Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate, HDAC Inhibitors & NAD+

Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate, HDAC Inhibitors & NAD+

July 21, 2019 100 By William Morgan


Rhonda: Hello, everyone.
Welcome back to another episode of the “FoundMyFitness”
podcast.
I am sitting here with Dr. Eric Verdin, who
is the president of the Buck Institute for
Research on Aging.
Now, I recently saw a quote from you that
said you stated that a child born in the year
2007 had a 50% chance of living to be 104
years old.
Dr. Verdin: Yes.
Rhonda: First of all, yes, you did.
Can you explain what you mean by that?
Because that’s pretty exciting.
Dr. Verdin: I think it says what it says based
on the projection of where the progression
and lifespan that has happened during the
last 100 years, which has been about 2 years
per decade.
I think scientists at Berkeley actually have
been able to…
This data comes out of a book that was based
on data from Berkeley suggesting that a child
born in 2007 has a 50% chance of living to
104.
Rhonda: After reading that quote, I was thinking,
“Well, maybe some of these lifestyle interventions
that we know to regulate the aging process
that we know that can have a positive effect
on healthspan.
Can you maybe tell people a little bit about
what are some of the main lifestyle interventions
that are known to regulate the aging process
at least in animal models?
Dr. Verdin: Yes.
And in humans as well.
I think, there are, you know, four broad categories
of things that are being considered by the
aging field.
One is exercise is to this day the surest,
best intervention that we have to increase
healthspan and lifespan.
The second one is nutrition, and there’s
a lot of research going on today trying to
understand what is it about nutrition and
carbohydrates versus fat, versus proteins,
what is the relative role of all these nutrients
in your lifespan and healthspan.
The third one, which is actually an active
field of investigation, is the identification
of molecules that mimic either exercise or
the sort of exercise mimetic or mimic restriction
in terms of nutrients, what we call calorie
restriction mimetics.
And, finally, the last part of the whole aging
field is the idea of rejuvenation.
So, the first three approaches are geared
towards slowing down the process of aging.
Rejuvenation takes the approach that once
the aging has occurred how can you repair
it and how can you fix it.
So, I think, you know, we have programs here
that are studying all four different approaches.
I think you’re probably familiar with Jack
LaLanne, who is one of the gurus that started
the American sort of infatuation with exercise.
He lived to 100 years old, and he said that,
“Exercise is king.
Nutrition is queen.
Put them together, and you have a kingdom,”
which I think is really true.
You know, for me and many of my colleagues,
I think exercise and nutrition is the cornerstone
of what we’re trying to do today until we
have better drugs.
Rhonda: It’s a beautiful quote.
And in terms of the nutrition, when I think
of nutrition, you mentioned, you know, the
macronutrient content, trying to understand
the ratios of carbohydrates, and protein,
and fat, I often think of the micronutrients
when I think of nutrition.
My mentor for my postdoc was Dr. Bruce Ames,
and, of course, you know, he’s very focused
on micronutrients, vitamins, minerals, essential
fatty acids, and amino acids.
But, in the past couple of decades, the research
has seemed to show that limiting these certain
macronutrients, protein, fat, carbohydrates,
you sort of tweak the amount that you take
in, you can alter the way an animal ages at
least in terms of the way their tissues are
aging.
You’re not necessarily going to, you know,
increase their maximum lifespan, but you may
increase their average lifespan, which is…
Dr. Verdin: Yes, I think, in the last 20 years,
we’ve learned a lot.
And, a lot of these research has been actually
causing a reevaluation of some of the public
policies that have been enacted in the last
20 and 30 years in terms of what should you
eat, when should you eat.
So, a lot of work is ongoing today and actually
generating lots of really interesting data.
Along with this, the basic science of aging,
I think what people have studied is trying
to understand what are the pathways that control
aging in C. elegans, in Drosophila, the fruit
flies, in the little nematode, or in mice.
One of the major pathways that has emerged
is insulin signaling pathway.
That was the work of Cynthia Kenyon back in
1990 showing that the insulin signaling pathway
is one of the major pathways that controls
aging.
Well, if you know this, you can already sort
of backtrack and say, “Well, what does insulin
do?”
It’s the major hormone that allows you to
utilize carbohydrates, and so the implication
of this is the more carbohydrates you eat
the more you activate the insulin signaling
pathway, and the prediction would be that
the more or the faster you age.
And I think the real data really suggests
this model.
Now, it lies completely in the face of what
we’ve assumed to be correct.
You can walk into any store and find low-fat
diet and low-fat products.
Turns out that we really believe that the
culprit is more carbohydrates.
And a recent paper just came out, which is
really remarkable, showing, analyzing in thousands
of humans fraction of their total calorie
intake that is represented by carbohydrates,
and they were able to…just by interviewing
them and asking, you know, “What do you
eat?”
And what they showed in this paper is all-cause
mortality was directly correlated to the amount
of carbohydrate that one eats.
So, the people who ate the least amount of
carbohydrates showed the lowest all-cause
mortality.
Rhonda: Wow.
Did they differentiate between refined carbohydrates
and, for example, vegetables which are carbohydrates?
Dr. Verdin: They did.
They didn’t.
And I think, you know, this is obviously not
all carbohydrates are created equal, but I
think…
Rhonda: Possible confounder.
Dr. Verdin: Irrespective, total carbohydrate
was a very strong predictor.
But, obviously, you know, if your total carbohydrates
intake…
It’s very hard to eat a high amount of carbohydrates
that are all sort of a low absorption type
of carbohydrates.
So, typically, the people who eat a lot of
carbohydrate will eat a lot of the bad ones
as well.
Rhonda: Right.
Yeah.
