[Rhonda]: Welcome back, my fellow "FoundMyFitness"
longevity fanatics.
Today is a treat.
My guest is Dr. David Sinclair, a professor
in the Department of Genetics at Harvard Medical
School where he researches and tries to understand
the biological mechanisms that regulate the
aging process and how to slow them.
I can't think of a more interesting question
than understanding the biological mechanisms
that regulate aging and how to slow it.
I'm very interested in it myself, for sure.
[David]: Well, thanks, Rhonda.
Thanks for having me on.
[Rhonda]: So what are the mechanisms?
[David]: What is the secret to the universe?
Well, I've been studying this, as you know,
for over 30 years now.
And when we first started out, we knew nothing.
And then we went to little yeast cells and
then we worked our way up to worms and mice.
And now, myself and probably a couple of dozen
other researchers around the world have broken
through a barrier of understanding about why
we age and how we can actually reverse it.
[Rhonda]: Wow.
So what's the...
[David]: Detail?
[Rhonda]: What's the...
Yeah, what's the breakthrough?
[David]: Well, there were a number of breakthroughs.
So in the 1980s, the big breakthrough was
that there are...and early '90s, that there
are genes that control aging.
We call these longevity genes, do not call
them anti-aging genes.
We don't talk about anti-aging, we talk about
longevity and healthspan.
And so, these longevity genes were first found
in organisms like a nematode worm, tiny little
one, and yeast cells that we use for baking
in bread and that's where I started my career
at MIT with Lenny Guarente running the lab.
And those same genes are in our bodies and
in pretty much every life form on Earth.
And what we've discovered is that when you
go for a run or you're fasting, the reason
that those are beneficial actually is because
they trigger those longevity genes to repair
your body and make sure that you don't get
as old as you would otherwise.
[Rhonda]: Just as a sort of a side note, because
you mentioned these longevity genes in the
yeast and the worms, one of the first...
So, in college, I went to UCSD in San Diego
and I was a chemistry major.
And I worked in biotech.
At the time, it was a sort of a start-up,
it was Illumina.
And I worked in the chemistry department.
Now it's a very big company.
But I was working there my junior and senior
year in college and I, you know, it was sort
of like I was making peptides and doing a
lot of organic chemistry and after a while,
I just didn't feel, like, very interested
in it anymore.
So I went to the Salk Institute to kind of
get a little bit of a taste of biology because
believe it or not, I didn't have a lot of
biology classes as a chemistry major.
Had a few, but it was mostly just, you know,
chemistry.
And so, at the Salk, I joined Andrew Dillin's
lab and...who uses, you know, nematode worms
to understand the genetics of aging.
And I remember the first time I was working
with these worms that had a decreased insulin
IGF-1 signaling pathway, how they lived like
100% longer and how they were, like, youthful
when they were supposed to be dead.
And I saw it with my own eyes when I was doing
the experiments and it was like, "Holy crap,
this is cool.
We have genes that are similar to these little
worms and they are like this?"
You know, so that kind of got me interested
in, at least, on the genetic side of aging.
[David]: Well, I'm not surprised.
Even I don't do all the experiments in my
lab, you may be surprised to know.
And people would tell me results, "Oh, the
mice are living longer downstairs on the NMN,"
or whatever, or, "We've accelerated aging
in mice because we've tweaked the epigenome,"
and, you know, this all sounds great and,
you know, I go back to my email.
It's not until I go in to the animal room
and I see them with my own eyes, and these
are living creatures that are getting older
and getting younger.
It really is an impact to actually see and
hold them with your own hands.
So, yeah, that's the thrill.
Even with the yeast studies that I was doing
back in the late '90s, I was very intimate
with the yeast cells.
It sounds weird that you could really adore
little microscopic organisms, but you look
at them under the microscope and they live
for about a week and you have to monitor these
mother cells and her little daughter cells
that you pick up, used to pick off with a
microscope and a little pick.
You get to know those cells pretty well.
You don't give them names, you give them numbers.
But when they were getting big, fat, old,
sterile, and then they died, you know, it
was a little twinge of sadness that these
little dudes that you'd been looking after
all the time or females, in this case, were
dying.
So I think, we biologists, we get attached
to these living organisms and it's really
rewarding to see that we're not making them
sick, we actually end up making them live
longer and healthier lives.
[Rhonda]: Right.
So I became familiar with your work back in
those days when I was actually doing research
on these little nematode worms.
And I remember some of your work was on resveratrol
and how resveratrol, like, helped to regulate
one of these, I guess, longevity pathways.
Sirtuin, the sirtuins and how that was involved,
and basically if you could activate them and
certain ones seem to delay aging.
So maybe you could talk a little bit about
both sirtuins and also what resveratrol is.
[David]: Oh, sure.
Let's start with sirtuins.
So when I arrived at MIT, it had just been
discovered that there was a gene called SIR4
that when it was mutated, it would make the
yeast cells live longer.
In a fair amount of work, we figured out that
the SIR proteins, which are enzymes that control
gene expression, genes on and off, they would
become dysregulated over time and we found
out that's because they were being distracted
by a whole bunch of DNA instability that was
accumulating in those cells.
But the lesson was that the sirtuin enzymes
that were controlling genes were also controlling
lifespan, which was a real breakthrough.
No one had really expected to find gene regulators
controlling aging.
We thought we'd find antioxidant producers
and DNA repair proteins.
That's not what we found, not initially.
And so the sirtuins became very interesting
in yeast and Matt Kaeberlein who's now out
in Seattle, he's a leader in the field as
well.
He came in and his first project in the lab
was to put an extra copy of one of the SIR
genes, number two, SIR2 into yeast and those
yeast lived 30% longer, and later, Lenny's
lab and my lab at Harvard showed that this
was through a process of mimicking calorie
restriction.
If you have a lot of sirtuins, you get the
benefits of calorie restriction or dieting
and other types of little stresses on the
cell like heat and a bit of a lack of amino
acids.
And if you get rid of the sirtuin or SIR2
gene, the real breakthrough was that now calorie
restriction doesn't work anymore.
And that whole setup was the basis of most
of the research that the field has been doing
since in the sirtuin field.
Trying to understand that concept of what
we learned in the 1990s in our bodies and
in mice.
And I'm lucky and happy to say that a lot
of it is very similar in our bodies as well.
[Rhonda]: And when you say calorie restriction,
usually, you're talking about for, like in
mammals and humans like eating 30% less than
you normally would or something?
[David]: Yeah.
Well, in the old days, we typically would
take out 30%, sometimes even 40% of the food
with the mice and they'd be hungry all the
time and it wasn't very pleasant.
With yeast, if you're wondering how do you
calorie restrict yeast, we just dropped the
level of sugar in the Petri dish.
I think it was fivefold and that was enough
to make them live longer, but they still grew
quite happily.
These days, as you're aware, intermittent
fasting seems to kick these longevity genes
into action.
The sirtuins still come on, but you don't
always need to be hungry.
You can eat, you know, four days out of a
week or even six days out of week and still
have a period of fasting that gets the sirtuin
activity up to levels that we think would
be beneficial.
[Rhonda]: Right.
Yeah.
And there's certainly a lot of overlap, at
least in the scientific literature between
calorie restriction and intermittent fasting
having beneficial effects, a variety of beneficial
health effects.
But, you know, some of the differences would
obviously be, you know, when you are intermittent
fasting, you're shifting your metabolism from
carbohydrate, glucose, to fatty acid metabolism
and you start to, you know, ketogenesis can
kick in after, at least if you're doing a
more prolonged type of intermittent fast.
So, there's certainly a little bit of differences
as well between those.
[David]: Right.
Well, one thing that's interesting that connects
everything is, so we showed in 2005 in a Science
paper that when you take a calorie-restricted
rat and look at its organs...we looked at
the liver and muscle, the levels of one of
the sirtuin genes, number one, we have seven
of these genes.
So we looked at number one because we only
had an antibody in those days to number one.
It went up dramatically.
I think it was about five to tenfold in levels
in the calorie-restricted livers.
And then we recapitulated calorie restriction
in the Petri dish.
We grew cells in serum from animals that had
been calorie-restricted and we found that
that was also enough to stimulate this boost
of sirtuin production.
But getting back to what you did in Andy Dillin's
lab, we found out the reason it went up in
the dish was because of having low insulin
and IGF-1 levels.
