
So we've now got a larger cohort of mice.
We're repeating the whole
thing. We'll see how it goes.
But right now with the small
number of females, yeah.
They did do better than the male.
- And even though mice
live pretty short lives,
what we have to understand here
is that there's still live
two, three years on average.
Right, and so in order to
see lifespan extension,
especially if they live much longer,
it takes some time to do these studies.
- Yeah, it's quite painful actually,
because you think about this,
an average experiment takes three years
and then you have to repeat
it. So that's now six years.
Then to analyze the data and publish it
is another three or four.
That's a decades worth of
work for one experiment.
And, you know, your career only goes
for about five of those times.
So, five experiments?
- Well, that's how careers used to go.
But we're going to change that, right?
- We're going to live a lot longer.
We run things in parallel
as well. That's important.
But we can also mimic
things, not just in animals,
but growing tissues in the dish
will be the subject of a later episode.
- So, so far what I'm
hearing is in animals,
NR and NMN both have some
similar effects, right?
Lengthening lifespan, restoring
mitochondrial activity,
restoring NAD levels,
enhancing insulin sensitivity.
But in NR the human studies haven't always
confirmed that that's the exact
same thing that's happening in humans.
What are we seeing in the
human studies for NMN?
- I know a fair bit about the effect
of NAD boosters in humans because
I'm helping a group that is actually
doing clinical trials at
Harvard Medical School
and they've been giving a
molecule that's similar to NMN
to subjects for many years now.
First of all, importantly,
there's been no evidence of
any negative side effects.
That's important.
We're about to learn whether
it actually does anything
that's similar to the mice.
We don't have results in
yet, but hopefully by 2022,
we'll actually know if
people have more energy,
more mitochondrial
function, better blood flow,
more endurance, which is
what we saw in those mice.
- There's been a little bit less
human research on NMN then in NR,
but we're starting to see just
in the last couple of years,
especially sort of a flood of studies
being published, early
results, for instance,
from Yoshino et al. in
2021 showed increase
insulin stimulated glucose disposal.
We talked about this a little
bit when this study came out,
you were pretty excited
about it. Tell me why.
- It's one of the real first proofs
that NMN does something in humans
the way it works in mice.
So this was a 10 week study.
It's well done, it's
randomized, placebo controlled.
It was 250 milligrams, which
is a relatively low dose.
Remember, I'm taking
in my clinical trials,
a gram and two grams,
this is 250 milligrams.
Nevertheless, it improved what you said,
insulin stimulated glucose disposal.
That's basically insulin sensitivity.
And that's a hallmark of longevity.
Keeping the glucose
out of the bloodstream,
keeping it low levels is
a hallmark of wellness
and ultimately longer life.
So that's the beginning but we
have a lot more to figure out.
We need to figure out if
that increased endurance
that we see in my lab with NMN
treated mice is true for humans.
We also want to note,
are organs protected?
Other labs, not mine,
but other labs have shown that NMN
protects the organs when they're damaged.
Kidney and heart, the two main ones.
Even increased wound healing.
I'd love to know if NMN
does that in humans.
That'd be a big deal.
Kidney injury is huge.
And particularly, I don't
know if you know this,
but most surgeries on the heart end up
damaging the kidneys and there's not
much you can do about it.
So ultimately we've seen a
glimpse with Yoshino et al.
My studies that I'm involved
with at Harvard Medical School
are looking promising,
we'll know more next year,
but yeah, there's a lot more in the works.
And there are other NAD boosting molecules
that have been made that
are even better than NMN.
So-called NCEs called,
new chemical entities.
And those I'm aware of
probably in the next year
will go into the first human study.
- I mean, that can be a whole episode
of this podcast in and of itself, yeah.
- We should do it.
- Yeah, okay.
Why don't we just give NAD directly?
We're talking about like NAD boosters.
NR creates NMN, NMN creates
NAD, that boosts NAD.
Or NMN boosts NAD, but
it all gets us to NAD.
So why don't we just, you know,
set up the drip line and get it going?
- Well, we don't, but others do.
There's a lot of activity
going on in Florida and LA,
particularly, of having large drips,
long drips of over an hour of NAD.
- These are not in a study settings.
This is not in a research setting.
This are like people trying this out.
- Well, they're done
under medical supervision,
but I haven't yet seen a
placebo-controlled trial
that would tell us for sure
if it's just wishful thinking or not.
I don't think so given how many people
have been now treated and
there's a serious amount
of anecdotal data on this, better mood,
better energy, but you know,
you cannot conclude
anything unless you actually
have one of these
placebo-controlled trials.
I'd love to be involved if
anybody's going to do one,
I'd love to help.
But I'm asked this probably every day.
NAD IVs, do they work?
My answer has to be we don't know yet.
- What do we think they might be doing?
I mean, what are people trying them for?
- Well they're used for various things.
It's been used for many
years are to treat addiction,
whether it's drug or alcohol,
it's also used for depression,
and also increasingly for hangovers.
- Is it as good as the
Australian hangover cure
that you've given me a few times?