Most people that are eating that are probably
eating more of a standard sort of American
diet, you know, where it’s chips, crackers,
and cookies, and I think people that are following
more like of a Paleolithic type of diet, where
they’re eating, you know, whole foods, and
meat, and nuts, probably would eat their carbohydrate
intake.
The bowl could be from vegetables, things
like that.
But, you’re mentioning a really important
point, is that the carbohydrate intake and
the insulin signaling pathway, these things,
carbohydrates regulate that, but also you
limit your carbohydrate intake when you’re
fasting, right?
I mean…
Dr. Verdin: You limit all of your intake.
Rhonda: Oh, yeah, all of it essentially, yeah.
But, your insulin signaling goes down, right?
And, maybe you could talk a little bit about,
you know, fasting, because fasting is one
of the well-known, you know, dietary interventions
that can regulate the way we ate.
Dr. Verdin: Yes.
And the key question about fasting is there’s
growing evidence that it is beneficial.
Intermittent fasting, episodic fasting can
actually illicit a response in our bodies
and many animal models that are protective
against aging.
The question is, how does it happen?
So, fasting has growing evidence that it actually
increases lifespan and healthspan, and the
so-called fasting mimicking diets are emerging.
A group, Valter Longo’s, suggesting that,
you know, these diets have really beneficial
effect on healthspan, even in humans.
Now, the key question is how do they work,
and there are multiple possible mechanism.
And it’s possible that the resulting effect
is a combination of all of them, of all mechanisms.
So, one is decreasing carbohydrate intake.
So, that would lead to a decrease in insulin
signaling.
Second one is restricting protein intake,
which would actually lead to decreased mTOR
signaling and so on.
The third one is induction of ketosis, which
is a small nutrient which is generated by
your liver during the fasting process, and
all works indicates that just ketosis and
a ketogenic diet might have beneficial effect
all by itself.
Rhonda: Yeah.
So, you recently published a paper.
Your lab recently published a paper where
you had taken male mice and given them a cyclic
ketogenic diet.
So, that started in mid-life?
Dr. Verdin: Actually, it started at one year
old.
Rhonda: One year old, okay.
Dr. Verdin: So, this is about a third of their
normal lifespan.
So, that would be equivalent of a 30-year-old
human.
Rhonda: Okay.
So, exactly you found that it increased the
healthspan of these animals?
Dr. Verdin: Yes.
Rhonda: And also there is some effect on the
brain?
Dr. Verdin: Yes.
Very interesting data suggesting…
Again, the whole experiment started on the
idea, the observation that there are many
similarities between what happens during ketosis
on a ketogenic diet and what happens on calorie-restriction
or fasting.
And so, with a colleague in the lab, John
Newman, a number of years ago, we started
asking the question, you know, “Would mice
on a ketogenic diet live longer?”
So, we spend about a year and a half with
John trying to identify the conditions where
this mice would be on fats and protein diets,
essentially had zero carbohydrates, after
one year of age.
The problem we had initially is that they
actually loved the stuff so they would just
devour this diet, and they got fat.
So, we were worried that by becoming obese
we would sort of counterbalance beneficial
effects of the ketogenic diet.
So, we spend a bit of time trying to solve
this.
Eventually, were able to put them one week
on, one week off, and that resulted in a stable
weight in the mice, and that allowed us to
look at their healthspan and lifespan at the
end of their lives.
And what we’ve saw was an increased medium
lifespan by about 10%, so their early mortality
was decreased.
But, eventually, they ended up having no increase
in maximum lifespan.
We also found a number of other variables
associated with healthspan that were significantly
increased, in particular memory.
These mice, the most remarkable thing we saw
is that these older mice on the ketogenic
diet showed actually better memory than younger
mice, and certainly we did not see the loss
of memory function that one would normally
see associated with the aging process.
So, I think it was a pretty profound observation.
I should say also Jon Ramsey and his colleague
at UC Davis conducted the same type of experiment
except that instead of putting the mice on
a cyclic one week, one week off diet, they
allotted fixed portions to the mice so they
couldn’t overeat.
They gave them the same amount of calories
that they would’ve been eating had they
been on a normal diet, and so these mice did
not get fat and were continuously on the ketogenic
diet.
And what they saw is essentially parallel
to what we saw, but the effects were even
a little better, which suggests that the cycling
might have been actually a bit stressful for
the mice over the long run.
And so I think we’re very excited by these
two studies, because they were conducted independently.
We found out only that we were pursuing the
same thing right at the end at the time of
publishing, and then we decided to coordinate
publication of the stories, and they came
out in the same journal together.
So, I think they both reinforced each other.
There is really clearly intriguing biology
there happening, and this was the first time
that this had been reported.
Rhonda: Wow, absolutely.
It’s very exciting.
I read your paper.
I did not read the parallel paper.
I did see the headline for it.
But, just to kind of go back to the memory
thing that your lab identified, so the ketone
body, the major circulating one that’s generated
is beta-hydroxybutyrate, and that’s involved
in energy metabolism, but also you have found
it has other roles in addition to its role
in energy metabolism, which we can talk about
in a minute.
But, what are your thoughts as to why, you
know, the memory enhancement was so good or,
you know, so robust?
Do you think that has to do with energy metabolism,
mitochondrial function, or do you know?
Dr. Verdin: We do not know, but it’s the
central question of everything we do right
now with respect to the ketogenic diet, is
really trying to understand.
So, beta-hydroxybutyrate is generated from
our own fat during the fasting process.
So, when we start fasting, the body needs
energy, and we’ll grab it out of our fat
cells.
These fat cells release fat in the circulation.
It goes into the liver, and the liver transforms
the fat into beta-hydroxybutyrate.
Now, why does it do this?
Because our brain cannot use fat as a source
of energy.