Because when we put back in normal insulin
levels in IGF-1, the sirtuins went back down.
And that was a nice link between...for the
first time in mammals, the sirtuins, calorie
restriction, and the insulin pathway.
And actually, in those days, we were all fighting
amongst ourselves that we were going through
a paradigm shift, which is always stressful.
And Andy was saying, "My pathway is more important
to sirtuins."
And then there was the mTOR people saying,
"No, no, we've got the most important pathway."
And I'm trying to say, "Hey, folks, all the
pathways are important.
In fact, they're all talking to each other."
We showed that sirtuins and TOR are talking
to each other.
So, fortunately, in the field now, we've grown
a little older and wiser and we are in agreement
that there is this network, it's not just
one straight pathway from food to long life
and that you can tweak one pathway and the
others will also come on to help.
[Rhonda]: Something that comes to mind when
you...
So you're talking about, really, this important
role that calorie restriction or intermittent
fasting plays in activating this sirtuin pathway
and also deactivating things like the insulin
signaling pathway and IGF-1 pathway, it is
the fact that the sirtuins are regulated by
something called NAD, nicotinamide adenine
dinucleotide plus.
But that is something that actually, those
levels rise during a fasted state.
[David]: They sure do...
Right.
And in response to exercise as well.
And so the reason NAD is so exciting compared
to the 1980s when we thought it was just a
housekeeping molecule for reactions, is that
the levels of NAD go up and down depending
on not just what you eat, but whether you're
exercising and even what time of day it is.
So, during the day, your NAD levels will rise
and then you eat a big meal and they'll go
down again.
And it's...
We think it's one of the reasons you also
get jet lag, is your NAD cycles are out of
whack.
[Rhonda]: Is it on a circadian rhythm?
Is it completely regulated by meal intake?
[David]: It's a combination.
It will be going up and down with circadian
rhythms, mostly, but you can adjust it within
the...
[Rhonda]: What about macronutrient composition?
Like if you eat more high fat versus carbohydrate?
[David]: Yeah, no one knows.
That would be a good experiment.
The circadian field hasn't looked at nutrition
as far as I'm aware.
But what I can tell you anecdotally is that
if I raise my NAD levels when I'm traveling,
I feel a lot better if I have a shot of an
NAD booster in the morning when I get to Australia,
which I travel to pretty often.
And so I don't know if it's truly working,
we need more than one person in a clinical
trial.
But it fits with the mouse studies, which
is that you can use NAD to reset your clock.
What's interesting about this is that NAD
isn't being driven by the clock, the clock
is being driven by NAD.
[Rhonda]: Okay.
Yeah.
So for people that are viewing or listening,
the clock, meaning what's regulating circadian
rhythm?
[David]: Yeah.
How your organs coordinate what time of day
it is.
And when you're jetlagged, your brain might
realize that it's morning because your eyesight,
you know, sees sunlight, but your liver still
thinks it's the middle of the night, so you
feel queasy.
And that's the feeling.
[Rhonda]: And the reason why NAD is...
I mean, NAD is really important for a variety
of metabolic...
I mean, it's required for metabolism, for
metabolizing glucose, metabolizing fatty acids,
your mitochondria need it.
But it's also important for a variety of other
tissues as well, activating sirtuins and then
DNA repair enzyme, PARP.
[David]: Yeah.
Right.
You could argue that NAD is the most important
molecule in the body, maybe with the exception
of ATP, but without either of them, you're
dead in about 30 seconds.
So NAD and ATP were probably the first two
molecules that life on this planet used to
survive.
And it's, to me...
And amino acids as well.
And so isn't it interesting that the amino
acid levels, ATP, and NAD are the three main
molecules in our bodies that are sensed as
to what our environment is like and whether
we need to hunker down and survive or go forth
and multiply?
And those are the three main pathways.
There's the sirtuins, there's AMP kinase,
which is the metformin pathway.
And then there's mTOR, which is rapamycin,
which I'm sure you and many of your listeners
are aware.
But we're tapping into very early aspects
of life that's found all over the planet and
that's why I think we're having such big effects
in the animals.
Often, people say it's too good to be true.
You know, you tweak one pathway and all this
good stuff happens.
Well, these are pathways that have existed
for going back probably more than 3 billion
years.
And we're only just learning how easy and
seemingly safe it is to tweak them.
[Rhonda]: So NAD levels decrease with age,
and you think this is causal for...plays a
causal role in the aging process?
[David]: Right, right.
So why is NAD linked to sirtuins?
So, sirtuins are enzymes....
And this is my picture of an enzyme, but think
of like a Pac-Man that's chewing off chemical
groups of other proteins, telling them what
to do, like a traffic cop.
And without NAD, they don't work.
They're stuck shut.
And so there's always NAD around, otherwise,
you'll be dead.
But if the levels go down as they do, as you
get older, and I'm almost 50, so my levels
probably are half what they were when I was
20, scary thought.
[Rhonda]: Wow.
[David]: So my sirtuins are working maybe
half as well as they did telling the troops
to go out and fix my body.
So when I go for a run, I get less benefit
from that.
I feel tired, I don't make as much energy.
Mitochondria are down.
But by raising up the levels of NAD to when
I was young, what I think is going on based
on the animal work we've been doing for many
years now is to trick the body into thinking
that it's young again, or it's been exercising,
or dieting, and that allows the sirtuins to
do their job the way they once did.
[Rhonda]: By just having that level of NAD
higher, like, it's basically like a signal.
[David]: It is.
So I think of it as the fuel in a car if the
sirtuins are driving.
And then the resveratrol that we worked on
years ago works on the same enzymes, but it's
the accelerator pedal.
So, it actually...
The NAD is making it work, but resveratrol
will come along and make it work even faster.
So the combination of those two, we find,
is even better than just one alone.
[Rhonda]: Cool, really.
Let me ask you this.
This is kind of something that comes to my
mind.
I don't think it's often thought about this
way, at least, in the field.
But, you know, because NAD is required for
cells that have a really high energetic demand
like activated immune cells, for example,
activated immune cells require a lot of ATP
for energy and a lot of NAD.
And if you think about like chronic inflammation,
how, you know, especially as you get older,
and you're unhealthy, and with age, you know,
basically it is increasing.
If you're having more activated immune cells,
is there any way to test if, like, the NAD,
like there's a triage where NAD is kind of
being sucked away to these activated immune
cells and, like, then your mitochondria are
now suffering and you get, like, mitochondrial
decay because you're sort of shunting all
this NAD to, like, take care of, you know,
what your body thinks is potentially an infection
that could kill you, right?
So there's probably some sort of evolutionary
mechanisms at play that say, "Oh, yeah, immune
cells need this NAD more than mitochondria,"
or something, I don't know.
So it'd be kind of interesting.
Do you follow what I'm saying where...?
[David]: Oh, I absolutely do.
I think you're probably right in thinking
along the same lines that as you get older,
you're losing the ability to make NAD, but
you're also chewing it up.
And as it gets worse and worse as you get
older, the immune system is a big drain on
NAD, and actually, so is DNA repair with the
activation of PARPs.
And once you drain NAD a little bit, then
your PARPs and your immune system won't work,
but then they'll need more NAD because you'll
get more damage.
And this is a positive feedback in a bad way
so that once you start going down the NAD
decline, the cells just start to need more,
and more, and more with accumulating DNA damage.
And that's actually what happens in yeast
cells, going back to those little critters
that we found that they became overwhelmed
with damaged DNA and the sirtuins were overwhelmed,
they had to go over and repair that genomic
instability, the DNA instability.
And one of the reasons old cells became sterile,
which is a hallmark of yeast aging, is because
the sirtuins are keeping the cells fertile
back here, but they're so distracted by all
this other DNA damage that's going on over
here that they lose their identity.
And that's a theme that we've discovered is
likely true in mammals as well, that accumulations
of DNA damage distract the sirtuins from their
normal job of keeping a cell with the proper
gene expression, and cellular identity and
we see the loss of cellular identity over
time in mice, at least.
And what we're trying to do is to raise NAD
levels back up so that they can fix the DNA
damage, but also get back to where they came
from and make sure the cell doesn't lose its
identity too much.
[Rhonda]: I didn't know sirtuins played a
direct role, and I guess they're regulating
so many genes that they're playing a role
in DNA repair and DNA damage.
[David]: Well, they're one of the first proteins
to get to a broken chromosome.
