(exciting rock music)
- Welcome to FODI Digital, a
weekend of online conversations
about dangerous realities
that surround us.
My name is Simon Longstaff.
I'm Executive Director
of The Ethics Center
and co-founder of the
Festival of Dangerous Ideas.
Like many other Festivals,
FODI was canceled
at the last minute by a
government that was concerned
to protect the health and
safety of the community.
And so now, we're picking up
on some of the conversations
that might have taken place,
but also with the added lens
of COVID-19 and a pressure
which is bringing a number
of topics to the boil.
COVID-19 has exposed, in
particular, the vulnerability
of the elderly, but as
we have new understanding
about the aging process
and the role that genetics
and other forms of
technological developments
might bring in better
understanding this phenomenon,
we're now reconsidering
what the future might be
for all of us in terms of aging.
So now we can join
Professor David Sinclair,
live from Boston, in conversation
with health communicator
and doctor, Dr. Norman Swan
- Thanks very much, Simon,
and welcome to you all
to this online Festival
of Dangerous Ideas,
and the idea that we're,
the dangerous idea
that we're gonna be exploring
in this next half hour,
and hopefully, with your
participation, is the idea
that aging is not necessarily
a natural phenomenon,
but actually is the disease itself,
and the person whose lifetime
research in this area
leads him to this conclusion
is, as Simon indicated,
Professor David Sinclair,
who's professor of Genetics
at Harvard Medical School and Co-Director
of Center for Aging Research at Harvard.
Welcome to the Festival
of Dangerous Ideas, David.
- Hi, Norman.
It's great to be here,
thanks for having me.
- And given that Simon's
invited us to anchor this
on COVID-19, I mean, age
is the dominant risk factor
for serious illness and
death with COVID-19.
- Well, yeah, absolutely, it is,
and even if you subtract all
of the age-related diseases,
such as diabetes and obesity,
which, of course, play a role,
age is still the biggest risk factor.
There was a study that
came out just last night,
from the UK, that said the
top risk factors are actually,
in order, the top five, the
least is diabetes, then obesity,
then being male, then cancers
of the blood, and by far,
five times more than
anything else, it's your age,
how many birthday candles
you've had, and my point
is that aging is a disease,
and it's treatable.
That's the main point, and
the same way we've worked
on those other diseases,
one by one, now's the time
to turn our attention to
the main driver of illness
and susceptibility to death,
and that is aging itself.
- So why, just give me the
evidence and the argument
leading you to the conclusion
that it's a disease.
I mean, I'm obviously following
the whole aging research
for a long, long time, and
people say that one of the,
some of the critics of
this whole field say,
well, we focused too much
on heart disease and cancer,
in other words, the diseases of aging
rather than aging itself,
but they don't imply
that aging is a disease.
They imply that we don't
actually understand
this underlying, this underlying
biological phenomenon,
where, to put it crudely, we fall apart.
- Well, we do and all sorts
of bad things happen to us
as mortal, living things,
but while we've rallied
against particular diseases,
we've left one thing
on the table, the most important one,
which is our physical decline over time.
We call this aging,
but aging is a disease.
Let me explain why.
So first of all, aging
results in a physical decline.
I think we do agree with
that, that's a disease.
It limits the quality of
life, that's a disease.
And it has a very specific
pathology, and I can look at you
and I can see that you have
some of that pathology.
If I look at your organs, I
can see that it has pathology.
Aging does all of this, and in doing so,
it fulfills every category
of what we call a disease,
except one, and that is that
it impacts more than half
of the population, but
there's no good reason
why we have to say that
something that happens--
(Norman mumbles)
To 49%--
- Hold on a second.
It affects half the
population, what do you mean,
it affects half the population?
- Well, so, if you look at
the manuals of geriatrics,
the definition of aging,
is that it's exactly the same as diseases,
except that it affects more
than half the population.
Okay, so, what I wanted,
make the argument here
is that there's no good reason
why we have to say it's
something that happens to 49.9%
of the population, whether
it's heart disease or diabetes.
Why do we call that a
disease, but then something
that happens to say 51%
or, in the case of aging,
70 to 80% of us, if we live long enough,
why that is something we
should just cast aside and say,
well, that's just life, let's
just do, that's natural.
We don't call cancer natural anymore.
