Video summary
Dr. David Sinclair explains that aging fundamentally results from cells losing their packaging and identity, a process known as senescence which eventually leads to organ failure and death. This degradation occurs because biological stress, particularly broken chromosomes, forces cells into an arrest state where they must repair DNA by unpacking it and diverting proteins away from normal cellular functions. During this repair cycle involving the repacking of DNA, cells lose their original gene expression patterns; for instance, nerve cells can no longer function as nerves or liver cells maintain their specific identity. Sinclair emphasizes that these processes are driven not by inert molecules but by enzymes acting like tiny machines or "Pac-Man" figures and Bob the Builder tools within the cell. Specifically, he highlights sirtuins—seven types of protective enzymes—as crucial for packaging DNA compactly through a process called gene silencing; however, as we age, these enzymes become distracted by constant repair needs, causing DNA to loosen like an unspooled hose and allowing harmful genes in the brain to activate erroneously. To counteract this decline, Sinclair points out that proteins function dynamically rather than statically, utilizing chemical reactions accelerated by molecules such as NAD (nicotinamide adenine dinucleotide) which acts as fuel for sirtuins. He introduces resveratrol, a molecule found in red wine discovered years ago, as an accelerator that enhances the activity of these enzymes to ensure efficient DNA packaging and repair. The core strategy involves creating a cellular environment where the body perceives it is under threat without sustaining actual damage. Sinclair utilizes the analogy of running from saber-tooth cats or facing starvation to explain how adversity triggers sirtuins; however, he clarifies that while chronic stress leads to death, manageable levels of "fear" regarding future threats are beneficial for longevity. This concept relies on hormesis, where a small amount of bad stimulus produces extraordinary good effects by keeping repair systems active and preventing them from becoming complacent over time. A significant shift in understanding comes through the lens of antagonistic pleiotropy, which suggests that traits or behaviors advantageous when young can become detrimental later in life. Sinclair notes that natural selection historically favored organisms to stay healthy only until reproduction age, after which survival was less critical for passing on genes; consequently, humans evolved bodies suited to last roughly forty years rather than a thousand. While studies show that chronically restricting caloric intake by about 25% can extend lifespan in rodents by approximately 30%, such constant deprivation often leads to misery and aggression. Instead of enduring lifelong starvation or malnutrition, Sinclair advocates for pulsing the body with stress followed by recovery periods. Research indicates that if an organism experiences a period of hunger once daily or twice weekly, it can subsequently gorge itself on food while still reaping the same longevity benefits as those who maintain a chronic caloric deficit throughout their lives. Ultimately, the goal is to avoid overdoing stressors like starvation, which causes lasting damage and unspooling of DNA that leads to disease. The ideal approach involves being "a little bit puffed" or slightly hungry without crossing into malnutrition, allowing the body time to recover after periods of adversity. This pulsating method ensures that sirtuins remain active enough to package DNA correctly and repair breaks efficiently, effectively keeping the cellular machinery running like a well-oiled engine rather than letting it degrade due to complacency. By integrating exercise to induce breathlessness and intermittent fasting into one's routine, individuals can stimulate these protective enzymes without sacrificing quality of life or enjoyment of food. Sinclair concludes that while we may not live for a millennium given our evolutionary history, adopting these lifestyle choices prevents the repair systems from slowing down prematurely, thereby significantly extending healthspan and delaying the onset of age-related diseases caused by lost cellular identity.
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What I'm saying is aging is caused
because cells lose their packaging and
then eventually cells lose their
identity. Disease
ensues. Cells check out. They become
zombie-like.
Mhm.
And then our
It's senescence, right?
Senescence. And then our organs fail and
we die.
But until recently we had no idea why
that was happening.
And so why is it happening?
Well, so the the packaging's the really
important part. Because uh much like the
software runs the code, the epigenome
controls which genes are on and off.
And if you stress the system, and by
that I mean biological stress, and the
biggest stress you can cause to a cell
is to break its chromosome. Cuz it's
going to die if that if it doesn't fix
it or worse uh for the body you get a
tumor. So the cell has to hunker down,
stop dividing, arrest just about
everything it's doing
and then try to repair that broken DNA.