[Rhonda]: Really?
[David]: Yeah, we discovered that.
It's a while ago, it was a cell paper in 1999,
if anyone would like to look it up.
Mills, myself, and Guarente published that.
SIR2 goes to a broken DNA end and then helps
recruit other proteins.
[Rhonda]: A single-strand break or...?
[David]: Double.
[Rhonda]: Double?
Really?
So, like gamma-H2AX?
[David]: Yeah.
So the first thing that happens is gamma-H2AX
gets lit up on the break and then within seconds,
SIRT1 brings in HDAC1, helps remodel the DNA
in the chromatin so that it's ready for the
repair proteins to come in and without SIRT1
getting there, these other repair proteins
are very inefficient...
[Rhonda]: Interesting, I didn't know that.
[David]: ...but they're distracted.
Sirtuins should actually be regulating genes
elsewhere.
[Rhonda]: Right.
Wow.
That's really important to know..
[David]: Right.
This is all part of my idea, my hypothesis
called the information theory of aging, is
that we're really losing the information regulation
over time and all of these other things that
occur such as telomere loss, and mitochondria
loss, and loss of proteostasis, as Andy would
call it, loss of protein folding mechanisms,
this could be upstream of all of that, that
our cells lose their identity and don't turn
on the right genes the way they did when we
were young.
But the trick is how do you get everybody
to go back and reset?
And that's what we've been working on.
[Rhonda]: Well, if you think about, as you
know, Steve Horvath's work on this epigenetic
clock and how he's shown now, I mean, in several
different cell types, you know, including
from humans, that there's this very distinct
epigenetic aging clock that...
[David]: So, what...
You know, I got to jump in because I get a
little excited about this.
What I've been telling you about the sirtuins
and their movement, we've shown, is intimately
linked to Horvath's methylation clock.
[Rhonda]: Really?
[David]: Yeah.
It's all part of the same process.
So this distracted protein DNA repair system,
what's happening as that happens is that you
get the methyls on the DNA that we use as
a clock, but what we're finding is that clock
is a way of resetting the proteins to go back
to where they came from.
That there are modifications on the genome
that say, "Hey, sirtuins and these other proteins,
go back to that gene because that's where
you belong 20 years ago and ignore these other
changes which have come on since you were
20."
And we think we've literally found what the
signal is to get them to go back.
Now NAD is part of that.
You need the fuel, but what's the genetic
trigger to say, "Get off there and go back
there"?
And we think we've found that and it's got
to do with the Horvath clock being reversed.
[Rhonda]: Is this in your publication?
[David]: It's something we were writing up
right now for a journal.
[Rhonda]: That's super exciting.
That's really exciting.
Has there been any...and I know we're going
on a tangent here, but has there been any
evidence looking at, like, for example, like
supercentenarians, what their epigenome is,
like do we know?
[David]: Very...
I mean, they've done the Horvath clock on
it.
[Rhonda]: They have?
[David]: Yeah.
[Rhonda]: And is it different than, like,
elderly?
[David]: For the same age, yes.
Right.
And actually, the Horvath clock has now been
done on people who are smokers or obese and
it's quite clear.
[Rhonda]: Cancer [crosstalk 00:22:18] or...
[crosstalk 00:22:20] tumor tissue, yeah.
[David]: Is that right?
[Rhonda]: Yeah.
Yeah.
Tumor tissues, like, looks like 10 years older
in the same person, like age match, normal
tissue.
[David]: That's interesting because we're
reversing the Horvath clock with our new found
genetic trick and we're finding that we're
having benefits on those cells as well.
So I think this could be...
[Rhonda]: On cancer cells.
[David]: Yeah.
[Rhonda]: Wow.
[David]: And damaged neurons.
[Rhonda]: That's so cool.
I'm so excited.
[David]: It seems to be something radically
new, but...
So I know Steve well and his research is really
interesting in that it is showing that it
doesn't just predict your chronological age,
it's predicting also how long you have to
live, which is a really interesting thing
that if you've abused your body and had a
lot of smoking and been sedentary, Steve can
take your blood and he can say, "Hey, you're
10 years older than you should be."
[Rhonda]: Even if you...
Let's say you were a previous smoker, you
know, and you hadn't smoked for 20 years and
you've become active and eat healthy, do you
think that epigenetic mark is there or do
you think that....
[David]: I think it is.
[Rhonda]: It's there.
[David]: Yeah.
Well, we know the rates of cancer go down,
but all the other damage, the changes to the
epigenome, what I'd been drawing with my hands,
this movement of proteins, that's one-way
street.
It's not that if you suddenly start running
in your 60s that it's all going to be reset.
[Rhonda]: Unless you can identify the signal.
[David]: Well, the signal, yeah.
We've been putting that into animals and restoring
eyesight in old mice and regrowing optic nerves
in old mice and it seems to be safe.
They're not getting any...no downsides there.
[Rhonda]: And this is by manipulating the
epigenome?
[David]: Right.
[Rhonda]: Wow.
[David]: Right.
So, we use...
We haven't published it yet.
So my graduate student, Yuancheng, will probably
kill me for saying too much.
But we're both so excited.
Even today, he sent me a text about, a new
breakthrough is that we've found not only
the genes that trigger them to move, but then
the genes that reset the Horvath clock once
they get there.
[Rhonda]: Really?
You've identified the genes that can make
them move...make the methyl groups move?
[David]: Methyl groups.
Yeah, and reset the methyl groups and what
gets them to go back.
[Rhonda]: Okay, okay.
Wow.
[David]: Yeah.
So, I'll give a hint to the viewers.
And maybe this will be published and, shortly,
we'll see.
So we're using what's called the Yamanaka
factors.
And so, the first, person to do this...
[Rhonda]: Explain what that is.
[David]: Sure.
Well, the first person to use these factors
was Shinya Yamanaka, a Japanese scientist
who looked through a lot of different genes
and found a set of four factors that if you
put them into an adult cell, say, a skin cell,
they would go back to being very primitive,
so primitive, what we call a pluripotent stem
cell that you could then turn those cells
into a nerve cell or even regrow an eye in
the dish.
It was a breakthrough that led to the Nobel
Prize being awarded to him in 2012.
[Rhonda]: You just take a person's skin cell
and turn it into a neuron.
I mean, that's, like, amazing.
[David]: Why not?
We do...
I mean, a high school student can do that
these days.
It's not that difficult.
Typically, with science, once you know how
something works, it's pretty easy.
Same with aging, I think.
But what we've discovered is that...
And first of all, I want to give a lot of
credit to someone at the Salk whose name is
Juan Carlos Belmonte, a professor there.
A good friend of mine and he's...and he did
the experiment that we were trying to do,
so we were just slightly scooped on that.
But he made a mouse where he could turn on
these four Yamanaka genes.
And that, for sure, they stand for O,S, K,
and M. And that mouse, when he switched them
on, died within a couple of days.
So that's not great for those mice.
But what he then cleverly did was he didn't
give up or his postdoc didn't give up.
What he did was he turned the genes on for
a couple of days and then stopped, let the
mice recover for a few days, and then turned
them back on.
So, you know, I feel for the mice because
they were headed towards death and they could
recover and then they cycle, but actually,
they ended up being healthier.
The premature aging mouse model that he had
lived, I think it was 40-plus percent longer.
But also, he's shown since then that you can
use these factors to improve wound healing
and kidney healing.
[Rhonda]: So was he boosting their stem cell
pools, and their...
So he was, like, regenerating tissues or?
[David]: What I think he's doing is what we're
doing in the lab, which is getting those proteins
that have moved around and lost their way
to go back to where they were when they were
young and then reset the methylation clock.
And now a cell doesn't just think it's young.
It's literally young.
[Rhonda]: Was he using CRISPR to do this?
[David]: Well, he might've, but it was a transgenic
mouse, which means he inserted those four
genes into the mouse's genome with an on-off
switch.
[Rhonda]: Yeah.
Okay.
[David]: We don't do that.
We use viruses that we can give to old mice.
He has to start from a single egg.
We can go into old mice and within a few weeks,
figure out if we've reversed aging in a tissue
or in the whole mouse.
And we've also discovered that it's best if
you don't use all four of those factors, we
have to leave one of those off because it's
toxic.
It's the Myc gene, Myc is an oncogene, but
the other three worked great.
