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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