But in doing so, it has to do two
things. First of all, it has to take
proteins from somewhere else that are
doing good job
keeping the cell from functioning or
making sure the cell's functioning
correctly. And those proteins are used
by the cell to repair the DNA that's
broken.
But also what's happening at the break
is that that's all opening up as well
because you
remember if you if you break a DNA and
it's spoled up,
Mhm.
you can't fix it. You can't glue it back
together unless you unpack it,
stick it back together and then you've
got to repack it.
So this movement of proteins and the
unpacking repacking of the DNA,
I believe leads to cells losing that
original youthful what we call a gene
expression pattern of how the genes are
turned on and off. And nerve cells as
they get older lose their ability to
stay nerve cells and liver cells lose
their identity as liver cells.
All right, so
do proteins, the way that you're talking
about them, sound like little creatures?
I think of them because of my background
like powder, like just sort of inert
molecules which clearly, judging by the
way that you're talking about them,
they're not. I've seen them animated
before as having like articulatable
shapes and they actually move.
Is that accurate?
Uh
That's essentially it. It's it's super
exciting when you realize that proteins
aren't just blobs or powders in the
cell. They're actually little little
machines like Pac-Man that go around and
they can change the function of other
things. They can package the DNA.
And what they they do is they create
chemical reactions that normally would
take a billion years to happen.
This is what an enzyme does. It
accelerates reactions. And so you we've
got about 20,000 different types of
enzymes in the body.
Uh and they do different things. But
what we've discovered over the last 20
years is there are certain types of
enzymes
that help package the DNA and help with
the DNA repair. These are the ones that
doing the ping pong game.
And without those
we're screwed. We basically will will
age more rapidly. Conversely, what's
really exciting is is we've discovered
that you can make them more active to
make sure the DNA is packaged correctly
and the repair is very efficient. And
there are ways you can do that.
Exercise, dieting, being hungry.
They allow these enzymes that control
our body and make us healthier. They
make those enzymes much more active. So
instead of a Pac-Man doing this,
you exercise, you diet,
take a take a molecule that we work on
and it'll go around and fix everything
much more efficiently and keep you
younger for longer we think.
Why do you use the Pac-Man analogy which
makes me think of it's eating something?
Is that what's happening? Is it eating
cells that have a level of senescence or
is it uh more Bob the Builder and it's
going around tearing some things apart,
putting some things back together?
Yeah, it's it's more like Bob the
Builder but it I think a good example
for at least the enzymes that we work on
called sirtuins that protect the body.
They're they're like a little tiny pair
of scissors. They they chip up clip off
chemicals
Mhm.
called acetals. And in doing so, when
they clip off the acetals off those
packaging proteins, the DNA gets more
compact, and that's called gene
silencing.
And over time
as we get older and through this DNA
damage process
the sirtuins get inactive, they're
distracted by DNA repair, and the
packaging of that DNA that that hose
spooling
starts to loosen. And now genes that
have no business being on in the brain
come on. And partly I believe that's why
we we have these diseases of the brain.
that's so interesting. Um okay, so
one I want to know from a lifestyle
perspective, what are we doing that's
speeding that up? And then two, what can
we do from a lifestyle perspective to
begin slowing that down or reversing it?
Well, so I've been studying these
enzymes, the sirtuins. We have seven in
our bodies. I've been studying them for
about 25 years.
And what we've learned is that they
respond to the cellular environment. Um
there's a chemical that they require for
gas. Think of them as a fuel called NAD.
And there's another molecule that is
like the accelerator on the enzymes
uh that makes them go in even faster,
and that's uh one of them is called
resveratrol, which we discovered years
ago from red wine. And together they
actually do really great things on these
enzymes and make them keep the body
younger at least.
For 25 years we've been studying mostly
um animals um and even little fungi, uh
yeast cells. And what we've learned from
those studies is that these are largely
involved in responding to when organisms
are under threat of survival.
So how do you make the body feel like
it's under threat? Adversity. Uh so one
is run a lot or at least become out of
breath, you know, a few times a week.