And the results that came in through the tech
today use those three genes to protect neurons
from dying in the mouse but also in the dish.
And the gene that can restore the Horvath
clock was required.
And so we're very close, I think, to seeing
the future of where maybe eventually we don't
use viruses, maybe we have molecules that
can do this that we can put in a drip or in
a pill that can send us back another 20 years.
[Rhonda]: Wow.
That's super exciting.
I'm, like, very pumped up about this whole
epigenetic clock research and linking it to,
you know, basically, like, being able to reverse
aging.
I mean, I think that...
Do you know...
Is there any evidence that fasting has any
effect on that epigenetic clock?
Has that been shown, do you know?
[David]: I have not seen that.
I think what I've seen from Steve's work and
others is that you can slow the rate of the
clock, but I haven't seen reversal yet.
And I've shown Steve the results I just told
you and he's pretty excited that someone's
figured out...
We think we've figured out why the clock ages,
what's causing it, but also what's the first
reset that's ever been found.
But I would suspect that fasting can help,
but probably, it's not enough to really do
what these powerful genes are doing.
One day, we'll figure it out but...
So fasting, I still do that as much as I can
for one main reason, and that is that it's
going to activate these defenses that, at
least, slow down and somewhat stabilize the
epigenome decay that we call.
But we're probably going to need something
more potent to really go back 20 years.
But do we slow down aging by fasting and running?
Absolutely, no question.
[Rhonda]: Yeah.
We're, I mean, affecting these pathways, the
AMP kinase, the sirtuins, mTOR, and then IGF-1
insulin signaling, all those aging pathways,
certainly, are affected by fasting and caloric
restriction.
[David]: What's good about those pathways
is that they seem to be really safe, relatively
safe.
So metformin has been tested in millions of
people, NAD boosters have been in mice for
many years now and in some humans for a while,
even clinical trials that I'm helping to run.
So that's good.
But on the more potent age reversal, what
we call epigenetic resetting, now we're playing
with fire because we're really setting cells
back decades.
And if you do it too much, you end up turning
a mouse into a giant tumor, which is not what
you want.
And we're never going to do that to a human.
So we need to find ways to make this new very
potent effect safe.
So, you know, you could theoretically come
to my lab and I could inject you with this
stuff and you could take doxycycline and turn
it on for as long as you want, and that's
all theoretical.
But we're not crazy, we're not going to do
that.
We probably need another few years of clinical
testing before I can say that this is going
to be usable in a wider context.
But if you're wondering why are we testing
the eyes, we're testing glaucoma, and blindness
in old mice, it's because that's already on
the market for AAV, so viral use.
And it's localized, so if there's any problem,
it's not going to hurt the rest of the body,
anyway.
[Rhonda]: Yeah, wasn't there a clinical study,
Japan, maybe it was where they used induced
pluripotent stem cells to, like, heal some...I
don't remember if it was like macular degeneration
or some other retinal problem.
It was some kind of form of blindness or something,
I think I remember reading that study.
But just kind of to go back what you were
saying about the epigenetic clock, and the
aging, and I had always wondered about with
the Yamanaka, you know, these transcription
factors that are able to sort of take a already
differentiated cell, like a skin cell, or
a neuron, or a liver cell and turn it back
into a stem cell, a pluripotent stem cell.
You know, I always wondered, "What about the
epigenome?"
Right?
Is it like, do you have an older epigenome
but you're like somehow, you know, like...
[David]: You actually reset the epigenome,
and that's how it works.
Yeah.
So, think of the genome as the digital information.
So this is zeros and ones, or in this case,
A, T, G, C. But the epigenome is the reader
of that, and it's analog, and it's very hard
to maintain over 80 years.
[Rhonda]: That has to be the key.
[David]: It's a loss of information.
[Rhonda]: It has to be.
[David]: Yeah.
But how do you get back that information?
So I'm going to geek out a little bit because
your audience is a smart one.
So back in 1938, there was a man, a brilliant
person called Claude Shannon who was at MIT
and he wrote a theory, mathematical theory
on communication.
And his goal was to correct the loss of noise
during a transmission of a radio signal during
World War II and beyond.
And he came up with a mathematical theorem
of how do you make sure that the signal that
starts here is pristine when it gets to the
actual receiver?
And what he decided was you can either make
it digital or you can have somebody who's
observing the signal and then if it gets messed
up, you then send a replacement signal.
We now call that TCP/IP.
It runs the internet.
That's how it all works.
That's why it works.
And we wouldn't have an internet if it wasn't
for Claude Shannon's work back in the '30s
and '40s.
I think that's a good recipe for understanding
why we age, loss of noise over time, analog
systems, very prone to noise.
But that system of resetting aging, how do
you get the original information back that
it was when the signal was first sent, that's
what we're working on.
That's what we think the Yamanaka factors
are able to do.
They're the group that sits above and says,
"Oh, that signal is degraded, use that signal."
[Rhonda]: Yeah.
That's cool.
[David]: Well, so that's all part of...
[Rhonda]: High-five.
[David]: Thanks, Rhonda.
[Rhonda]: I'm excited.
[David]: That, I've been writing up in a book,
which is coming out later this year in September.
And so I've been so busy writing a book, I
haven't even put this out in scientific publications.
So maybe one of the first times that a scientist
puts his whole ideas and theories in a book
before it comes out in peer review.
So, we'll see.
But, you know, I think it's there for people
to judge.
Maybe by September, I'll have some scientific
papers written up as well.
[Rhonda]: What an exciting field.
Do you think other scientists in the aging
field will start working on this?
I feel like this needs to be...there needs
to be a big push, like there need...
[David]: Yeah.
It's going fast.
So right now, I mentioned Juan Carlos Belmonte
in the Salk, he's the pioneer.
Steve Horvath is part of our dream team.
There's another guy...unfortunately, they're
all guys currently, but hopefully not forever,
is Manuel Serrano.
He's been working on...
He's in Spain, in Barcelona.
He's been putting these factors into mice,
but there aren't just men working on the epigenome
of aging.
So a couple of really top leaders.
So Anne Brunet is at Stanford.
She's been working on the epigenomic causes
of aging.
And we have Shelley Berger at UPenn who's
been studying, among other things, what makes
the difference between a short-lived ant and
a long-lived ant, they have the same genome,
just different epigenomes.
And Jessica Tyler works on the epigenetics
of yeast cells and trying to work out exactly
what I was describing earlier about the distribution
of proteins between DNA breaks and controlling
a cell's age.
But that's it.
That's basically the world's elite teams of
epigenetics of aging, but it's exploding.
Two, three years from now, we'll have hundreds
of labs.
[Rhonda]: Yeah.
It sounds...
I mean, this is cool.
It's something I've definitely...
This whole idea, like, is definitely, in some
way, come to my mind with the Yamanaka factor
and using that to, like, reset, you know,
for aging, not just about making...
I mean, there's always the, okay, well, you
can keep, you know, replenishing your cell
types in different organs and kind of keep
it going, but like, to like turn it back,
to like think it's a young cell.
Like, there's got to be a way, there's got
to be a way.
[David]: Right.
Yamanaka did us a big, a big favor.
Actually, John Gurdon who won the Nobel Prize
with Yamanaka, he really told us years ago,
back in the 1980s, that reversal of aging
is possible.
And we didn't really get it.
What he did was he took an adult cell nucleus
from a tadpole, put it into a frog's egg,
and made a new tadpole.
What that actually tells you is that your
genome can be reset to go way back, and aging
is not a one-way street.
[Rhonda]: Yeah.
The fact that you can take your adult cell
and reset it to a stem cell is proof, right?
I mean...
[David]: Right.
But now we know the machinery, at least the
beginnings of it, and it's a very exciting
time.
[Rhonda]: Yeah.
And I'm so excited right now.
I'm like, there's all this other stuff we
were going to talk about, you know?
You've mentioned these NAD boosters and we
probably should definitely get into that.
But...
[David]: Well, they're central, too, because
as I mentioned, the proteins, many of them
like the sirtuins were moving around controlling
the epigenome.
You want to stabilize that as best you can.
Animals like whales and naked mole rats have
a very stable epigenome, so there's moving
around of proteins and epigenomic noise accumulating.
If we're exercising, we're taking NAD boosters,
we do slow that process down, I believe.
[Rhonda]: Let's talk about what NAD boosters
are, so the precursors for NAD.