Our brain can only rely on glucose or on beta-hydroxybutyrate.
And so the way the system is geared up is
the fat gets released into the liver, and
the liver distributes the beta-hydroxybutyrate
to the whole brain who can then use it and
spare glucose.
So, why do you want to spare glucose?
The reason is that once you are fasting, at
least for four hours, the only way you can
make glucose is from proteins.
And so if you’re in a prolonged fast, you
start digesting your muscles to make proteins,
to make glucose, and you don’t wanna lose
all of your proteins and all of your muscles.
So, the glucose-sparing effect of beta-hydroxybutyrate
is to spare muscle mass if you’re fasting.
So, the system is really carefully engineered
to really generate a whole new way for your
body to utilize energy when you’re fasting.
Rhonda: Right.
Are you aware of the glucose-sparing effect
in the brain where…
I know it’s been shown at least in terms
of lactate.
So the astrocytes in your brain do make lactate,
because they’re glycolytic, and then neurons
will take it up much like beta-hydroxybutyrate.
They go through the same transporter.
Dr. Verdin: Yes, yes.
Rhonda: But, when there’s an abundance of
lactate, and I don’t know if studies have
been done on beta-hydroxybutyrate in the brain
looking at this specific thing or not, but
the glucose sparing that occurs is the glucose
gets shunted into the pentose phosphate pathway
to make NADPH, which is a precursor for glutathione
synthesis.
And so the idea is that under, like, a traumatic
situation, like traumatic brain injury, when
there’s a lot of oxidative stress happening,
you need glutathione to counter from that.
So, it’d be interesting to see in your study
if you can look at some of those pathways
to see if they’re upregulating or making
glutathione, because brain aging kind of is
like a traumatic insult, but, like, slowly
chronic, right?
I mean, in a way.
Dr. Verdin: Well, you know, we published a
paper.
What got us into this field was an observation
that we published in “Science” in 2010
showing that beta-hydroxybutyrate, in addition
to being a nutrient, as we just discussed,
is also a signaling molecule.
And what we found at that time was that beta-hydroxybutyrate,
which is quite similar to butyrate, butyrate
is a byproduct of bacterial fermentation in
our gut.
Actually, when we eat fibers, these bacteria
will digest the fibers into butyrates, and
this butyrate actually circulates in many
of us as we live.
Butyrate was the first known or first identified
inhibitor of HDACs, histone deacetylases,
which are epigenetic regulators, and so that
suggested that maybe beta-hydroxybutyrate
might be an endogenous regulator of these
HDACs.
Now, the reason why we were interested in
HDACs is because they have been linked to
aging as well.
Stephen Helfand’s work has shown that an
enzyme called Rpd3 in yeast is actually a
regulator of the sirtuins, which are themselves
a regulator of aging.
So, there’s a pathway that’s in yeast
that’s been established actually in Drosophila
as well linking Rpd3 to sirtuin to aging,
the aging process, and these HDACs that I’m
talking about are in the same pathway.
So, that got us to start thinking, “Could
beta-hydroxybutyrate be also an HDAC inhibitor?”
and it was.
And then this implicated that it might actually
be able to regulate gene expression, and some
of the key targets that we found were enzymes
such as FOXO3, which is a major sort of transcription
factor in humans linked to aging, and it turns
out that FOXO3 actually controls the response
to oxidative stress.
So, there’s another link there that, you
know, brings not only the pentose phosphate,
NADPH, but beta-hydroxybutyrate actually protects
against oxidative stress, both as a nutrient,
but also as a transcription or regulator.
Rhonda: That’s super cool.
Do you know what levels of beta-hydroxybutyrate
are required to sort of flip that switch and…
Dr. Verdin: It’s a very good question.
It’s probably one of the reasons why no
one did the experiment before us.
Butyrates and beta-hydroxybutyrate are poor
inhibitors.
They have very low efficiency as HDAC inhibitors.
It’s in a millimolar concentration.
And, as an inhibitor, nobody wants to work
on millimolar inhibitors, because it’s not
potent enough.
What most ipeople did not realize is that
the concentration of beta-hydroxybutyrate
in your plasma or in your brain during fasting
can go in the millimolar range very quickly.
I was reading a paper, discussing these concentrations,
and was astounded.
I thought, “Well, millimolar concentration,
this means that it might really work as an
HDAC inhibitor.”
And so we tested this by putting a pump under
the skin of a mice with beta-hydroxybutyrate
and then measuring histone acetylation throughout
the mouse, and we found that histone acetylation
marks were going up, suggesting that there
was indeed an inhibition of HDAC.
And I think that was the turning point for
us.
Rhonda: By giving them exogenous beta-hydroxybutyrate.
Dr. Verdin: Yes, not even the fasting.
Because fasting or a ketogenic diet is much
more complicated than just giving beta-hydroxybutyrate.
Rhonda: They were on a normal chow diet.
Dr. Verdin: Normal chow diet.
They were not fasted.
And we found that their ketone body levels
were going very high in the millimolar range.
And, within a few hours, their histones were
becoming hyperacetylated.
And so that for us, I think, signified that
here’s a molecule that is produced during
fasting, and they’re conditions that we
know are good for your health.
So, ketogenic diet has been indicated, has
been shown to have some beneficial effect
under a series of circumstances.
I was on this.
We had a potential signaling mechanism, and
that’s what we’ve pursued.
Rhonda: Yeah.
I do remember saying that paper was published
in “Science” at 2010 or something like
that.
Dr. Verdin: Or ‘11.
Rhonda: Yeah.
I do remember that paper.
Very super cool paper.
I actually talk about it quite often, you
know, when I’m talking about beta-hydroxybutyrate.
So, what do you think of exogenous ketone
esters?
Like, do you think that they’re safe?