We don't call heart
disease natural anymore,
even though they are natural.
What we do is we fight against
them, and the difference
between those things and aging
is that we didn't have an
understanding of why aging occurs,
but now we do, and so we can address it
just like every other medical condition.
- So there are lots of downstream
pathologies, if you like.
I'll trust the audience,
getting technical here,
but a little downstream pathology,
so the biggest risk factor
for, it's not just COVID-19,
biggest risk factor for
heart disease is aging,
cancer is aging, dementia
is aging, so in other words,
or high, to use your phrase,
the number of birthday candles
that you've had, so it's
upstream, aging, disease or not,
is upstream from all these conditions.
What's the pathology,
the core pathology here
that's driving all this stuff?
- Well, we used to think it
was just damage to the DNA.
We found out that it's not just that.
There are a lot of other
things that happen.
And we came up, in my field,
there's a few hundred
excellent researchers
who work on this.
We call this aging research
or longevity research.
We came up with eight or
nine hallmarks of aging.
We don't call these causes of aging
'cause that would be too scandalous,
but we call them hallmarks of aging,
and these are things
you've probably heard of.
I know you've reported on them.
Senescent cells, zombie cells in the body,
loss of stem cells, telomeres,
so the end of chromosomes
get shorter, there's a list,
but what I've been
working on for my career,
and I believe getting increasingly close,
is to identifying what makes
all of those things happen.
Can you boil the aging
process down to an equation
that explains why we don't live
longer than we actually do,
and why some species do
live for hundreds, and some,
for thousands of years?
- Which species are those?
- Oh, well, there are lots of species
that live longer than us.
We tend to forget that we're
not at the peak of evolution.
So, one of the best
examples is a bowhead whale,
or a Greenland shark.
They live hundreds of years.
We know this, for example,
because people captured bowhead whales
and they found a spear
tip embedded in the skin
of the whale, and those
spear tips hadn't been around
for at least 150 years,
and they dated the whale
to at least 200 years old.
- So what is, so, okay, so
take us upstream because,
as you say, you see
these downstream effects,
you see these old age cells
that don't seem to do anything
but get in the way of others.
People are saying, well, if we
clear out this garbage from,
so-called garbage, we will rejuvenate,
people have looked at
muscle and the mitochondria,
the energy compartments in muscle,
and shown that in older people,
if they go through
high-intensity exercise,
that you can actually turn their
muscles into young muscles,
and then they talk about
smoking and lifestyle and diet
can stop your telomeres shortening.
Where is the, where's the magic sauce here
in terms of what's
fundamentally going wrong?
- Well, so first of all,
it's important to know
that our lifespan and
our health in old age,
only 20% of that we
inherit from our parents.
The rest is mainly up to
how we live our lives.
So that's very, that's
empowering, and what we have seen
is that there's an
internal biological clock
that ticks away and we
can measure it in the lab.
Norman, I could take your blood
or you could send it to me,
and in a few days I could
tell you, pretty precisely,
how old you are, and what you're,
when you're likely to die,
what year and even could
make a guess at what month.
That's if you continue doing what you do,
and I hope that you're healthy,
and you, I'm sure you are.
You're a doctor, but if you smoke,
you can have the clock
accelerate, and if you eat well,
if you eat less often, if you exercise,
you can slow that clock.
So what is that clock?
It's called the epigenetic
clock, and it's actually,
the epigenome is the keyword here.
So let me explain briefly.
There are two types of
information in the body.
One is genetic, information
we get from our parents,
but the other type of information
that is equally important
is what's called the epigenetic component,
and that can change with
how we live our lives,
and the epigenome, just to summarize,
is how the cell reads the DNA.
So a cell that's in your brain
has to use a particular type
of epigenome to stay a nerve cell,
and a skin cell uses
a different epigenome,
and it's the loss of that
epigenomic information
that I believe is the main
driver of the aging process.
In other words, aging
is just simply a loss
of information over time.
- Now, is that, so just,
let's just, 'cause people,
soon as you start talking
about epigenetics,
people kind of lose the plot a little bit
because it gets
incredibly, so essentially,
you've got your genetic code
and you've got the shape,
if you like, of the double
helix, which can get contorted
and affected by the
chemicals on the outside
of the double helix,
and different things can influence that,
and the different shape and
confirmations can affect,
almost like a volume switch,
how well the genes work,
but there are lots of different things
that affect the epigenome,
and there are lots
of different chemical
structures on the DNA,
which influence that.