Right, we make NAD in our bodies, in our...
So...
[David]: Yeah.
We do.
And so, NAD is recycled in the body because
there's grams of it, you can't eat that much
easily.
And there's a cycle, it's called the salvage
pathway of NAD.
And it all starts with nicotinamide, which
is a form of niacin, vitamin B3.
But you can't just...
Well, you can, but it's not very effective,
just overdose on vitamin B3 because you need
other things to make the big molecule, NAD.
So NAD, the reason it's called nicotinamide
adenine dinucleotide is that it's got these
three main components, and the dinucleotide
is related to DNA.
But that's beside the point.
It's a big molecule so that if you give a
big molecule to cells, it doesn't get taken
up.
So we don't feed animals NAD.
And we don't just feed them nicotinamide,
which is the little end part of NAD because
it's too small in that you need these other
parts.
So NMN and NR are two molecules.
So it stands for nicotinamide mononucleotide,
which is essentially the precursor, the immediate
precursor to NAD.
If you'd give a cell NMN, it will be taken
up by a transporter, which was just discovered
by my buddy Shin Imai, we used to work together
at MIT.
Now he's at WashU.
A few weeks ago, he wrote about it.
I wrote about it, that there's a transporter
that sucks up NMN, and the NMN is converted
within one step to NAD in the cell, and now
it's locked.
It's a big molecule, it's locked inside the
cell.
And that step is carried out by an enzyme.
It's got a name, it's called NAMPT.
And that enzyme goes up under stress and calorie
restriction.
And in yeast, it's the same step.
And so we showed years ago that that step
of conversion of NMN to NAD or in yeast, what
is it?
Nicotinic acid to NAD is the critical step
for boosting NAD when you're going through
your circadian rhythms, when you exercise,
when your cells are stressed.
And without that step, you don't get the benefits
of calorie restriction, your organs start
to get old.
So what is NR?
So NR is fairly popular, a lot of people have
heard of it.
It stands for nicotinamide riboside and all
it is, it's just a smaller version of NMN
without a phosphate on there.
So there's no phosphorus on it.
So if you take NR, your body has to first
put on a phosphorus and then it has to basically
link two of them together to make the NAD.
So with all that said...
[Rhonda]: NR gets converted into NMN first
and then into NAD?
[David]: Yes.
Yes, it has to.
Yeah.
But NR and NMN have both been shown to raise
the NAD levels in animals and in humans as
well.
And there's small nuances about the differences,
but they both seem to be effective, not just
in humans, actually, I should say, in mice.
But in yeast, they work as well, which is
nice.
I suppose people are interested in the plant
world and what we eat, these same pathways,
these sirtuin pathways exist in plants as
well and they get turned on in response to
stress.
And we call this xenohormesis, the idea that
when we eat stressed plants, we get those
molecules and they help our bodies.
So resveratrol, going back to that old chestnut,
it's a great molecule that is produced when
the grapes get stressed and...
[Rhonda]: It's got fungus, right?
[David]: Well, fungus will stimulate it.
[Rhonda]: Fungus stimulate it, okay.
[David]: Yeah.
Or lack of water.
So when they harvest red wine, they hope for
a dry season, that'll boost the resveratrol
levels and other good polyphenol molecules.
And we think that...I think that when you
ingest those molecules, the sirtuins have
evolved to sense the plant world and if your
food is stressed out, your body will hunker
down and become fitter as a result of sensing
that because, you know, we can see crops that
are dying or if the water table's drying up,
maybe we can sense that, but little animals
that we evolved from or even, you know, a
squirrel, it's too dumb to know that its food
supply's stressed out, its body has to take
care of that message.
[Rhonda]: Yes.
So the resveratrol is activating all these
stress response pathways that are basically,
you know, in our, you know, we have in our
body and basically turning on all these genes
that are helping you deal with stress.
But they're, like, staying activated for longer.
And so, when, you know, basically aging, which
is a stress, you're basically dealing with
aging better in a way.
Right?
[David]: Couldn't put it myself.
And then the opposite, if you spend your whole
day sitting, or typing, or you're always satisfying
your hunger, your sirtuins, and your other
pathways, AMP kinase, mTOR, they say, "Hey,
times are good.
Let's just grow tissue, go forth, multiply
and not build a sustainable body in the long
run."
Because there's always a tradeoff, which Tom
Kirkwood called the disposable soma hypothesis.
And it seemed to be very true.
So you want to always have your body in a
state of a little bit of stress, hormesis,
we call that.
[Rhonda]: Yes.
People that are listening to the podcast have
heard me talk about hormesis quite a bit.
My favorite is sulforaphane, the molecule
in the cruciferous vegetables.
But I've been...
You know, the resveratrol field, when I first
was following it back in, I guess, the early
2000s, you know, I was very skeptical that
there would be any effect in humans taking
resveratrol because, certainly not from drinking
a glass of wine.
But from supplementing, just because it seemed
as though, like, the doses required to get
some really beneficial effects, at least in
some of the rodent studies seemed sort of,
you know, high and it didn't seem very attainable.
But as you know, there was a really sort of
compelling primate study in rhesus monkeys.
I forgot when that was published.
It was like mid-2000s, or 2011, or something
like that.
[David]: Right.
Rafa de Cabo's group with NIH.
[Rhonda]: Yes, that's right.
They gave these rhesus monkeys resveratrol,
and I think they started out with a lower
dose, like 80 milligrams per kilogram and
they went up to, like, 480.
Any reason?
Do you know why they start with...
I've seen more than one study do that.
[David]: Yeah.
So just anecdotally, what Rafa told me, I
think, is that they started at the low dose
and didn't see a change in pulse wave velocity
in the blood vessels, so they upped it and
then that's where they saw the benefit.
[Rhonda]: Oh, okay.
Well, this study was...
You know, the doses were very doable on humans
when you, you know, convert and basically,
you know, feeding these monkeys, they're feeding
them, like, this terrible high sucrose diet,
high sucrose and high fat, and they, like,
it caused them to have, like, 40% increased
aortic stiffness, but the resveratrol completely
ameliorated it, like...
So I was like, "Holy crap, that's pretty cool."
I think that was the one study that sort of
changed my view and then I started to sort
of get into the literature and read ones that
there was, you know, there's been a variety
of clinical studies, as you know, and...
[David]: Yeah.
Well, I'm glad somebody is reading the literature.
Because there was a "hate me" club with resveratrol
because it got so much attention.
And anything that gets a lot of attention
gets the "hate me" club in reverse.
But resveratrol, I still take resveratrol,
probably a gram or so every morning.
[Rhonda]: A gram?
Really?
[David]: Yeah.
In my yogurt.
I don't measure it out, I just shake it in.
So it might be half a gram to a gram.
[Rhonda]: Is this from your own, like, stash
or is it like a...
[David]: It's a stash in the basement.
I've had it for years.
[Rhonda]: It's a private stash?
[David]: It is.
I'm not a drug dealer.
[Rhonda]: Because I don't usually find doses
of resveratrol above 250 milligrams, I think.
[David]: Yeah.
Right.
You made a good point, which is it's a really
insoluble molecule and that's one of the...
Well, there are two problems with resveratrol,
one is it's really insoluble.
So if you just give it as a dry powder to
an animal or a human, it's less likely to
get absorbed.
We know that as a fact.
Include it with a bit of fat, it'll go up
five to tenfold in the bloodstream.
[Rhonda]: Really?
[David]: It's like a big effect we've seen
in mice and monkeys, it was with a bit of
fat in the diet as well.
And then the second problem with resveratrol
is that it's light sensitive.
And so those people who...researchers who
put it in a plate with worms or didn't treat
the molecule with respect, it goes brown.
It goes off.
It's one of the reasons it's very hard to
put in a cosmetic because your cosmetic will
turn brown.
If you use brown resveratrol, it won't work.
So you've got to keep it in the dark, in the
cold, and it'll be fine.
[Rhonda]: Okay.
So...
[David]: Or in a basement.
[Rhonda]: ...cold, dark, and also I think
there's various forms like trans-resveratrol.
[David]: I'd go for the trans because when
we gave the cis form to the sirtuin enzyme,
it didn't activate it, but the trans worked
brilliantly.
Yeah.
Rafa de Cabo, actually, he's been a good friend
over the years.
A great colleague.