- Oh, the raw egg and the Vegemite?
I hope it's better than that.
- Because the truth is that doesn't work.
I just pretend it works
because it makes you happy.
- That's true and you're one
of the few people that eat my Vegemite.
But the reason that it probably works
is there's an enzyme
that detoxifies alcohol
called alcohol dehydrogenase,
and a lot of Asians are susceptible
to high levels of alcohol because
they lack a lot of this enzyme.
Alcohol dehydrogenase needs NAD.
And so what's probably
happening is when you wake up
with a hangover, you lack
NAD, your liver is depleted,
and if you take NMN or NR,
you can raise those levels back up,
get your liver working again,
and get rid of the excess alcohol.
- So you think chances
are that is actually,
it's not just like a placebo effect.
That there's a chance that, like,
it makes sense that that would work.
- I think makes sense is
the right words to use,
you know, I'm a Harvard professor.
I'm not going to say something works
unless I've seen hardcore proof.
And I hope that'll come
in the next year or so.
- Just so I'm clear on this though,
'cause it's still a little fuzzy to me.
I can understand why we
might want to use NAD.
I'm not understanding why we're
not starting, for instance,
all the research with NAD and then
moving backwards to NMN and
then moving backwards to NR.
- It all started in yeast when
I was at Harvard early 2000s.
Even in yeast if you give
them NAD it doesn't work
because it's too big, it doesn't get
taken up into the cells.
So what we want to do is back off in size.
So the next smaller
molecule behind NAD is NMN
and there we know there's
a transporter protein
that sucks it into cells and NR
is even smaller and it gets
taken up even better into cells.
And so that's the reason why it may be
that NMN is at the sweet
spot of the right size,
but also has the right components
to make just the right amount of NAD.
- It feels like a good time to talk
about bioavailability and making things
available to our body's machinery.
How do we make NR and
NMN most bioavailable?
- Just swallowing it is enough
in our studies to raise
NAD by two to three fold.
- So if you buy the, for instance,
the capsules, they're
often sold in capsules,
just swallowing. That's going to be?
- Or the powder, just drink it.
We make tablets and give it
to the patients that way,
the subjects, but there were others,
there was a sublingual version.
I have heard there's evidence that works.
I haven't yet seen it.
It makes sense that it would be
absorbed under the tongue,
or you can inject it.
- In terms of the research right now,
it doesn't seem like there's
a huge advantage one way or another?
- No, I haven't seen any
reason for saying that
you need to put it onto your
tongue versus swallow it.
What I can say for sure is that
I've seen so much data on swallowing it
that it definitely works
to raise NAD levels.
- There has been some concern
around the use of NAD boosters
when it comes to the potential that
it might stimulate cancer growth.
And obviously that's something that
we don't want to be dismissive of.
It does you no good to
be boosting your NADs
and extending your lifespan if
you're just giving yourself cancer.
What's the latest research on that
and how concerned should people be?
- Well, so most of
these studies, actually,
there's only two main studies
have been done in mice.
So here's what they are.
There was one, again, out
of Washington University
by a different group that found
that knocking down the levels of NAD
in brain tumors slowed
the growth of the tumor.
And unfortunately the news
story ended up being, oh,
NAD causes cancer, which
is not the same, right?
That's the complete opposite.
So that study, I wouldn't
put a lot of stock into,
but there is one other
study that came out in 2019
by [indistinct] and they found that NAMPT,
this NAD boosting gene,
it increases the number of senescent cells
and makes them more inflammatory,
giving out these SAS
proteins as they're called,
the senescence associated
secretory phenotype is the word,
but also there were mice
that were predisposed
to pancreatic cancer and when given NMN
they developed more precancerous
and cancerous growths
when they consumed this NMN.
Exactly how it works we're not sure,
but it might be because
it was down-regulating
a tumor suppressor gene called P53.
- And this was a subgroup of mice
that were already predisposed.
They had a gene that made them
more likely to get cancer.
- Right, but remember we fed NMN to mice,
but normal mice, not predisposed,
and if anything they lived
longer and healthier.
So it's a question whether it's this
predisposition that's the difference.
- Something to watch
for and to think about
and to work into anyone's calculations
if they're going to be considering
an NAD booster in any case.
- For sure and another reason
to consult your physician.
- Absolutely. Okay.
Now there are other NAD boosters,
sirtuin inactivating compounds.
One of the ones that you've
been really interested
in that I think a lot
of people are interested
in, probably really widely
used, is resveratrol.
You started working with resveratrol
back when you were trying to understand
sirtuin inactivation in yeast.
- Right. I was just a kid.
I was in my early thirties
and I'd just come out
of MIT with Lenny Guarente where
we'd found that up-regulating
the sirtuin gene
in yeast extends their lifespan.
But of course we can't up-regulate
genes easily in our body.
We're not going to genetically
modify ourselves anytime soon.
- Not anytime soon.
- We can but we're not going to.
IT's easier to find a safe,
natural molecule that does the same thing.