So there's methylation
and various other things,
don't wanna get too technical here,
but is it the whole suite of things,
or is there one particular
element of the epigenome,
one particular chemical
species that affects it all,
or is it a generalization?
Well, we know of one
particular chemical mark
that gets changed over time,
and that's what we call
the epigenetic clock.
That's the DNA methylation.
So methylation is just a
little chemical that sticks
to the the letter C in our
genome, and we can read that
with a little machine about
the size of a candy bar.
And we can, that's how we read the clock.
Those little methyl groups
change in our bodies over time,
and we just read them, but
that's not the only thing
that changes with time.
The epigenome, as you said,
involves proteins that loop DNA
or bundle it up very tightly like a spool
or a hose on a driveway so
that those genes stay off,
and we're just learning
how to fully understand
how that structure is behaving
over time during aging,
but those DNA methyl marks
are a very good clock.
Now, one of the biggest
discoveries that's happened
over the last 12 months,
and I was very fortunate
that my PhD student was one of the people
who helped discover this,
is that those DNA methylation marks,
when we wind back aging,
and we, as I mentioned,
we have a way of doing that now.
Those DNA methylation marks,
you have to remove them
for the age of the cell to
go back, and for the cell
to behave as though it's young again.
So, in other words, the clock
isn't just measuring time on the wall.
It's actually part of time itself.
- It sounds like we're getting
to creating this argument here
'cause you keep on going upstream.
What is it that speeds up,
so what creates this problem
in the first place of the
epigenome being distorted?
- Excellent point, and
so, for the last 15 years,
we think we've figured out
one of the main drivers
of the clock advancing,
and it's broken DNA.
So every time you go out and
you get sun, a bad suntan
or you get an X-ray, you're
breaking chromosomes,
and the act of having to
stick those chromosomal ends
back together, the DNA
molecule, the double helix,
it has to open up the
chromatin, as we call it.
The epigenome has to
rearrange, and then the cell
has to repack all of those
structures back together,
and it doesn't do it perfectly,
so every time you get a broken
DNA molecule in your cell,
and that happens in our
body about 20 trillion times
every day, totally, that advances
the clock by a little bit,
and over time, over
decades, these DNA breaks
will accelerate aging, and we
have good evidence for this,
and one of the bits of evidence
is that if we break the
chromosome in a mouse,
and we do that for a few
weeks, that mouse will go on
to age 50% faster than
the brothers and sisters
that didn't have that treatment.
- So, okay, well, let's
go to the question.
We'll double back to some of these issues,
but everybody's now wanting
to know, what reverses that?
So, there's been a lot,
because there's been a lot
of research that suggests the same things,
that short telomeres as a marker of aging,
also affects the genome.
It's whether or not you're
eating lots of vegetables,
how much red meat you're eating,
whether you're getting exercise,
those things all influence the epigenome,
whether you're smoking, and so on.
And is that all we're talking about here?
That it slows, so in
other words, those things,
are they just slowing down
the epigenomic distortion
or are we getting a reversal?
'Cause I mean, what
everybody has to realize
is that you're actually 94,
and you just look as if you're 36.
- (chuckles) Well, under
lockdown, I'm starting to feel
like 94 with three teenage
kids in this house,
but this is the incredible thing,
is that over the last 25
years, my colleagues and I
have found that there are certain genes
that control the health and age of cells,
and we can slow that down, as you said.
Some of the genes we work on,
they have a name called sirtuins.
There are seven of these
genes in our bodies,
and these proteins, the
sir part of the name
stands for silent information regulators,
and these are the proteins
that help bundle up the DNA
in those spools, as I mentioned,
but they're epigenetic regulators.
Now they're just part of the story,
but they're very important ones,
so if we get the cell more of
these epigenetic regulators,
we can do that genetically or
turn them on with molecules
like resveratrol or NAD boosters,
which we can perhaps talk about later.
What's important is that
they stabilize the epigenome,
and animals that have the
most stable epigenome,
they actually live longer,
but here's the really important thing.
We've just discovered
in the last year or so,
that we can tell the cell
how to reset the epigenome
and reset the clock.