He did the study with us on the mouse, resveratrol
study that showed that on a high-fat diet,
those mice were extremely healthy and longer
lived and their organs, when they opened up
the mice, they were pristine.
So the mice were still obese, so we didn't
give them a lot of resveratrol, it was pretty
low dose, but their organs were so beautiful.
Their arteries, when you stain them for oil
or fat, it was night and day.
The ones on resveratrol or the ones without
resveratrol were stained with fatty lumps.
resveratrol, clean.
And that alone makes me say, you know, resveratrol's
probably not going to hurt me and it may very
well help my cardiovascular system.
[Rhonda]: It seems to be really important
for a cardiovascular system, like...
And I'm just kind of, do you know why, why
is it...?
[David]: We have a number of ideas.
And resveratrol is a dirty molecule, so there's
not just one way it works.
Sirtuins definitely are involved.
We now have a mouse that's mutant for the
resveratrol activation of SIRT1, so we now
see that some aspects, like endurance, of
resveratrol seem to be through SIRT1.
So one of the effects is through SIRT1's anti-inflammatory
actions in the lining of the blood vessels,
the endothelial cells.
[Rhonda]: Oh.
Okay.
[David]: Yeah.
That seems to be important.
And there's other aspects also in DNA repair
as well.
infiltration of macrophages in there seems
to be dampened.
And we also looked at oxidative stress in
those arteries of those mice treated and it
was way down in the resveratrol mice.
[Rhonda]: Yeah.
With the rhesus monkeys, with the, you know,
basically like, you know, completely reversing
that 40% aortic stiffness, that's like pretty,
it's a pretty dramatic effect.
So I was...
[David]: It is.
And so, yeah, I think resveratrol, it's...
People are, you know, "Oh, is it true, is
it not?"
"60 Minutes" did a story and then there was
an argument about how it was working.
And so people are confused about the molecule,
and I still stand by it because the results,
like you say, in animals.
And there are clinical studies now that are
really positive in humans.
Not all of them, sometimes it has no effect.
There was one study where it interfered with
endurance exercise.
Don't understand that.
[Rhonda]: Metformin was kind of shown to do
something similar where it prevented mitochondrial
adaptations in [crosstalk 00:47:47] but who
knows?
[David]: I mean, maybe...
Rhonda, what's maybe happening is that if
you're dampening free radicals too much, you're
actually losing that benefit.
[Rhonda]: Hormetic effect.
[David]: Exactly.
The mitohormesis.
But I haven't seen any downside.
You know, I'm a N-of-one, as you would say,
in a clinical trial.
I've had my heart checked out with a 3D movie
MRI.
My heart looks like it's 20, it's got no sign
of aging.
So, it doesn't seem to be doing myself and
my dad any harm.
So...
[Rhonda]: How long have you been taking it?
[David]: Oh, geez.
Since 2003.
[Rhonda]: Wow.
And you take about a gram [inaudible 00:48:22]
or so a day.
Yeah.
There was a couple of studies, as you know,
there's phase one and two clinical studies
on Alzheimer's disease where they were given
500 milligrams or 1,000 milligrams of resveratrol
a day and both of these studies found that
there was a reduction in amyloid beta 42 in
cerebral spinal fluid.
There was an improvement in cognitive function
and a couple of other parameters.
So it was kind of interesting because I recently
had Dr. Dale Bredesen on the podcast and he
has this whole protocol where he's able to,
with certain, you know, diet and lifestyle
factors, you know, improve cognitive function
and also by MRI, like, have shown to, like,
reverse some of the atrophy in the hippocampus.
And so resveratrol was on his...
He's got this long list and I kind of like,
everything in the kitchen sink where I was
like, "Geez, like, what is all..."
And resveratrol was on there.
I never really knew why until I, very recently,
was reading a little bit of the clinical studies.
I thought that was super interesting as well.
And then the other thing that was interesting,
as you know, was the autophagy because resveratrol
seems to be activating autophagy and I also
interviewed Guido Kroemer on the podcast.
[David]: Oh, you did?
Okay.
[Rhonda]: And he talks about these three signals
that are important for autophagy, and one
of them is the increase in protein...
Oh, wait, decrease in protein acetylation?
[David]: Yeah.
[Rhonda]: Yeah.
Because sirtuins are histone deacetylases.
So that would lead to, right?
A decrease in protein acetylation.
[David]: That's exactly right.
So that's how these Pac-Man enzymes are working.
And one of the enzymes that they work on is
an autophagy protein that goes and destroys
bad protein.
So it's perfectly reasonable to think that
if you take resveratrol, it might be clearing
the body of those proteins.
[Rhonda]: Yeah.
I have seen the study with resveratrol, so
that's...
[David]: Yeah, Richard Turner, I believe.
That's the study I think you're referring
to and it looked really promising.
And he did what looked like a very convincing
study, but he actually is still trying to
raise the money to do his larger trial.
And I'm trying to help him with that, but
I would love to see that repeated in women
and more people.
[Rhonda]: Yeah.
I know that Dr. Kroemer has published a study
looking at biomarkers of autophagy in humans
after they've been fasted.
And I think one of those was looking at, like,
the acetylation on lysine or something.
So, it seemed to be working.
So it's all very interesting.
[David]: The NAD boosters also help the brain.
So, at least in mice, a couple of labs have
published now in top journals like "Cell"
that raising the NAD levels in the brain also
improves memory and slows down the advancement
of Alzheimer's.
In mice, admittedly, I know we've cured Alzheimer's
in mice [inaudible 00:51:23]...
[Rhonda]: Well, both nicotinamide riboside
and nicotinamide mononucleotide have been
shown to do that in animal studies, right?
[David]: Yeah.
You've been...
Yeah, I'm amazed how much you know.
So that's true.
I would love to do a human study.
Actually, one of the benefits that we might
see is also improved blood flow and that might
be helpful for vascular dementia because,
as I'm sure you know, we've shown that NMN
and others have shown for NR that it also
helps with blood flow and actually mimic exercise
and regrow the vascular system.
And we've done that for muscle.
We've got some early results that it also
helped restore blood flow in the brain, which
is badly needed for a lot of elderly people.
[Rhonda]: Right.
Yeah, I know that's a big...
I mean, that's a big thing for cognitive function.
So NMN was able to do that.
[David]: In mice, yeah.
[Rhonda]: In mice.
Yeah.
So with the clinical studies, you know, I've
seen a couple with nicotinamide riboside,
but I guess the, you know, the question is
with the nicotinamide riboside, there's been
a little confusion about like, you know, whether
or not nicotinamide riboside's even really
getting converted into NAD inside cells and
different organs other than the liver.
This was this NAD flux paper that was done
by Rabinowitz?
[David]: Rabinowitz?
[Rhonda]: Rabinowitz.
Thank you.
Yes, that study he recently published just
a few months ago looking at nicotinamide riboside
and how orally, at a dose half of what typically
is used in all the other nicotinamide riboside
animal studies.
So typically, they do 400 milligrams per kilogram
body weight per day.
I don't remember how long, the duration they
were doing it.
But in the NAD flux study, he did 200 milligrams
per kilogram body weight, which is significantly
less than what all of these other studies
like the one you mentioned with Alzheimer's
disease and other studies that have shown
improvements in mitochondrial function in
mitochondrial mutator mice, and also muscular
dystrophy, and all that.
So...
[David]: Yeah, we use double that dose for
a while.
[Rhonda]: Yeah, so maybe, you know, this NAD
flux study that showed nicotinamide riboside
given orally didn't form NAD in the muscle,
but it did in the liver could have been a
dose-dependent thing?
[David]: It would make sense because we've
done a lot of this in mice and now in humans,
and that there's a threshold that you need
to cross, you need to take a certain amount
to get over probably the body's clearance
mechanisms and then you get up to a level
that plateaus after about nine days.
And they may have just been under that threshold,
so the body was just clearing it out.
But you have to seemingly overwhelm that clear-out
system, so that's why we do at least 400 mgs
per kilogram in mice.
[Rhonda]: And that's with nicotinamide riboside.
The question is, I mean, that's like if you
talk about a human equivalent dose for like
a 180-pound man, that's like over two grams
a day.
And it kind of leads me to my next question,
which was the most recent clinical study with
nicotinamide riboside where they actually
used a much higher dose than the original
study that was done with Basis, the Elysium
that had pterostilbene in it.
This dose was like 1,000 milligrams a day
and they looked at a variety of endpoints
in addition to...I mean, they looked at endurance,
looked at...