And so our goal back in
the early 2000s at Harvard
was to look for any
molecule that we could find
that was safe that would
activate the protein,
not the gene, but the protein,
it's an enzyme that controls
other proteins, remember.
And so he set up an essay that looks
for what's called Sirt-1 activation.
Sirt-1 is the first out of
seven of them in the body,
and Conrad Howards, my collaborator,
and I were using an essay in a test tube
that would fluoresce when
you had more activity.
And so we added these
chemicals, we added a dozen.
Then we added thousands and
eventually tens of thousands
to Sirt-1 and found which ones
raised the level of fluorescence.
- And you've found a bunch of them.
There were like 20 of them that did.
- We published 20. Yeah, in Nature 2003.
The one that was the best at the time,
which activated 13 fold Sirt-1
activity was resveratrol.
And there were others,
of course, [indistinct],
which are actually now used
by others for longevity.
But resveratrol got most of the attention
because it's found in red wine.
- And you've told me
this a bunch of times,
red wine stock went out the roof, right?
Like people started buying
red wine like crazy.
- 30% Sales, and they've
stayed up ever since.
And I've started drinking more
red wine as a result as well.
- The truth is though,
how much red wine would
you actually need to drink
in order to increase your
levels of resveratrol
and get an actual effect out of this?
- You know, you can't
drink enough red wine
to get the kind of doses
that are efficacious.
- You can't.
- Well you can try, but
I don't recommend it.
You'd need hundreds of
glasses of red wine a day,
which I don't recommend.
Even if your doctor says
so, not recommended.
- That's not going to extend your life.
- Probably not, no.
But what you can do is you can purify it
out of grapevines or polygonum cuspidatum,
which is an herb, a plant
mostly grown in Asia.
- When you say that, can
you just take your pen?
All right, now say that word again
and go like this when you do it.
- Polygonum cuspidatum.
- Okay. Thank you. I appreciate that.
- This is magic I think. Harry Potter?
- How much resveratrol do we
actually need to see an effect?
- There are a lot of human studies now.
The minimum that I've seen
is 250 milligrams a day.
And some people take 1000
or 2000 milligrams a day.
- This is a Sirt activator like the other
NAD boosters we've been talking about,
works a little bit
differently, but like you said,
really well studied and
for almost 20 years now.
What's happening when we put resveratrol,
let's start with the animal
studies. What do we know?
- Well, we know, first of all,
if you just give it to
them in their water supply,
it's not going to work.
You can't just swallow it and
expect it to get in easily.
- Why not?
- Well, resveratrol is the equivalent
of brick dust, it's really insoluble.
If you put it in a glass of water
it will fall to the bottom.
So what you need to do is we
found in both mice and humans,
mix it with some food.
You can use yogurt, you can
use that kind of olive oil,
that kind of oily food,
and it will dissolve.
It's hydrophobic. This is the
problem, it's scared of water.
- And this is actually why you suggested
that maybe some resveratrol studies
that have shown that it doesn't work
as well as other studies show,
those studies may have involved people
who were feeding mice resveratrol
without that additional fat.
- Yeah, that's the case.
Some of these studies didn't include food.
We found that early on in the mid-2000s
that if we gave it with a meal,
the levels in the blood went way up.
- There have been a
number of animal studies
on resveratrol going back almost 20 years.
Now we're seeing extended
replicative lifespan in yeast.
We're seeing activation
of AMPK in rodents.
What are these things telling you?
- Well, they're similar to what
we expected from the sirtuins.
They defend the body. They
raise the metabolic rate.
They protect against free radicals.
And when we see research
given to these rodents,
what the biggest surprise was
was that they were protected
against a high-fat so-called Western diet.
Those mice on resveratrol,
even though they were really obese
on this really chunky meal,
they lived as long as the lean mice
that we had as the control group.
And that was really, as far as I know,
the first study of any that
showed that you could mimic
caloric restriction with
a molecule and be fat
but live as healthy as a lean animal.
- Have those findings translated over
as we've moved resveratrol
into human studies?
- Yeah, somewhat.
Not all studies have worked,
but there are a number of them that have.
And for instance,
resveratrol has been shown
to reduce fasting
glucose and significantly
increase insulin sensitivity.
This was a study in 2019,
and then again, in 2020,
Battista and George et al.
showed that a randomized
control study of 25 individuals
ranging from 30 to 60 year
olds with a slightly high BMI
of 30 were able to lower
their cholesterol levels,
their urea levels, which is
important for kidney function,
as well as raise their
good cholesterol, the HDL.
- Well, once again,
we don't know long-term
what this is going to do
but the trajectory seems
good when we consider it
in the context of what
we've seen in animals
and what we are seeing in
these early human studies.
- Yeah I think so.
Even before I worked on resveratrol,
it was known to be an agent
that suppressed cancer.
If you put a carcinogen on the skin
of mice and then rub resveratrol on it,
a 1999 science paper
showed that those cancers
are much smaller in those treated mice.
So the anticancer activity of resveratrol
has been known before I came along.
And since then we've seen effects
on body composition, on metabolic rate,
mitochondrial boosting, glucose levels.