Is that something that you know about or have
thought about?
Dr. Verdin: Well, we’ve thought about it.
We are experimenting with them as well.
It is one of the central questions.
It’s most of the beneficial effect that
we have seen have been with the ketogenic
diet.
Again, that’s very different from a high
beta-hydroxybutyrate level.
And one of the remaining or at least the next
step in this whole field is really to understand
what can we recapitulate with beta-hydroxybutyrate
alone, and I think we’re working actively
on this and so are many other groups.
The ketogenic diet itself it’s important
to realize is not an easy diet to live on.
You know, I don’t mean to be diminishing
the merit…
Actually, I highlight the merit of people
who are on a long-term ketogenic diet.
It takes a lot of discipline.
You basically cannot eat a significant amount
of carbohydrates.
Many people who have been on this diet for
a long time actually tout its benefits and
the fact that they feel very healthy and they
feel very present.
There are a lot of brain effects linked to
ketogenic diet.
Now, big question is what can we replicate
just by administering BHB, beta-hydroxybutyrate,
alone.
Rhonda: Yeah.
I think that you’re absolutely right, you
know, and not to mention that with a ketogenic
diet there’s also…
You know, some people can’t really do them.
You know, there are certain gene polymorphisms.
I know there’s one in the PPAR-alpha gene
which is important for the whole process of
making ketone bodies and that people have
that they actually can’t do that very well,
and so it can be sort of dangerous, and they
can have inflammation.
Sort of the opposite profile will happen,
you know, so it’s certainly something to
consider.
And then not to mention, like, you found in
your paper that you just published this year…was
it last month?
Dr. Verdin: Yeah.
Rhonda: Yeah, last month.
That you found, you know, there were multiple
changes going on.
I think there was a decrease in insulin, obviously,
and IGF-1, and mTOR activity went down.
And then, you know, so that’s something
you’re not gonna just get from beta-hydroxybutyrate.
Maybe, we don’t know.
I don’t…
Dr. Verdin: We don’t know.
I suspect, not for the mTOR part, but we compared
the ketogenic diet to a high-fat diet which
was not ketogenic, which mice ate a large
amount of fat and enough carbohydrate to suppress
ketogenesis.
And one of the biggest difference, I think,
actually between these two was the activation
of PPAR-alpha.
And this is also very exciting, because that
indicates that maybe a lot of the beneficial
effect that we see on the ketogenic diet come
from PPAR-alpha activation.
We’ve been reading that literature.
There’s quite a bit of information there
that really hasn’t been pursued as a next
direction to try to dissect these effects.
Rhonda: Because PPAR-alpha’s doing something
to the mitochondria.
What’s the main…
Dr. Verdin: It’s a key enzyme of the fasting
response, but it seems to be more highly activated
in response to the ketogenic diet than to
a pure high-fat diet.
Rhonda: What about fasting, if you compare
fasting to…
Dr. Verdin: It is activated.
We did not compare to fasting.
We compared it just high-fat to…but I think
it just points to a new direction in which
we can start dissecting what is the role of
PPAR-alpha in these responses.
Rhonda: But, with your diet, you limited the
protein intake, and you didn’t limit the
caloric intake, that was the other study?
Dr. Verdin: No.
The protein intake was actually 10% isocaloric
between all of the diets that we tested, and
the other group did the same thing.
So, we were very careful not to change the
protein intake.
And the other group actually did change a
bit the protein content, which could be taken
as a confounding variable.
So, I think we were very careful in not changing
the protein count there.
Rhonda: Is that standard for…
You know, ketogenic diets have grown in popularity.
And, you know, so do you think that the ketogenic
diet you used you hadn’t have done a 10%
protein if they had done a little bit more?
I’m not sure if maybe that technically wouldn’t
have even been a ketogenic diet.
But would it have changed the IGF-1 mTOR axis
as much, or…
Dr. Verdin: You’re bringing an important
point, which is that a number of people who
go on a ketogenic diet tend to compensate
by increasing their protein intake, which
might actually put them at risk for exactly
what you’re describing, increase IGF-1 signaling
and increase actually risk of cancer.
There’s a really close correlation between
your IGF-1 level and your risk of cancer.
So, I think this is something that needs to
be considered in the future for people who
are on a long-term ketogenic diet.
Rhonda: And with the caloric restriction diets
as well, there was a study I remember reading
that humans that end up doing caloric restriction,
like just the whole society of caloric restriction,
they eat, you know, 30% less calories than
they normally would or whatever, something
like that.
But, they end up eating a higher percentage
of protein, because it’s more satiating.
So, humans sort of naturally gravitate to
eating more protein when they’re eating
less food.
And so what’s interesting is a lot of those…
I think you even published a study recently
looking at biomarkers of aging in lymphocytes
or monocytes?
Dr. Verdin: Yes.
And we saw no difference between people in
calorie restriction.
This is something important to consider when
lot of the work that we do in the lab are
done on mice that are isogenic or congenic,
so these are mice that are also mated to one
another.
When you bring discoveries to the human population,
it is critical to take into consideration
the incredible variation between different
people and how they might respond to the same
interventions.
We know from everything that we’ve studied
in the medicine that I am not the same as
you are and you are different from your neighbor
in many biological responses, and that includes
response through calorie restriction as suspected.
In a number of people, it would actually do
them harm, and in a number of people, it will
do them good.
We know this when we test it from strains
of mice by calorie restriction.
Half of the strains actually responded by
shortening of lifespan, the other half by
an increase in lifespan.
So, we take calorie restriction, for example,
as a universal modification that will increase
lifespan.
It’s not what is seen in the literature,
and I would say the same is going to be even
more true for humans.