[David]: Right.
It was Doug Seals' study.
[Rhonda]: Yes.
And there was no statistical significance
in anything.
It raised NAD levels, but there was no statistical
significance.
There was trending improvement in the vascular
system, but there was no effect on endurance.
And I'm wondering again, well, if we go back
to the human equivalent dose, what was given
to the animals, that was still less than half.
I mean, so the question becomes, is it not
even making NAD in the muscle tissue at that
dose or, you know, so...which brings me to
the nicotinamide mononucleotide.
You know, like now those studies have been
done in animals at a much lower dose than
400 milligrams.
[David]: They have.
Yeah.
So we, in my lab, and at the company, Metro
Biotech, we've been using a whole variety
of different molecules and different...
We're doing what's called pharmacokinetics.
So there's a lot of literature that I could
talk for another hour on.
One of the big questions people ask me is,
"Have you ever put NR and NMN head to head
in a study?"
And we need to do a lot more of those, typically
they're not done.
And I'm unaware of it being done in humans
at this point.
But in mice, what we see...
And for all the NR folks out there, please
don't be angry, this is just data.
I don't run the experiments, I just deliver
the message.
That at the same dose, NMN will increase endurance.
And I forget what that dose was.
It might've been 200, 250.
[Rhonda]: Yeah, 200.
[David]: NMN didn't increase...
Sorry, NR did not increase endurance, but
NMN did.
We do find that for some parameters, and Matt
Kaeberlein, who I mentioned earlier who, he
works on dog aging now after doing the SIR2
extension lifespan.
So Matt also has published that, comparing
NR and NMN, only NMN worked in his disease
model, which was a mitochondrial disease where
those animals really need a boost of NAD.
So one of the issues could be that NMN is
a better molecule in that regard.
It could be that maybe the mice just worked
better than humans and we need a bigger dose.
But what I'm working on, which is not talked
about a lot because it's in the commercial
realm, is there's been a team of seven chemists
working on much better molecules than any
of these two that I'm talking about, super
NAD boosters.
And we have ones that work far better than
NMN.
And these are timed release.
These are what we call prodrugs.
And those are the ones that I'm really excited
about for medicines of the future that don't
just increase someone's endurance but could
actually treat diabetes, and heart disease,
and cancer, and Alzheimer's.
That said, we are doing a clinical trial right
now with a molecule called MIB 636.
MIB is just Metro Biotech.
And that's a couple of clinical trials that
are being done at Brigham and Women's Hospital
in Boston, separate group for me, it's all
independent.
And that's just a safety study.
So when I come back on your show, if I come
up back on your show, maybe I'll tell you
if we see some actual efficacy, some results.
We're going to be looking in the phase two
study at strength and endurance in the muscle
of people after some NMN dosing.
So we're on the verge of knowing if this is
real or not for people.
[Rhonda]: Is this the first NMN study that's
being done in humans, clinical study that
you're doing here?
Or is...
[David]: So we've done a couple, but yes,
as far as I'm aware, we're the only ones that...
Actually, you remind me to say something important
for the listeners.
Make sure your NR and your NMN is kept in
the cold.
If it's just on the shelf and it's not in
a stabilized form, then it will degrade into
nicotinamide, which is something you don't
want to take high doses of because we've showed
in my lab many years ago that nicotinamide
will inhibit the sirtuins, and PARP as well,
and interfere with DNA repair.
[Rhonda]: What?
Really?
[David]: Yeah.
[Rhonda]: Like the form that's in vitamins?
[David]: Right.
It doesn't have a super long shelf life, that's
not very well known.
So keep it cool, in a freezer or the fridge.
[Rhonda]: But I mean, like, if you're buying
nicotinamide riboside, you know, from a variety
of companies that make it, it's certainly
not shipped to you cold.
So the question is how much of it's already
degraded just on the shelf?
[David]: I don't know.
[Rhonda]: I mean, it's kind of the case with
probiotics.
You know, when you get probiotics, you want
them to be shipped to you cold, you know,
so that they're live.
[David]: Right.
Same thing here.
We have to also replace our mouse NMN.
We put it in their water.
We replace that every week because it goes
off, but if it gets wet or it gets a bit of
humidity in the bottle, it's only a short
time before it's degrading.
[Rhonda]: Wow.
And we were talking a little bit before the
podcast about...
I was super excited.
I think it was the 2016 "Cell" paper, you
mentioned the group that published the NMN,
basically, that was given to normal mice without
any...
[David]: Yeah.
Shin Imai's study.
[Rhonda]: Shin Imai's study.
That's right.
And basically, I think it was about 200 milligrams
per day, like that dose, because I remember
looking at the dose and going, "This is significantly
lower than a nicotinamide riboside dose.
And it seemed to delay tissue aging in multiple
organs where, I mean, it was like...
I don't know, did it extend lifespan?
[David]: He didn't take it long enough.
He ran out of material.
And in those days, NMN was hard to get and
it was very expensive.
It still is very expensive.
We're still paying tens of thousands per kilo.
But what he showed was that over a year of
treatment, pretty much all the parameters
of health in these mice were improved.
And if those mice didn't live longer, I'd
be surprised.
But we have done an NMN lifespan in my lab
and it's still ongoing and it's being crowdsource
funded.
So thank you for your donations.
But it, already, it looks significantly different.
The group that's on NMN in their water supply.
And also, it improves frailty.
In other words, they're less frail.
Looks like it improves heart function as well.
The dose, I can't exactly remember what we're
using.
It's probably around the 400, which is what's
our standard dose, but don't quote me.
But yeah, NMN and NR seem to do remarkable
things to rodents.
But like you say, like you brought up the
challenges, A, does it work in humans?
And B, if it does, what dose is necessary
to get those effects?
[Rhonda]: Right.
And is it going to be side effects with, like
if you read the most recent study, the clinical
study where the dose of nicotinamide riboside
was, like, 1,000 milligrams, there were a
lot of people that dropped out because they
had rashes and...I mean, there was flushing.
[David]: Oh, they did?
[Rhonda]: Yeah, there's some side effects.
There were some side effects.
[David]: It might be with NR.
We've never seen anything like that with NMN.
And I take a gram of NMN every morning.
[Rhonda]: So the NMN is the reason why there
are more studies with NR because NMN is so
expensive?
[David]: Yeah.
Well, historically, some companies started
making NR early on and made it widely available
and cheap to researchers, in fact, so cheap,
they were giving it away to researchers.
So, it became used much more often than NMN.
But increasingly, and if any scientist, lab
wants some NMN, let me know, I'm happy to
subsidize it if they'd like.
But, yeah.
And NMN was late on the scene because it was
harder to synthesize because it's a bigger
molecule, needs that phosphate, and phosphate
chemistry is quite difficult.
[Rhonda]: So you mentioned that the company
that you're...
Is this the company that is trying to get
supplements of NMN or is this like...
[David]: So I don't do supplements and I don't
endorse products.
You can only do one.
It doesn't work for both.
So I've committed my career to making pharmaceuticals
that are proven to work and are proven safe
and are awarded, you know, marketability by
the FDA.
[Rhonda]: So a drug, basically, from...
[David]: It's a drug.
It's a drug.
And that's because early in my career, I dabbled
in the supplement world with resveratrol.
And it only lasted about three weeks before
I had to get out because of...
It's incompatible for me, at least, me to
be able to, without getting criticized, "This
is what I think, this is the data," and I
want to be able to say that without making
any money off it.
But also, I find that the supplement world,
it's so controversial and litigious that I
was scared away.
It's a sad thing that I'm unable to talk about
supplements by name because I obviously know
a fair bit, but I just can't because, you
know, I've already been dragged into lawsuits,
I've lost a lot of money by that.
I've done nothing wrong except open my mouth.
And there are a lot of companies out there
who have a lot of money who don't want me
to say things.
So, unfortunately, you know, I really am unable
to do that.
I do tweet out and do social media where I
can.
I've written blogs about it.
Like, I'm probably one of the few scientists
that tells the world what I do personally
and use myself as a role model for people
to judge.
But I never recommend anything because, first
of all, I'm not a physician.
I'm just a scientist and I mostly study mice.
So I don't really know yet how this is all
going to play out in people.
[Rhonda]: It'd be nice if NMN could be available
without a prescription now.