The list goes on,
there's probably 1000 papers now
showing at least the benefits
in animals and a dozen in humans.
Cardiovascular disease
I haven't mentioned,
but that's a big one.
May help explain the French paradox.
The French can eat high-fat foods
and with this glass or
two of red wine every day,
it helps mitigate the effects.
- I mean like, but what you've just said,
like you actually have to drink
so much red wine in
order to get this effect,
but then we're thinking maybe the French
who don't drink that much red wine,
even though they do
drink a lot of red wine,
but they don't drink that much red wine.
- There's two considerations here.
One is that drinking
red wine over 30 years
could have a cumulative effect
and a buildup in the body.
And the second is that red wine
has more than resveratrol and it has some
of these other xenohermetic polyphenols
that we talked about in earlier episodes
that could give a combination effect.
- Okay.
The two other molecules
I wanted to mention,
you mentioned them
earlier actually by name,
these were part of the group molecules
that were identified in
those early experiments
with the yeast that identified resveratrol
as a potential sirtuin
activating compound,
these are fisetin and quercetin.
And both in addition to
being serotonin activators
potentially also seemed to have
this other property to them
that is making them sort
of like a hot number now.
- Right, they are what
are called senolytic.
Kill senescent cells.
- Senescent cells.
- Are zombie-like cells.
The ones that accumulate
over time in your body
probably because their
epigenome gets screwed up.
But what they do is they shut down,
they stop dividing and they
start secreting inflammatory
factors and also factors
that cause cancer.
- Yeah, and so getting rid of those
would be presumably a good thing.
And that's what fisetin
and quercetin appear to do.
- They do in the dish and in mice
and there even some human studies now
that show that killing
off these senescent cells
in the body can improve health.
And ultimately, we think,
could extend lifespan.
- And these have been shown,
in the case of fisetin at least,
to extend lifespans in
some model organisms.
- Like fruit flies?
- Yeah.
- And even in mice recently.
I was particularly impressed
by the mouse studies.
Couple of colleagues out at
the University of Minnesota
were able to show that
fisetin put in either
in the food of the mouse when it's young
or even late in life after 700 days,
which is like a 75 year old human,
was able to extend lifespan
quite dramatically,
up to 30%, including
improving their health.
And that's extensively because both
it's removing those senescent cells
and activating the Sirt-1 defenses.
- And there's been human studies
in both of these as well.
I know we kind of talk
about these in a group
because they were discovered
as sirtuin activators
and now they're being seen
also as potential senolytics
but maybe we can differentiate a little.
- Well, a lot more is
known about quercetin.
That was discovered first as a senolytic
by Jim Kirkland at the Mayo Clinic
who combined it with a
drug called dasatinib
and together those two molecules
are potent killers of senescent cells.
And those have been put
into mice and into humans
where they are showing
really remarkable effects
in treating age-related diseases.
- And we've had some
randomized controlled trials
with humans and quercetin.
The effects are?
- Reduces liver steatosis, or fatty liver,
as well as other effects like
inflammation in the body.
You can actually see that the number
of senescent cells in the body goes away
when you treat with
quercetin and dasatinib.
- Dasatinib is a drug that's
used to treat leukemia.
It's got a lot of promise as
a senolytic too, it seems.
As of right now you can really only
get it for treatment for leukemia.
- That's right.
You can only get it if you're
part of a clinical trial,
you can't just go buy it on the internet.
It's a regulated drug
as well as another drug
that's senolytic which
is called [indistinct].
These are being tested.
They're not ready for prime time at all.
But fisetin is the interesting one.
That one is a plant molecule,
it's found in grapes.
It's found in apples.
Relatively high levels in strawberries.
You can now buy that relatively
cheaply on the internet.
- So if people are like, man,
I really like want to get into senolytics,
the gateway right now,
the most accessible place
for people is fisetin.
- Well, it is, but it's early days.
There's not a lot of data compared to,
quercetin and dasatinib.
Really we know that it
reduces inflammation.
That's about it in humans.
I think we still have to wait
to see whether it's really
truly safe before people
rush out and try this.
I'm excited about this affirm light study
by Jim Kirkland with fisetin.
He's got a number of
patients are on 20 milligrams
per kilogram of body weight and this,
over the next year or so,
should tell us whether
fisetin is truly a senolytic
in humans and can have
some health benefits too.
- Okay, so there's a third class
of drugs we want to talk about today.
We're not going to spend
too much time with them
because, broadly speaking,
they're not available for
purchase or even prescription
right now, except for very,
very narrow instances.
I'm talking about
rapamycin and these drugs,
rapalogs, drugs are supposed to mimic
the effects of rapamycin perhaps
without all the toxicity.
These drugs have a really
interesting history.
- Well, they do, these are
drugs that inhibit mTOR,
which is mimicking fasting.
They were discovered a number
of years ago on Easter Island.
Rapanui, which is why
it's called rapamycin.
On the back of a statue,
I believe, somebody found.