So, I think this brings out one of the key
things that is lacking in the field of aging,
is the identification of biomarkers that would
allow us to test on an individual basis whether
the intervention or the modifications that
you’re imposing is actually pointing you
in the right direction or in the wrong direction.
And I would caution anyone who’s considering
doing something long-term in terms of their
health to be very careful in how they feel
and how…because we don’t have these biomarkers
of aging.
They’re emerging, but they’re not validated,
and certainly not in the human populations.
They’re emerging in mice models and other
models, but sort of that’s really where
we will be going in the next few years, is
really having true biomarkers that allow us
to predict whether a given intervention is
beneficial or actually hurtful.
Rhonda: Yeah.
What do you think are the top three right
now we have for biomarkers for aging?
Dr. Verdin: I can tell you the one that are
really exciting me.
Alexander Zhavoronkov has a company called
Insilico Medicine that is building biomarkers
of aging based on facial recognition and based
on metabolites.
Just consider how…
Rhonda: Metabolites.
Dr. Verdin: Yeah.
So, consider how you and I can look at a human
and pretty much guess what their age is for
most people, and consider the fact that where
this is coming from is the fact that we’ve
lived, and we’ve met thousands of people,
and we’ve heard about their ages, and we
sort of build a database of information.
So, what Alex and his company have done is
they’ve taken the pictures of thousands
of people and fed them to a deep neural network
and artificial intelligence, and the computer
has been able to learn how to recognize and
to link on average what is the face of a 7-year-old
versus a 60-year-old.
So, you can do this, and they will tell you
what the computer thinks your age is, and
for some people you fall right on, but some
number of people you find that your age based
on your face actually looks younger or older.
So, this would be a reflection your biological
age.
He’s also been able to do this with the
blood markers.
With 20, or 30, or 40 sort of usual blood
markers, by screening a large number of people,
he can actually generate curves, and then
you can put in your blood values and see where
you fit.
So, that’s one approach.
BioAge is a company in the Bay Area that is
actually pursuing the same idea, looking at
artificial intelligence and biomarkers in
plasma or in urine and so on for identifying
your age.
And, finally, one big area is the whole idea
of the epigenetic clock.
Rhonda: Steve Horvath, yeah.
Dr. Verdin: Steve Horvath and Trey Ideker
have shown that there are changes in DNA methylation
that are actually pretty closely chronological
age.
So, I think all of those together are emerging
as indicative that there are markers that
we can reliably measure.
The key is how many of those do we need, how
can we reduce this to something that can be
a very strong predictor, not so much of your
chronological age, but of your biological
age.
Rhonda: Right.
Yeah.
I think there was a study I did read, maybe
it was the company that you mentioned, where
there was a panel of blood biomarkers that
they looked at, like, telomere length, and
immunosenescence, and, you know, the standard
panel.
And then they had people, I think it was people,
that were asked to identify their facial age
or something like that, and then they asked
their chronological age, and their facial
age actually matched their biological age
more than their chronological or something
like that.
Dr. Verdin: Exactly.
We all know in our acquaintances some people
that actually look younger and some people
that look older.
And we know this because we have a deep neural
network in our head that has allowed us to
build, you know, reference points so that
we can pretty much guess how old people are.
And the computer does it even more efficiently,
because it can be fed tens or hundreds of
thousands of pictures and…
Rhonda: That’s cool.
I want to try it out.
Dr. Verdin: Yeah.
It is actually pretty cool.
Rhonda: I’m gonna be getting my telomeres
tested, you know.
Just I don’t know how reliable that’s
gonna be.
We’ll see about it.
You know, I’ve been getting less sleep than
usual, because I’m a new mother, and that’s
what I’m trying to effect, but it’ll be
interesting to see.
Anyways, I sort of digressed.
I kind of wanted to ask you a little bit about,
you know, we’re talking about fasting, and
we talked a lot about, you know, insulin signaling
decreasing, IGF-1.
We’ve talked about before in the podcast
before with Valter Longo and others just how
protein restriction seems to really regulate
that, and that also regulates aging process,
mTOR as well.
But, something else that really seems to change
with fasting is the NAD levels, and that’s
something that, you know, your lab has studied
extensively with the sirtuins.
So, maybe could you talk a little bit about…
Because NAD is also extremely exciting to
me, and it’s pretty popular these days as
well.
Dr. Verdin: Yes.
So, NAD has emerged as one of these critical
intermediary metabolites.
Think of ketone bodies, NAD, all, I call them
currencies.
I mean, so think about the organism as a country.
You need to circulate energy, and NAD is one
way that our body is utilizing within the
cell to convert and transfer energy.
It’s almost like the Brinkman truck.
It carries the money.
And NAD is a hydride acceptor.
While we oxidize foods, it can actually serve
as an acceptor for electron, and then it can
transfer them, for example, to the respiratory
chain.
So, it’s one way for the energy to be circulated
within the cell, and there’s growing evidence
that its level decrease during aging.
Why that happens is still one of the big mysteries,
and so this has yielded a whole approach.
They’re trying to understand, first, what
are the consequences of decreased NAD levels,
and one of the consequences is that enzymes
like sirtuins which rely on NAD to exert all
of their beneficial activities actually function
less well.
That’s what happens during aging.
But, also many other enzymes that are involved
in our metabolism are relying on NAD, and
so they function less well, so your intermediary
metabolism functions less well.
The sirtuins, which are global regulators,
function less well.
Your…
Anyways, I lost my…
Rhonda: You’re basically falling apart.
Dr. Verdin: Yeah.
Essentially, you know, everything becomes
a little less efficient.
So, out of these discoveries came the idea
that maybe we should replenish the decreasing
levels of NAD, and so this has yielded some
discoveries, such as nicotinamide riboside,
nicotinamide mononucleotide, which are now
being taken by a lot of people with the hope
that they will, you know, correct some of
these problems.