So not just slow down
the progression of aging,
but truly reset the age,
and there are three genes
that we've discovered that
if we put them into the cell
and turn it on, and in the
case of the mouse study
that we hope to publish shortly,
we can reprogram the eye,
and get the back of the eye
to be young again, the retina,
and those old mice get their vision back
like they were young again,
and we can see that those cells
aren't just behaving like they were young,
but when we read their clock,
their epigenetic clock,
they are literally young again,
and so this is the first
evidence that you can reprogram,
in a safe way, a very
complex tissue of an animal,
and perhaps a human one day.
- And what's the
methylation, is it a drug,
is it environmental change, what is it?
- Well, we're working, my colleagues and I
are pretty excited about finding molecules
we could eventually rub on
the skin or put in our mouth,
but right now, it's a gene
therapy, and we deliver it
into the eye of the mouse,
and in a couple of years,
we think, glaucoma patients,
it's a viral genetic
delivery of gene therapy,
and these three genes
are really interesting.
These three genes control
embryonic development
when we're very young, but when we're old,
even when we're teenagers,
they switch off,
so that we are at the mercy
of aging, but we found
that if we turn those three
embryonic genes back on
just slightly and for
three weeks, that is enough
to tell the cell somehow
to flick the reset switch
and get back the original
youthful function
and age of the cell, and
these three genes, actually,
are called Yamanaka genes
because a Japanese professor
by the name of Yamanaka
won the Nobel prize in 2012
for discovering that these sets of genes
could actually turn an
adult cell into a stem cell
that you could then make new
tissues and organs out of.
Now that's an incredible discovery,
certainly Nobel Prize-winning,
but what they didn't consider
at the time was that you
could use the same kind
of technology to partially
wind back the age
of organs and tissues as well.
- And, so just to explore
that a little bit,
some people have said if
you do that, paradoxically,
you could actually
increase the risk of cancer
because you're affecting, you
can affect the immune system,
you can affect how cells divide.
It's not necessarily an
unalloyed good when you do that.
- Right, and it's a fair
point, and actually,
some of my colleagues who've
published brilliant papers
on turning on all four
of the Yamanaka factors
have actually found that
those mice do develop tumors
if you turn it on for a
long time, but we discovered
that if you take out the
one that causes cancer,
the other three are very safe,
and we've had them turned on
at high levels in the eye
of mice for over a year,
and in the whole body of mice
for at least nine months now,
I think longer with, if
anything, fewer tumors.
So we think that we're
turning on a program
that animals like
salamanders or axolotls use
to regrow their limbs.
Perhaps you could say a reptile
could regrow their tail,
and we think that we're finally learning
how to use those systems
in mammals once again.
- Now not everything
that happens in a mouse
or a reptile happens in humans.
How confident are you and
what signals are you getting
that the discoveries you're
making are actually applicable
to humans 'cause there's
been a lot of disappointments
down the years that
between cancer research
that we get very excited or
things that happen in mice
that kill 3,000 mice but it
doesn't happen in adults.
Yeah, humans.
- Well, it's a fair point,
and I've spent my career
working in biotech so I know
that how long things take
and how risky they are.
Well, firstly, I would say
that I think we've turned a corner
in at least scientific understanding
of how to reset the body,
at least of a mouse,
but also consider that we found
a very fundamental process.
We first discovered the reset system,
with the sirtuins and
aging, in yeast cells.
These are your baker's yeast.
You drink them in beer.
We see the same system occurring
in other rodents, in mice.
We see it in whales, for example.
It looks like it's conserved,
and, but of course,
humans are very different than mice,
but the fundamental basis
of what I'm talking about
is true seemingly for all life,
whether you're a yeast cell,
a whale, or a human, and so we'll see.
There'll probably be setbacks,
of course, like all biotech.
We have to be very
careful to be very safe,
but whether I'm gonna be successful,
or someone else who comes along behind me
will be successful, I'm not sure,
but I think we've turned a corner now.
It's as though we've, we built the glider
down at Kitty Hawk.
We know that we can actually
glide down the sand dunes,
and now it's a question of not an if,
but when we will have powered flight.
- I just want to go back to
a question I asked earlier
'cause I noticed that one of
our viewers has asked as well.