- [Matthew] Yeah, there's like the mold
and they are some fungus and they
scraped it off and lo and behold,
we have a drug that actually
has been used for other purposes.
- Immune suppression.
- Yeah.
- Cancer.
- Like, really, I mean,
this is a life saving drug.
We just don't know yet if
it's a life extending drug
that's going to be useful in humans.
- I'd put good money on it.
The reason is that it's
extended the life span
of every organism it's
been given to in low doses,
not immune suppressing doses.
In humans it's considered
around 10 milligrams per week,
but you definitely don't want
to suppress your immune system.
But even from yeast to
worms to flies and mice,
if you give it late in life
it still extends lifespan.
It's really quite potent.
The only downside is
that it could be toxic.
So you have to be extremely careful
and right now it's not available.
- And rapamycin works by inhibiting mTOR.
- Yeah, actually, TOR stands
for Target Of Rapamycin.
So that's how mTOR was discovered.
And when you give animals rapamycin,
you're mimicking low protein intake.
- You're mimicking this
adversity that we've been
talking about throughout
this entire series.
- Right, so your body
says, oh my goodness,
I'm running out of protein.
I need to scavenge protein from within.
And so the body starts
recycling old proteins
in this process we talked
about earlier called autophagy.
- And that brings us to
another drug, spermidine,
which is also working on
this autophagy process.
- It does. So, spermidine is more recent.
You've only recently been able
to get it on the internet.
It has an interesting history.
Anton van Leeuwenhoek, the inventor,
basically, of microscopy,
was looking at his sperm.
No one believed him that there were
these swimming things down there,
but he started to get
crystals in the sperm,
and that was spermidine, hence the name.
- Kids, if you want to get into science.
And what do we know about spermidine now?
Because this is really old.
I mean, this has got an old history,
but like really new
research that's showing
potentially extensions of lifespan.
Well, we know it extends lifespan
of yeast and flies and worms.
- And even mice.
- And mice.
- There's a new study that
was really compelling.
If you give spermidine to mice,
either when they're young
or even late in life,
they live longer and they
have better heart function
or other youthful capacities.
There are two ways that spermidine
is known to work in mammalian cells.
One is it stimulates autophagy,
just like rapamycin does
in the mTOR pathway.
There's another really
interesting property
that seems to be true
which is it also stabilizes
changes to the epigenome,
which as you know,
is one of the major causes of aging.
- There have been a number of
human studies on spermidine,
particularly revolving
around enhancing memory
and dealing with memory
loss in older Americans.
- That's true.
We don't know a lot about aging itself
but cognition has greatly
improved in a number of studies.
The one that stands out for me
is the one by Schwartz et al., 2018.
They were giving people 1.2
grams per day over three months
and there was significant
enhancement of memory.
- I want to go back to
the history of this stuff.
You mentioned earlier the
Antony van Leeuwenhoek
discovered the crystalline structures
that led us to spermidine
by examining his own sperm,
presumably his own sperm, in a microscope.
Is that still where
we're getting spermidine?
- No, not that I know of.
- Where are we getting it from?
- We're getting it from wheat germ.
It's a lot easier. It's
much more abundant.
You can also find it in soy products.
- That makes me feel better about it.
All right. We've talked
about sirtuin activators.
We've talked about mTOR inhibitors,
but really one of the most
exciting classes of drugs
is also sort of actually
kind of the most boring
because it's been around for so very long,
an AMPK activator called metformin,
which hundreds of millions of people
around the world already
take for diabetes.
- Yeah, it's been used since the 1950s
as the frontline medicine to bring down
glucose levels in type two diabetics.
And it is relatively safe as a drug goes.
Half the world it's available
over counter at pharmacies.
Here in the US and in Europe, and UK,
Australia, you need a prescription.
- And we know that Metformin
works by activating AMPK.
Do we know how that process
kind of unveils itself?
- Well, there are a lot of theories
and it's been debated for over 50 years.
One thought is that
the microbiome changes,
but a leading school of thought
that most scientists agree
on is that it activates a protein complex
called complex one which is involved
in making energy in mitochondria.
And what it does is it
lowers the amount of energy
that the cell has in the form of ATP,
this chemical that we use for energy.
And then you get mitohormesis,
mitochondrial hormesis,
what doesn't kill the
cell makes it stronger.
And the reaction is two fold.
One is to make more mitochondria,
so you get more energy a few days later,
but also by inhibiting mTOR it'll improve
what's called insulin signaling
so that the blood sugar
that's in your blood, and if
you're a type two diabetic,
it's too high, it gets sucked out
of the bloodstream and utilized,
which is why it's used to
treat type two diabetes.
- And this is another one
of those cases where there
is a perceived diversity and then not
just one of these pathways but multiple
pathways in this case are impacted.
- Yeah, similarly to all of these factors
which are talking to each
other, this is a good example.
Metformin will lower energy, inhibit mTOR.
It will activate AMPK, obviously,
we talked about that's
what it's mainly doing,
but it also raises NAD levels,
which as we all know will
activate the sirtuin.