One word of caution I think there is, we do
not know why these levels decrease.
They could decrease because we have decreased
production of NAD, but it could also decrease
because we have accelerated destruction of
NAD, which means, if it’s accelerated destruction,
bringing more into it is sort of like pouring
more NAD in a leaky sink.
So, I think a lot of our work right now is
trying to understand what is the cause of
the decrease in NAD during aging, because
I think it will yield very different solutions.
If you find that there’s a leaky sink, we’ll
work at plugging the sink versus keeping pouring
water.
Rhonda: I have a theory.
Dr. Verdin: Yes.
Rhonda: So, I know, you know, I did a lot
of work with DNA damage, and knowing that
one of the main enzymes…
Dr. Verdin: PARP.
Rhonda: Exactly.
I mean, if you think about…
So one of the main enzymes that repairs damage
as we age, DNA damage, PARP, requires NAD,
and it’s like if you’re accumulating more
and more damage as you age, you have to repair
more of that damage, and the more and more
damage you’re having, maybe it’s sucking
the NAD sort of like almost a triage where
you got to keep repairing that damage, so
then other things like the mitochondria suffer.
So…
Dr. Verdin: I completely agree, and so there
are two major theories right now that have
been proposed in terms of why does NAD go
down.
One is activated PARP, and, indeed, as we
age, we accumulate DNA damage.
That’s been shown, especially in the brain
recently, and so the idea is, by activating
PARP, you constantly deplete your NAD levels.
The second one is we all have in our body
a so-called salvage pathway for NAD, because
NAD turns over.
There’s this so-called salvaged pathway
that allows it to be recycled back to…so
we can get NAD from the food, but also we
salvage the one that we utilize, and the salvage
pathway has been shown to becoming paralyzed
while you age.
There’s an enzyme called NAMPT that has
received a lot of attention.
That enzyme tends to be inhibited by chronic
inflammation and a high-fat diet.
So, it could be a combination of both of these
things, but it could be actually working on
another mechanism, which is that there might
be accelerated destruction by other enzymes
beyond par.
And getting some exciting results in this
direction.
Rhonda: Cool.
So, for people that are not familiar with,
like, in terms of what role it plays, you
know, in the aging process, you know, it seems
as though, at least in some of the studies
that I’ve seen, that mitochondrial function
really seems to be important and that you’ve
shown that the sirtuin-3 in the mitochondria
itself seems to be really important for the
mitochondrial function, keeping your mitochondria
young.
Mitochondria play a very important role in
aging as well.
Dr. Verdin: A critical role.
You know, many of the aging pathways that
we know, be it the unfolded protein response,
or mitochondrial biogenesis, all point to
efficient mitochondria as one of the key ways
to stay young.
And one reason is because this is a way so
you can generate energy from glycolysis, which
is glucose, carbohydrates, which, as we know,
is linked to aging, but also via mitochondria
via a process called oxidative phosphorylation,
and that process is not necessarily depending
on glucose, but is depending on an efficient
mitochondrial function.
So, we talked about NAD-dependent enzyme.
Many of these enzymes reside in the mitochondria.
And we found that, for example, the NAD supplementation
that is being tested in a variety of aging
model requires sirtuin-3 quite often, this
mitochondrial sirtuin, yes.
Rhonda: Oh, really?
Nicotinamide riboside?
Dr. Verdin: Yes, for example, the paper we’ve
published was focused on the age-associated
or noise-induced loss of hearing.
So, if you actually subject mice or humans
to very acute noise, they have a dose-dependent
loss of hearing.
You can protect the mice completely from this
effect by supplementing with NAD.
Rhonda: Wow.
Dr. Verdin: But with nicotinamide riboside,
so if you’re going to a rock concert…
Rhonda: Right, musicians.
Dr. Verdin: …and you wanna protect yourself,
this is definitely something that…
Rhonda: Harley-Davidson riders.
Dr. Verdin: Yes.
In mice, it actually had an enormous effect,
and we found that this effect was dependent
on sirtuin-3, so in sirtuin-3 knockout mice,
the effect was lost.
Rhonda: Do you know if that was dependent
on sirtuin-3 in the mitochondria of stem cells,
or was it just any cell, or do not know?
Dr. Verdin: So, in the case of hearing loss,
it’s dependent on some really uniquely sensitive
cells in the inner ear.
But, generally, there’s been sort of an
assumption in the field that most of the effect
of nicotinamide ribosides, protective effect,
are dependent on sirtuin-1.
I think in…
Rhonda: Oh, really?
Dr. Verdin: Yes.
And, in some case, it is.
In this particular case, noise-induced hearing
loss, it was really clearly sirtuin-3.
Rhonda: So, even the studies that have looked
at, for example, I think there was a mouse,
had some sort of mitochondrial disorder, even
that one was dependent on sirtuin-1?
Dr. Verdin: No, actually it did not.
In that case, I think the assumption was that
it might be helping global mitochondrial function.
And so there’s a growing number of cases
and, for example, DNA-damage-associated disease
where you see accelerated aging where people
have been testing the effects of supplementation,
because those conditions are associated with
decreased PARP activity, just like you mentioned.
And, in those cases, I think it hasn’t always
been clearly mapped what is the real target
of NAD that is dependent for the beneficial
effect.
Rhonda: So, NAD levels do decrease with age.
Has it been looked at, like, for example,
in animals, like in rodents, when they’re
fasted, because fasting increases NAD when
they’re fasting and they’re older?
Does that help rejuvenate the NAD irrespective
of their age?
Does it…
Dr. Verdin: I don’t know.
I don’t know the answer to that question.
It’s a great question.