[David]: Well, it would, but it will also
be nice if someone like me did a clinical
trial so we knew what would happen and what
dose to take.
[Rhonda]: Yes.
Well, that would be...
That's first and foremost.
I mean, knowing the dose to take that's actually
has any effect.
Right?
It's not just like, yeah...
I mean, don't just take some X amount just
because it makes you feel good.
I mean, a placebo does something, it definitely
is changing dopamine in the immune system
and stuff.
But I agree.
Yeah.
So you mentioned supplements, you take a gram
of resveratrol...
Sorry, not a...
Yeah, a gram?
[David]: It is a gram of resveratrol, whatever
I pour out into my yogurt.
[Rhonda]: And about a gram of nicotinamide.
[David]: And NMN. [crosstalk 01:04:29]
[Rhonda]: And that's also in your yogurt as
well?
[David]: No, I can just take that as a capsule
in the morning, down it with a cup of coffee.
And that's a pretty big boost, I find, physiologically,
those three things with caffeine included.
You can ask my friends.
Sometimes I have to temper it a little because
I'm like a mouse on oxygen, running around
the cage a little bit too much.
But it works for me.
It helps with...
I believe it helps me with jet lag as well
or a lack of sleep.
I've got three kids, so sometimes I don't
sleep well.
I know you have a young one, so you know what
that's like.
[Rhonda]: Thankfully, I'm starting to sleep
well now, but sleep is really important for
aging as well, particularly the aging brain,
you know, so...
In fact, I was wearing a continuous glucose
monitor.
I've been wearing one for a few months now.
And my son, like around Thanksgiving time,
started having teething and stuff and he started
waking up in the middle of the night and he'd
be up for like an hour and it was like...
So I was basically having very fragmented
sleep and my blood glucose levels, like my
fasting blood glucose levels and my postprandial
were, like, 15 to 20 units higher.
And this was, like, repeatable, very...
I was, you know, my diet's...
Pretty much, I eat the same thing, so it wasn't
like eating anything like a cookie or anything
like that.
I mean, it was just like...
And doing some high-intensity interval training
did help, and there are actually some research
on that, but I was astounded by the effect
sleep had or a lack of sleep.
[David]: Yeah.
If you take a rat and deprive it of sleep,
it will get diabetes within a matter of a
month or so.
[Rhonda]: I mean, it's just like it was...
You know, I'd read the studies.
I had Dr. Matt Walker on the podcast, talked
all about it.
But when it happens to yourself and you see
the data, I mean, of course, it's still just
an N-of-one for me.
But I mean, it was just like, it was very...
To me, it made it very real.
I was like, "This really is regulating my
insulin level, my insulin sensitivity."
[David]: Right.
I could see my age changing when I had young
kids.
[Rhonda]: Oh, absolutely.
I've aged for sure.
I mean, I can see it, like the...
You know, especially as a nursing mother in
the early, you know, days of my son being
born, it was just so hard.
I mean, it was so hard.
[David]: Yeah.
Just check out photos of me in my 30s and
early 40s when it was lack of sleep and stress
and my wife screaming at me for traveling,
that kind of stuff.
That wore me out.
You can see that I aged rapidly.
Since then, I don't think and others don't
think that I've aged much since then.
So it's sleep and stress.
All important.
Yeah.
How much do you sleep at night?
[David]: Well, often, I'm working up until
11:00, which is a bad habit, but I have found
ways to get to sleep pretty quickly.
Avoiding blue light, so I wear those yellowish
glasses.
What do I do?
Occasionally, I take a nibble of a sleeping
pill occasionally when I really have trouble
sleeping because I used to be an insomniac.
But what I've found is the doses that they
prescribe for some of these medicines, I won't
say which, but I'm way more than I need at
least.
And so I just nibble on it and it's enough
to get me to calm down and I go to sleep.
And then in the morning, I get my boost and
I'm going again.
But I typically get seven hours sleep.
And if I don't get more than that...sorry,
if I get less than that, I'm in trouble because
my brain needs to be going at 100 miles an
hour every day.
[Rhonda]: Yeah.
Doesn't work.
Have you ever heard of the Phillips Hue lights?
Philips Hue is really...it's like they make
these lights, we have them around our house,
that you can program your phone and they turn
red at a certain hour, so like ours go red
at sunset and so there's no blue light coming.
And it's really like, you know, to think about
it, it really makes a difference.
And developing children are really sensitive
to light, like even more sensitive than adults.
So, like I'll notice if we're traveling and
we're in a hotel room or if we're visiting,
like, my in-laws in, you know, another state
and they have lights on at night that my son,
it's like it's harder to get him to go to
bed and it's...I mean, it's very obvious,
and so I'm always like freaking out trying
to turn off the lights.
I'm like, "We're going to be in the dark."
[David]: Yeah, me too.
And so, my kids and I, three of us, we got
my wife for Christmas one of these indoor
plant growth, like, hydroponics and the light
for that hydroponic unit, it's about a foot
long, maybe two feet.
It's super bright and it's in the kitchen.
And it was so bright that I was finding I
couldn't sleep because it also comes on at
night and it's just this intense light.
So we've had to move it to the dining room
and drape clothing over it because, otherwise,
I wasn't getting...
[Rhonda]: Oh, yeah, like hotel rooms with
the alarm clock.
It's like blue lights, like, it's like lighting
up the room, you know, or I'm like always
throwing stuff.
We've got a HEPA filter and there's, like,
this right red light.
I mean, I'm just like, "Who's designing this
stuff?"
You know, you don't want light when you're
trying to sleep and stuff.
[David]: I'm with you.
In my bedroom, our bedroom, we've got lights
popping up.
Everything is glowing now, and they like to
put blue lights in these things now that they're
trendy.
Does anyone not think it's...
[Rhonda]: No.
Yeah, I know.
Anyways, that's a whole other topic.
Super excited about all your research.
The epigenetic clock stuff has me super pumped
up, David.
We'll have to, like, stay in touch.
I mean, I'm super...
[David]: That sounds good.
[Rhonda]: It's an understatement how excited
I am.
Like I definitely want to talk to Steve.
I want to get in touch with him as well.
But, yeah.
This is like...
[David]: Yeah, so the people I mentioned,
so Steve Horvath, Manuel Serrano, and Juan
Carlos Belmonte, have just formed an entity
to fund research in this area and to go into
human clinical trials, probably in glaucoma,
which is a disease that's extremely hard to
treat, you cannot reverse the damage that's
been done and we think we might be able to.
So it's exciting times.
The research is going extremely fast, makes
my head spin.
I get texts every day of breakthroughs, which
is a great, I guess, a privilege.
But yeah, I'd love to come back and tell you
more.
I tweet out some results these days.
I used to be very tight-lipped, but now, it's
too exciting not to tell people about it as
we discover it.
[Rhonda]: Right.
Totally.
I'm following you on Twitter, so that's definitely...
If people want to find you on Twitter, your
Twitter handle is?
[David]: @davidasinclair.
[Rhonda]: @davidasinclair.
[David]: A for Andrew.
[Rhonda]: A for Andrew.
And you have a website, a book coming out.
[David]: Well, we have a lab website.
We'll shortly launch a book website where
there will be information and build a community
around the book.
The book comes out in September.
It's an unusual book, it's illustrated by
one of America's greatest talents for medical
illustration, Katie Delphia, and so that's
speckled in there.
And we've got a cast of characters in there
that range from Captain Arthur Phillip, who
founded Sydney colony, who used to hang out
in my backyard in Sydney 200 years before,
all the way through to scientists in London
who were making major discoveries that led
us to today and then it projects forward.
With me having a front row seat on this field,
both in the biology and industry, what does
the future look like?
What does it look like if we don't succeed,
which is pretty bad.
What does it look like if our wildest dreams
come true?
What's that world look like for us and our
descendants?
[Rhonda]: Awesome.
[David]: And maybe we get to see our descendants.
[Rhonda]: Yes.
Definitely, I'm looking forward to the book,
for sure.
Thank you for connecting up with me.
Big fan of your research for quite some time
and I'm even more excited now about all the
new stuff going on.
I had no idea.
I mean, you just started talking about it
and was like, "Yes."
[David]: Well, thanks, Rhonda.
It's really great to be able to talk about
it with someone who literally knows as much
as I do about the topic.
[Rhonda]: That's flattering.
Thanks, David.
[David]: Thanks.