So Metformin is a remarkable molecule,
comes from the plant
world, is very simple.
The French hellebore
or lilac plant produces
what's called guanidines,
and these have been known to
treat diabetes for many years,
in fact, over a century,
and then chemists have
put methyls on them,
chemically modified it
so that it's more stable.
And we call this Metformin and that's what
we have as the drug today.
- And we've given this drug to animals.
In worms it's extended
lifespans, 30 to 40 days,
which is no small amount
of extension for a worm.
- Yeah I was involved in the mouse study
with Rafael de Cabo down at the NIH
and we found that the mice were healthier
and longer lived on Metformin.
- And what are the other
things, 'cause again,
what we want to look
for if we want to know
if Metformin is working in humans
like it works in animals, you know,
we're not necessarily just
going to look at the lifespan
extension 'cause that takes a long time.
What are sort of the intermediary things
that we're seeing with Metformin?
- In humans, you mean?
- Well in animals and that
we can look for in humans?
- Well, the main one of
course is glucose lowering,
but we also see more
energy, more mitochondria,
less inflammation, and muscle switching.
We haven't talked much
about muscle type switching,
but muscles, as you get
older, become more glycolytic.
They start to use more
anaerobic mechanisms
and you can see that switch back
when you give them Metformin.
Like they're more like an athlete.
- And we're seeing all of these things
in animals and also in humans.
- Right, and this is where we
can speak to a lot of data.
Because millions of people
have taken Metformin.
And one of the most
interesting things about it
is you can do a retrospective study
of tens of thousands of elderly people
on Metformin and ask, okay,
their type two diabetes may
be reduced and slowed down,
but what about other diseases
that they're susceptible to?
Cancer, heart disease,
Alzheimer's, frailty.
And the answer that's quite remarkable
is that Metformin lowers the risk
of all those other diseases.
- So when we control for everything else
what we see is that the people who
were on Metformin are living longer.
- Than people who don't
have type two diabetes.
It's a remarkable fact.
- So now the question becomes, okay,
take the type two diabetes
part of the equation out,
will we still see an effect?
And that is something that's
being investigated in this
really large study that's
underway. The tame study.
- Yeah, you're right.
The targeting of aging
by Metformin study run by
[indistinct] down at Albert
Einstein College of Medicine,
this is a very large study over many
different institutes and hospitals.
It's costing tens of millions of dollars.
It's taken a while to raise that money.
But ultimately the goal is
to show to the American FDA
that you can target aging
with a drug and slow it down.
The ultimate goal being having aging
a treatable medical condition.
- Why is it taking so long
to raise money for this?
Because this is really, I mean,
everybody I know in the aging
space is excited about this
and yet the money's
hard to come by because?
- Well, this is where capitalism
has a little bit of a downside,
which is that Metformin is very cheap.
It costs a few cents and it's off patent.
- Which means anybody can make it.
There's no profit motive for
making this drug right now.
- Right, so [indistinct]
has relied on the government
and they've given half the
money and the rest of the half
he's relying on donors and
he's still raising that money,
but he's getting started.
Fortunately he's off to the races
and we should know in the next few years
if he's seeing signs of slowing aging
and he's looking at a number
of things, not just diseases,
but also things like
stability, ability to walk,
strength, these kinds of
things, mental acuity,
these are things that would indicate
that aging itself is being slowed down.
And he's even now able to measure
the human biological clock with accuracy.
And that should also be slowed down
if this is truly an anti-aging medicine.
- We're seeing a lot of doctors
get a lot more comfortable
with the idea of prescribing
Metformin off-label.
Just a few years ago, you know,
the constraints of what
Metformin was actually approved
for was keeping it out of
the hands of a lot of people
who thought that it might be good
for them in their efforts
to slow their aging.
There's starting to be a
little bit of a shift there.
- Well, yeah, I'm seeing a lot
more people taking Metformin
with the approval of their physician.
And part of it is education.
Typically when a doctor sees the evidence
and there's extensive literature,
and sometimes it's the
patient takes the information
to the doctor or our book.
The doctor in most cases is convinced
that this is worth the risk.
Now, it's not risk-free.
We should mention that
Metformin has some downsides.
One is that it can cause lactic acidosis,
which is quite a severe
condition. It can be fatal.
You have to be very careful there,
but most people are fine on Metformin.
The biggest thing that happens to them
is that they have an upset
stomach, lack of hunger,
which can actually be a good thing
if you want to lose weight as well.
- But doctors now are saying, okay,
they're advising their
patients as to these potential
side effects and also saying, yeah,
either because that
doctor is sold on the idea
that there's a potential
aging benefit here,
or anti-aging benefit here,
or one of the other things
you and I have talked about
before is doctors are
increasingly getting sick
of waiting until patients
are full-blown sick
to prescribe the medications
and they're prescribing it
to pre-diabetic people and pre,
what we might call
pre-pre-diabetic people.
- Well, there's a shift in medicine
and the way doctors are
looking at their patients.
More and more doctors are saying, okay,
let's not wait until
the patient is so sick
that we have to treat them.