I didn't pursue it 'cause
I wanted to move on
to other things, but I
think it's worth clarifying.
Right at the beginning, you said 50%,
aging affects 50% of people,
and I was confused by that,
and obviously, the viewer was, too.
Just go back to that point
because I would assume
that aging affects 100% of people.
- Oh, well, if you live long enough,
of course, it's gonna affect everybody.
There's nobody who's immortal.
I think perhaps I cut out or I misspoke.
I meant that the definition,
once you pass that 50%
threshold, switches into aging.
Okay, if something that
happens to most people,
then it's no longer considered a disease.
For something that happens
to us that's horrible,
it has to be less than
50% to be a disease.
- Right, so in other words,
one out of three of us
will die of cancer,
whatever the number is,
that's a disease, but if three
out of three of us get it,
it's not disease, it's
assumed to be natural,
but what you're saying
is it could be a disease,
just like the Plague
or something like that.
Okay, let me just go to our substance
you've be looking at called NAD.
Just tell me a little bit about that
and what sort of results
you're getting with that.
- Oh, so NAD is the fuel
for the sirtuin enzymes
that control the epigenome and
seem to control many aspects
of health and survival.
So, the sirtuins in our body,
there are seven of them,
as I mentioned, and they
control the telomeres,
they control stem cells,
they control mitochondria,
they prevent senescence of
cells, the zombie cells,
so that, think of them as our protectors.
They respond to adversity,
so when we're running
on a treadmill or when
we're skipping a meal,
they'll be activated because
the body says now's the time
to hunker down and survive,
and that's what we believe
gives us our longevity when we diet
and exercise the right way.
Now, one of the ways that works actually
is the body raises NAD levels,
and NAD is a very small chemical,
it's used for chemical
reactions, and the sirtuins
are tuned in to how
much NAD is in the cell.
The more NAD you have, let's say,
you're young or you're an
athlete, ah, that's good.
The sirtuins will be active
and they will protect you.
If you're obese, you
don't walk, you don't run,
you're always fed, or you're old,
you'll have lower NAD
levels in your tissues,
and your sirtuins will
work less efficiently,
and you will age faster
and get diseases of aging,
and perhaps be susceptible to COVID-19,
as we hypothesize, as do others.
So what we're working on are,
and others around the world,
are molecules that we could
deliver to a patient who's sick,
either with COVID or with a rare disease,
or even a common disease like diabetes,
raise the NAD levels back
up to youthful levels,
and improve health.
Now in mice, again, I'm not
saying this is in humans yet,
but we are doing clinical
trials right now, in mice,
we can reverse the age
of the vascular system
and make mice that are old,
equivalent of about a 65-year-old human,
able to run like they were young again
with just a few weeks of treatment,
with the molecule that raises
NAD levels in the body.
- Okay, what, given that
it will be a while yet
before substances like
that are on the market,
what are the, what do we
know about the interventions,
and are they different
from what we already know?
So we know Mediterranean-style diet,
you're not eating a lot of red meat,
lots of different kinds of
vegetables with natural chemicals
that are in there, like
antioxidants and so on,
exercise which has a
degree of intensity to it
so that you're not just
going for a casual walk
with your friends, you're
actually stressing the body,
intermittent fasting of various kinds
where you're stretching your metabolism.
Those are the things
that people say are good
for your general metabolism.
Are those the things which seem to tie
into a healthy epigenome?
- They are.
That's the amazing thing.
Doctors and epidemiologists,
nutritionists who
discovered the kind of foods
and lifestyles that lead
to a healthy lifestyle,
a healthy life and also longevity,
such as the island of Okinawa
or the Mediterranean diet,
they discovered these
things independently from us
who are working on genes and enzymes,
but what we've discovered
is that the molecules
in those foods and those types of exercise
turn on these longevity genes.
There's sirtuins but there's others.
There's one called MTOR that
responds to the amino acids
and protein that we eat.
There's one called AMPK,
which responds how much energy
our cells have and how
much sugar is in our body.
And so, in other words,
what we've learned so far
is that these types of diets and exercise,
well, I wouldn't say inadvertently,
but not coincidentally,
are turning on these genetic
pathways, but what's important
is that now that we know
that, we can make medicines
that are a hundred times more powerful
than you could ever get from a
treadmill, and not only that,
you cannot expect an
elderly person to go running
on a treadmill for 10 minutes a day.