I think, you know, one thing that I remember
also about fasting and other critical effect
of fasting that is really essential in our
thinking is autophagy, and so, you know, there’s
growing evidence also that autophagy by itself
responds to nutrient availability, so NAD
levels, acetyl-CoA levels.
This is a new area that people are starting
to work in, including my labs, trying to understand
what is it about acetyl-CoA, which is another,
think about, currency exchanger in the cells,
intermediary metabolite that appears to have
not only a role as a nutrient, but also as
a signaling molecule.
Acetyl-CoA is in the Krebs cycle.
It’s one of the key intermediary product
of the Krebs cycle, but it’s also the substrate
for a whole family of enzymes called the acetyltransferases,
which are the opposite of what we were talking
about, the HDACs, earlier.
So, I think there’s really a lot of crosstalk
between all of these pathways, and we’re
working very actively now on modulation of
signaling the acetyl-CoA and these acetyltransferases.
Another approach is to mimic calorie restriction
in the fasting stage.
Rhonda: Yeah.
I had Dr. Guido Kroemer on the podcast, and
he has been studying that as well.
You know, it brings up a question I remember
I wanted to ask you that was sort of, you
know, biology is never just black and white,
because I remember him, with his work, he
was talking about how important decreasing
protein acetylation was for activating autophagy,
which happens during fasting, but also, during
fasting, you have these beta-hydroxybutyrate,
which is now…was it class 2 inhibitor?
Dr. Verdin: Class 1.
Rhonda: Class 1 inhibitor of the histone deacetylase,
which is kind of the opposite, a little…
Dr. Verdin: No, because you have to think,
so beta-hydroxybutyrate is one step above
the sirtuins, and actually the class 1 inhibitors
are inhibitors of…
Rhonda: Oh, they’re inhibitors.
That makes sense.
Dr. Verdin: Exactly.
And so it fits perfectly if you go back to
the…
Rhonda: So class 1 is an inhibitor of histone
deacetylase.
That makes sense now.
Okay.
Dr. Verdin: Yes.
Rhonda: Thank you.
There was a disconnect in my brain when I
find to…
Dr. Verdin: So, the whole idea of…
If you think about acetyl-CoA, and we really
draw a graph of acetyl-CoA regulating HATs,
histone acetyltransferase, and NAD+ regulating
the sirtuins, and these enzymes quite often
stay in opposition, not all of them.
But one of the key players in terms of histone
acetyltransferase is p300, and that’s the
one we’ve worked on and Guido Kroemer as
well has worked on, and it makes sense.
You get the same beneficial effects by activating
your sirtuins, which lowers acetylation, as
you do by inhibiting an acetyltransferase,
which also lowers acetylation.
So, the message is that nutrient feeding or,
you know, low histone acetyltransferase activity
or high sirtuin activity all lead to low protein
acetylation, which is beneficial.
Rhonda: And doing the ketogenic diet?
Dr. Verdin: Regulates one step above.
Rhonda: Does also, yeah.
Dr. Verdin: But, obviously, there’s some
complexity, because there are some histone
marks that are depending on one enzyme.
So, this is an oversimplified model, but so
far it holds.
Rhonda: What about autophagy with the ketogenic
diet?
Is that something…
I mean, I don’t know if it would be…
Dr. Verdin: It would be activated, because
clearly it’s a fasting mimicking diet, but
we haven’t really studied it directly.
Rhonda: Yeah.
That would be interesting to look at.
Also, the other question I would have is,
you know, there’s a lot of stress on the
liver when you’re doing that sort of diet,
right?
You’re relying on it for gluconeogenesis
to make glucose.
You’re oxidizing fat.
Has anyone looked at sort of long-term ketogenic
diets?
Dr. Verdin: Yeah.
We did.
The liver seemed perfectly fine.
Just imagine the liver is really…think about
it as sort of an energy redistributor.
If it’s not dealing with fat during fasting
and transforming fat into ketone bodies, it
is dealing with food coming in from the intestine
during feeding.
So, it’s always busy in one way or the other.
So, I don’t think that there’s anything
to be worried about it generating ketosis.
I haven’t heard of any side effects linked
to, you know, liver function and so on.
Rhonda: The other thing would be at least
with mice.
In your study, you did cyclic.
In the parallel study, they did, I guess,
continuous, but they restricted the calories,
but, you know, mice sort of, and this is something
that goes back to something that Guido was
talking about in the podcast, they have a
notoriously fast metabolism.
In fact, he said that, if you fast a mouse
for 48 hours, they can lose, like, up to 20%
of their body weight, which is, like, phenomenal.
I mean, if human could do that, there’d
be no obesity, you know.
So, do you think that the fast metabolism,
you know, coupled with something like the
ketogenic diet or even just a lot of the fasting
studies in general, is something that can…
Like, if we see something like an increase
in healthspan, and we see all these positive
benefits in rodents, is that something that
we may have hope in translating to humans,
you think?
Dr. Verdin: I do think, I mean, it’s important
to realize that mice are not humans and that
there’s a tall order in terms of proving
something that has happened in mice all the
way to humans, but that’s our mission.
I mean, that’s what we need to do.
Rhonda: And you have mechanisms.
Dr. Verdin: And we have mechanisms.
That’s the first step.
It’s not always predictive, and a large
number of drugs that have been shown to be
efficient in mice have failed into humans,
but that’s the first step that we can take.
From our work, I think the next logical step
is to go in humans and test.
Rhonda: Is a ketogenic diet something that
you’ve considered trying or doing?
Dr. Verdin: I have tried.
I have tried, and I’ve been on it for about
a year.
It’s hard to stay on.
I called it a somewhat antisocial diet, because
you can’t really drink alcohol, you can’t
eat a lot of the things that we base, you
know, our social interactions on.