Let's get ahead of that.
And let's start treating them earlier.
- The one other thing that
people should talk to the doctors
about if they're considering
trying to get on Metformin
is the concerns about the connection
between Metformin and muscle loss.
- Right, particularly in the
elderly this is an issue,
but actually if you look at the data
and there's been a
couple of human studies,
Metformin doesn't make a big
difference to muscle size.
It probably makes a difference
if you're trying to win Mr. Universe.
But other than that the
difference is really slight.
If you look at the graphs
it's only a 5% difference,
and actually 5% difference,
I'll give up 5% body size
for longevity any day.
But the other important
thing is that those muscles
on Metformin were just
as strong as the others
and had less inflammation.
So there's other benefits to that.
What some people are doing
just in an abundance of caution
is taking Metformin on days
that they don't exercise.
And if you're wondering,
why does it affect exercise?
Well, really it's pretty obvious.
It reduces the body's
ability to make energy.
And so you don't feel
as strong on the days
that you take Metformin so
you do less reps, fewer reps.
And so what you could really
do is just put a little bit
of extra effort in and probably
make up that 5% difference.
- If people are interested
in the effects of Metformin,
but are not able to work with a doctor
to get a prescription for it,
or if they've tried out Metformin
and it just doesn't sit well with them,
which is the case with
about 20% of people,
there's another alternative that works
on some of the same
pathways activating AMPK.
That's berberine.
- That's right.
This is a molecule from the
plant world bark and roots.
You can find it's a yellow substance.
Again, it's fairly insoluble.
So if you want to take it,
take it with some food.
Yogurt, olive oil, all this kind of stuff,
but it's been remarkable
what's been found in animals.
And even in people that it can mimic
the effects of Metformin.
Specifically what it does, is it, again,
it binds to this complex one and reduces
chemical energy in the body.
And in reaction this mitohormesis
is to amplify up mitochondria
and make the body
more sensitive to insulin
and lower the blood glucose.
We've seen this in my lab
in mice and human studies
have actually validated this as well.
The doses are high, one
to two grams per day,
but it does seem to work.
- And when you say it does seem to work,
you mean not just showing, you know,
the activation of AMPK and
increased mitochondrial energy,
but we actually in mice
have seen increases,
pretty substantial increases, in lifespan.
- Actually, it's really interesting.
In mice berberine will extend the lifespan
of mice treated with chemotherapy
and have a pretty big lifespan extension
of normally aged mice. That's
also true in fruit flies.
So it seems to be a common mechanism
that you lower the energy in an animal
and it responds by living longer.
- And I think you said you got to take
quite a bit of this stuff, though.
- Yeah, the clinical studies,
it's at least a gram,
there's one that worked with two grams,
but it does seem to
work just like Metformin
in improving the body's sensitivity
to insulin and lowering
the blood glucose levels,
which is a good sign that it's going
to have future health benefits.
- Any concerns about side
effects with berberine?
- I'm unaware of any
downside of berberine.
- We should say berberine does have some
of the similar side effects of Metformin.
We don't know in
different groups of people
might be different, but
you're looking at diarrhea,
constipation, gas,
potentially upset stomach.
- Right. Yeah, no molecule's perfect.
But this one's really interesting
because it's a natural
and commonly available one
that you can try at home.
Of course, talk to your
doctor first though.
- All right. Well, that kind
of brings us to try at home.
And again, with the caveat that
we're not telling anybody what to do,
we're not giving them medical
advice. You're not a doctor.
I know you have been really
open about what you do.
That has changed over the years,
but let's just sort of take it through
the things that you started doing,
you know, 20 years ago, 10 years ago,
five years ago, just start
from sort of a chronology.
When you started
investigating resveratrol,
you also started taking resveratrol.
How did you know how much to take though?
Because you were giving resveratrol
to yeast and eventually to mice.
- It's not a one-to-one,
it's not like you should take 3000 times
as much as the mouse had.
- If you were 3000 times
bigger than the mouse is.
- Right, it's not just proportional.
It's actually more related
to our surface area
and how much the drug can get into
our bodies versus the mouse and
the calculation for a mouse,
which is called the allometric
scaling, is about 12.
So you multiply it, let's say,
if the mouse has 100 milligrams,
1.2 grams for a human.
For a rat it's 3, for
a mini pig it's 1 to 1.
Turns out we have about the same
surface area as a mini pig.
- And so you take about a
gram of resveratrol every day.
- I do and I've been taking
that since about 2004.
But like I said, you can't just
put it in water and drink it.
- You have to add some fat to it.
- Yeah, so I typically have some yogurt,
a couple of spoonfuls,
not a lot because I'm
trying to fast until dinner,
but I could mix it with olive oil.
Olive oil, recently, as we mentioned
earlier in a previous episode,
seems to be really good
for activating sirtuins,
but also you can dissolve
resveratrol in it.
- So you get a twofer.
- You do. I don't have a lot of it.
There's a lot of calories in olive oil.
I don't want to break the
fast severely, but you know,
mix it with bit of
vinegar and basil leaves
and it doesn't taste too bad.