What we need is an IV or a pill
that we can give them to revive them.
- So, what do you do for
you in your own life,
apart from those things
that you've discovered,
that's a handy tip for, in
other words, that you've learned
and you're trying out for yourself
and not just your
resveratrol from red wine.
I mean, what are you, in
terms of your behavior,
your lifestyle?
- Yeah, well, I've been,
become a little bit
of a role model here,
not really intentionally,
I'm just a scientist trying
to do the right thing,
but the older I get, I find
that the more interested
I am in my own research,
and so I've just turned 50.
My father's 80.
We're both on a very similar program.
We monitor what we do very
carefully with rings like this
and blood tests that you
can get commercially,
at least over here in the US,
and we see what works for us
and what doesn't, so we're not
just blindly experimenting,
but we are trying to see
if, see what happens,
in a very safe, controlled way.
My father's also a scientist in Sydney.
He can judge for himself.
So yeah, resveratrol,
I've been taking for 13 years.
(Norman mumbles)
What's that?
- Go on, sorry.
Yeah, what's that?
- Oh, so this is called
an Oura Ring, O-U-R-A.
Kind of, it'll tell me heart
rate, movement, sleep patterns.
Very useful for optimizing sleep,
that's one of the great things about it.
Of course, we've also got
these devices now as well.
So my point is that if you just pop a pill
or do some exercise and
you don't measure yourself,
you're flying blind.
So, sometimes I just cut
to the chase and I say,
I wrote down what we do
in my family on page 304
of the book that I just put out,
but I'm not trying to sell books here.
I'm just trying to say if
we don't have enough time
to get through it, people can
go see what we do in a list,
but it's, resveratrol, I do
NMN, I take a bit of NMN,
which is an NAD precursor that raises NAD.
I'm taking more olive oil
since it was just discovered
that oleic acid activates one
of the main sirtuin pathways,
just like resveratrol,
so that's good for us.
Vitamin D is important, and
also, I'm taking metformin,
which is a drug that is
probably the craziest
and most dangerous idea
that I'll bring up,
which is, that there are drugs
on the market like metformin
for diabetes, type two
diabetes, that have been shown
in tens of thousands of
people, to slow down the rate
of age-related diseases, so
not just diabetes, but cancer,
heart disease, Alzheimer's, and frailty,
but you need a doctor's
prescription to get that
in Australia and the US.
- We've only got one minute left
and because it's The
Ethics Centre running this,
I'm kind of, they're
not forcing me to ask,
but I should ask anyway.
Somebody would say that
there's an ethical,
moral issue here, for people
living longer in a world
that's finding it hard to
sustain its existing population.
Should this be, what makes
this a priority for research?
Is it just a First World problem?
- Well, the last few months
have totally emphasized
that what I'm saying is the
right way to approach medicine.
We've been working far too
long just on one disease
at a time, which I call
whack-a-mole medicine,
and basically, a doctor
will prescribe a medicine,
push you out the door, hope
that you don't come back
with something else, if you
do, get another medicine,
and repeat until failure,
but it's not just important
to know why we fall off
the edge of a cliff.
It's to understand why we
get to the edge of that cliff
in the first place.
The amount of money we
would save by reducing,
even just by 10%, these chronic diseases,
would be in trillions of
dollars globally every year,
and as COVID-19 shows, if we had people
who had a younger biological age,
we may not even have a pandemic.
So, talk about cost-saving there.
This is the best way that
I know of to save money
besides eliminating
all wars on the planet.
- David Sinclair, thanks for joining us
on the Festival of Dangerous Ideas.
- It's been great, thanks, Norman.
- [Norman] Bye.
- Thanks for joining us.
The next session will be Stolen
Inheritance at 2:00 p.m.,
Australian Eastern Standard Time.
- [Man] The Festival of
Dangerous Ideas and FODI Digital
is presented by The Ethics Centre.
Our purpose is to bring
ethics to the center
of everyday life through
public experiences, education,
thought leadership, advocacy,
consulting, and leadership programs.
As a nonprofit organization,
every single dollar is invested
in pursuit of this purpose.
Thanks to our donors and partners
who help to make our programs happen.
And you can donate via the website.
Thank you.
(exciting rock music)