Your body will say, "Oh man,
we had we had to outpace one of those
saber-tooth cats again. Got to got to
build up the body." Um the other is to
be hungry either a couple of times a
week or every day, you know, skip a meal
or two. And then your body will turn on
these sirtuins, make more of that fuel
NAD for the enzymes, and we think that's
what's in part responsible for the
health benefits of those lifestyle
choices.
All right. One thing though that you
talk about that I found really
interesting is this notion of what may
be good for you when you're young may
come back to bite you in the ass when
you're older.
Yeah.
So it's like the whole notion of
hormesis that a little bit of bad is
actually extraordinarily good, which is
exactly what you're describing now. Get
out of breath, this stuff. And so when
the information started pouring out that
the only thing across every known
living organism that extends lifespan is
to eat less, which you talk about in
your own book, it feels like you're
saying to do it for that reason. Just
don't put as much stress on the system.
But now I hear you saying, "No, no, no.
What you actually want to do is stress
the system." Won't that stress of I just
ran from a lion. Oh, I'm starving.
Won't that begin to stack up and become
problematic?
Well, actually, if if you step on a
snail, it's going to die.
So
there's there's a certain amount of
stress that that you don't want to do.
But what you want to do is get the body
to fear adversity in the future, but not
enough to cause lasting damage or the
unspooling of the DNA that will lead to
disease and eventually death. So you you
don't want to overdo it. You want to be
a little bit puffed. You want to be a
little bit hungry. But of course,
starvation, malnutrition is not going to
make you live longer. So it's a fine
line and what we've learned from many
animal studies and increasing numbers of
clinical trials in humans is that you
want to pulse it. Let the body recover.
Not constant. We used to make animals go
hungry all their lives and it worked,
but it actually works better if you let
them recover and I think that's that's
the secret.
Then let's really dive into that. So I'm
guessing you're talking about where
animals were denied something like 20 to
30% of their caloric intake for very
long periods of time is extending their
life by what? Like 30% or something?
So super interesting, but you're saying
that if their caloric intake over a long
period of time is roughly the same as an
animal that's just allowed to eat until
it's satiated that if it's done in a
pulse pattern of hunger and and almost
overfeed,
um they actually have the same benefits
as the animal that has a chronic deficit
of calories.
All right. Well, well, let's be clear.
Nobody knows what the perfect diet is
even when it comes to fasting. It's all
largely based on rodent studies. So,
what I can tell you about the rodent
studies, which I'm very familiar with,
is that if you take a rodent and reduce
its calories by 25%
for its whole life,
it will live longer, 30%, but it'll be
really miserable and aggressive. Uh and
that's true for us, as well. I've tried
calorie restriction for about a week,
and I gave up. I was pretty angry. But
what we discovered, our my colleagues um
discovered is that if you
it's not just what you eat, it's when
you eat that's important. And what's
been found is that if as long as you
have that period of hunger,
um in a mouse, they can feed them every
other day, then they can gorge
themselves as much as they want, and
they do. They eat about 90% of what a
mouse having free access to food would
eat.
Um
but they
they have the same longevity benefit as
a mouse that's always been hungry. And
if that's true, what that means is for
us is that we can enjoy life as long as
we have that period of hunger once a day
or maybe twice a week. And I believe the
only reason we age,
um
you know, we could live for a thousand
years otherwise. The only reason we age
is that our repair systems
become complacent. You mentioned that
what what is beneficial for you when
you're young comes back to bite you when
you're old. What we think is that these
repair systems are very good when we're
young.
So, the idea is it's called antagonistic
pleiotropy, and I think it's right. And
that is that we evolved to stay healthy
and alive and fit till we're 40,
and then the the forces of natural
selection decline after that cuz we've
essentially bred we've often had
children
but we don't need to stick around beyond
that. And building a body that will last
a thousand years is pointless at that,
you know. So, most species only live as
long as they need to to reproduce and
then a little bit more.
If you're a mouse that could die within
two years, they only build a body that
lasts two years. If you're a whale that
has no predators, you can live for a
couple of hundred years. That makes more
sense.