- Okay, so resveratrol,
you're taking about a
gram a day in the morning,
Also in the morning you take NMN.
- I do, and there you don't
have to worry about food.
It's dissolved easily.
You can put it in water or swallow it,
put it under your
tongue. And so I do that.
That's my main combo in the morning.
- How much NMN are you taking?
- Again, it's a gram,
but that's not a guess.
That's actually based on the
human studies that we've done
that show that a gram over 10 days
raises your NAD levels about two-fold.
- And that's sort of the dosing amount
that we're seeing in a lot
of the human studies now.
Both the past studies
and the current studies.
- I take one gram of NMN every morning
along with my resveratrol.
The reason is in humans we know that
that doubles NAD levels which is important
because someone my age has half the levels
of NAD than I did when I was 20.
But you can go as high as two
grams and triple the amount.
It's important to
mention that I take these
at a certain time of day
based on science as well.
I take these in the morning
because that's when the natural
rise in NAD and Sirt-1
activity should happen.
And we actually know this,
that the Sirt-1 NAD cycle is part
of our body's natural 24-hour clock.
Sirt-1 regulates a protein called BML
that controls the genes that tell us
whether it's night or day,
should we be hungry or not?
Whether we have jet lag or not.
And I do find anecdotally that NMN
is remarkably good at
preventing jet lag as well.
I can reset my body's clock ostensibly
through the Sirt-1 BML pathway.
- You're also taking Metformin.
- Yes.
- How much? When?
- I take 800 milligrams at night.
- Okay, and you take
that at night because?
- Well, because doctors tell me
that it's a good time simulate a fast.
I take it with my dinner, just after.
And then through the night,
I'm presumably having
low levels of glucose
and my body has all the benefits
of stimulating those repair
pathways, those survival genes.
- And that's the most recent thing
that you've added to your regimen?
- It is. Actually what happened was
I had terrible blood biochemistry.
I was eating badly, I gained weight.
I wasn't sleeping. I was stressed.
And those numbers just
went through the roof.
And I said, I got to do something.
So I went on NMN and things
were somewhat rectified.
And then I added Metformin and they
really got back to my optimal.
- We mentioned earlier some
concerns about exercise,
Metformin, your practices,
where that's concerned?
- Yeah, I pause Metformin.
It doesn't sit well in my stomach anyway.
So on days where I know next day
I'm going to exercise and lift weights,
I might skip Metformin that night before.
- And then there's also spermidine.
- There is. You can buy it now.
There's a company that makes it in pure
from very low levels of gluten.
And just the last few months
I've added that to my protocol
and we'll have to see how my
numbers look on Inside Tracker.
- Okay, so that's not something
you've adopted and you're like,
I'm definitely taken with it.
This is I'm adopted and I'm testing
it out to see how it works.
- I am. And actually,
I advise that company.
The first supplement company I am advising
and I did that because I wanted to look
at the human clinical trials
and they look really promising as well.
- How much of that are you taking?
- A gram as well.
- [Matthew] Okay.
You are also periodically taking fisetin,
quercetin, aimed at senescent cells.
- There are clinical trials
being run out of the Mayo Clinic
for fisetin and for quercetin.
These are high doses.
They're typically two grams taken
one day a week for a matter of months,
Myself, I'm on a maintenance dose.
I take about half a
gram of each every day.
- Let's take this morning through
night just really quickly.
Resveratrol, one gram.
- In the morning with yogurt or olive oil.
- NMN as well.
- A gram, yep.
- Fisetin and quercetin.
- Half a gram in the yogurt.
- Spermidine.
- Definitely spermidine in
the morning, about a gram.
- And then in the evenings,
if you're not working out the
next day, Metformin. How much?
- 800 milligrams.
- Okay.
- That's it.
- That's it.
Now, you're not most people.
A lot of other people are
going to be different.
You don't advise people,
but it might be a good place for people
to start their conversation
with their doctor though, yeah?
- Well, I think so.
Most doctors are open to looking at, say,
Inside Tracker data and hearing
about the latest science.
It's very difficult for
them to keep up with it.
It's one of the reasons we're doing
this podcast in the first place.
- So David, this has been a really
comprehensive conversation.
Even still we could have gone deeper
on any one of these drugs or supplements.
Maybe we'll do that in future episodes,
in a future season of Lifespan podcast.
But what we're trying to do today
is really give people an opportunity
to really start thinking
about whether this
might be something that they
want to bring into their lives.
And if so, how, of course, again,
in consultation with their physician.
- And monitoring, this is important.
You don't know if you're doing
good or harm to your body
unless you measure it,
particularly your liver.
You can measure what's called ASTALT.
I do that routinely just to make sure
nothing's going wrong in that regard.
- Our next episode is?
- Things that are not supplements things.
Maybe you could regard
them as being on more
on the cutting edge,
things like testosterone,
growth hormone, exosomes, peptides.
We're going to dive
deep into those as well.
- All right.
- Sounds like fun?
- Yeah.
- Let's do it.
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