No breads, no pasta, and very little fruits.
I think it’s…
Rhonda: What about vegetables?
Dr. Verdin: You can eat some vegetables, but,
you know, depending which ones.
On a global population basis, it’s not a
realistic goal to expect that everyone is
going to be on this ketogenic diet.
Rhonda: Are you gonna continue doing it or…
Dr. Verdin: No, I’m not on it right now.
And I think I find that intermittent fasting
is a much easier way to…
Rhonda: Is that something you practice?
Dr. Verdin: Yes, yes.
Not right now, but I have intermittently.
Rhonda: So, intermittent fasting, like 12
hours, 16 hours, or 24 hours?
Dr. Verdin: Well, it’s still a growing question.
There’s really interesting work coming out
of the Salk Institute on something called
time-restricted eating, time-restricted feeding,
showing that it’s not just how much you
eat or whether you’re eating carbohydrates,
but it’s also how often you eat and allowing
your everyday for a fasting period.
I think that’s probably some of the most
important work that we’ve seen recently
in this whole field.
And, you know, just think about what dietary
authorities today are recommending, is three
meals and three snacks.
I think, based on what we are doing and learning,
this is the worst possible way that you can
possibly eat.
So, I think allowing for each day to have
this really restriction in terms of calorie
intake allows you to activate all these pathways
to suppress in certain secretion, to suppress
store, to activate autophagy.
All of these, I think, are really critical.
Rhonda: Yeah.
In complete agreement with you.
I’ve talked to Dr. Satchin Panda a couple
of times on the podcast, a phenomenal researcher,
and I’ve been doing time-restricted eating
ever since I first spoke with him.
Of course, when I was pregnant, I sort of
couldn’t of do it as well, but I’m back
doing it now, and, you know, I do feel much
better when I do it.
You know, I try to eat all of my food within
a 10-hour window, and I find that that’s
the best…
Dr. Verdin: Fourteen hours is…
Rhonda: Fourteen hours fasting.
You know, I think maybe you can answer this
question for me about, you know, it takes
anywhere between, like, 12 to 36 hours to
deplete your liver glycogen or something like
that.
Dr. Verdin: Actually, it could be faster.
Well, instead, from four to six hours, you
actually deplete most of it, yes.
Rhonda: Did it depend on your physical activity
levels or things like that?
Dr. Verdin: Yeah, obviously.
Physical exercise will deplete it much more
quickly.
In terms of entering ketosis, if you were
to do it 14 hours, it’s not enough to really
gain significant ketosis.
You start seeing this at about 16 hours where
your level will slowly rise.
Rhonda: Okay.
Yeah.
So, doing a 14-hour fast every night is something
that I at least try to practice.
Dr. Verdin: Yes, no nightcap.
Rhonda: I think that’s the easiest.
Yeah, no nightcap.
Dr. Verdin: No nightcap, no, you know, glass
of milk with a spoon of sugar going to bed.
Rhonda: No wine.
But, you get used to it.
Dr. Verdin: Yes, absolutely.
Rhonda: You know, you really do.
And, you know, like I said, I think it’s
the easiest.
I haven’t really done a prolonged fast yet.
I’ve spoken with Dr. Valter Longo, and,
you know, he was talking about the prolonged
fast in humans.
Like, in mice, I think it’s like 48 hours,
but in humans it’s a little like 4 or 5
days.
Yeah, and so he has got this fasting-mimicking
diet which sort of mimics some of the effects
of fasting.
I know several people that have done water
fast.
I haven’t braved it yet.
Have you tried doing a prolonged fast?
Dr. Verdin: Well, I’ve done, you know, Dr.
Longo’s diet, the prolon diet.
Rhonda: Okay.
How was that?
Dr. Verdin: I think it’s a really interesting
science.
What I like about it is the fact that it really
takes this fasting to a scientific level.
They’re doing the work.
Going on this five-day diet is actually a
really interesting experience, because it’s
not hard.
Maybe on day three it might be a little hard.
But one key question that has not been addressed
is, if you induce this protective response,
how long does it last?
And so how often should you do this?
Is it something you should do, you know, every
three months, or every once a month, or actually
once every six months.
I think this is the type of information that
will allow many of us to really, you know,
do the intervention when it’s needed, and
I think it’s going to be a lot of research
in this whole area that I’m very excited
about.
Rhonda: Yeah.
It probably depends also on do you do time-restricted
eating every day, and so what you’re sort
of baseline is, are you, like, obese, or overweight,
or metabolically healthy.
But, I agree with you.
I think it’s an extremely exciting field,
and being here at the Buck Institute, you
know, for Research on Aging, you’re sort
of at the forefront of it all.
And then, like you said, there are so many
different aspects of the aging biology that’s
being researched here.
If people wanna learn more about your work
and the Buck…
Dr. Verdin: Yes, so we were the first research
institute devoted to aging.
We were founded in 1998, and we have about
220 employees, all focused on aging.
And we take great pride in the fact that we
started the most simple model, yeast, we go
to C. elegans, a nematode, we go to fruit
flies, mice, and humans now.
And one of the thing that really excites me
about the Buck is the fact that we have built
this incredible body of knowledge over the
last 20 years in terms of the basic biology
of aging, and I think the field has moved
to the point that we’re really ready to
start translating all of these into humans.
All of us are seeing, you know, the incredible
interest from pharma and venture capital in
terms of investing in the aging space.
And I think, you know, we’re really well-positioned
to be riding that next wave which is going
to be bringing all of these incredible discoveries
into humans.
And so stay tuned.
Rhonda: I’m certainly gonna stay tuned.
Thank you so much for taking time to speak
with me today.
Dr. Verdin: My pleasure, my pleasure.
It was great.