- I have to say, I'm incredibly excited about the conversation
that's about to happen. I do want to thank Town
Hall for its partnership with ISB and bringing good science. And I think this is
really terrific science. And let me say a few words
about Dr. David Sinclair. He was born in Australia
and transported himself to MIT for a PhD and later to Harvard where he is now a professor of genetics. David is probably the
face of aging in the US and in the world today.
The book you heard about, "Lifespan: Why You Age And
Why You Don't Have To," I think is really one of
those transformational books that when you read it changes
how you think about a topic. And I suspect you'll
get that feeling tonight from our conversation. David has many academic honors, many beautifully published papers, but it's interesting to
note that Time Magazine in 2014 declared him one of the most 100 influential people in the world. And then in 2018, declared him one of the 50 most influential
people in healthcare. And I think in many ways, you'll see from the conversation tonight,
that that certainly is true. So with that introduction, I'd like to begin our conversation and throw out the first question to David. And that is: You were born in Australia. David, how did you evolve
from Australia to become one of the pioneers in aging and longevity? - Well, Lee, thank you
for the introduction. I've been introduced by a lot of people, but I think the introduction that you just gave is probably
the most important to me because I've had such respect
for you even before, you know before you even knew who I was. And so thank you for that and thanks for the
opportunity everybody for to be able to speak tonight. So yeah, I'm Australian,
so I have to be humble. We in Australia, if we start
to boast about ourselves we will have no friends. So I will try my best to
talk about myself tonight as much as you want. Yeah I was born in Australia. I was a pretty normal kid growing My family had a place with, oh, about a thousand acres of
forest in the backyard. So I spent a lot of
time looking at biology but I always had ambition. I was the kind of kid that if if I was born in ancient
Greece, I would head to Athens. And so I wanted to go
where the action was. And it as nice as Sydney is it's not the center of the
world where I like being. I also was raised by my
mother and my grandmother. And particularly my
grandmother gave me a very special education. She was a survivor of World War II and realized that that humanity
can do terrible things. She was from Hungary and escaped
to Australia with my dad. And so I was raised
being told that humanity can do a lot better and that David, you should spend your life
making humanity as best as it can be and as great as it can be because we know
humanity can do much better. And so I remember her telling me that. And so I've spent my life really trying to leave the world a better place. Every day I wake up
it's another challenge. To get to the US really
what happened was I realized at the age of 17, 18 as
I was entering college that we're probably the
last generation of humans, at least my generation, to be
living a normal human lifespan and that technologies
of the future, our kids our grandkids would
greatly benefit from these the understanding of why we age. I was also told by my grandmother that everybody eventually
gets sick and dies which to a four year
old is pretty shocking. And we all go through that but I couldn't get it out of my mind. So combining all of that, Lee I set my sights on the
US on Boston, on MIT. I met Lenny Guarente who
became my mentor at MIT. I coincidentally met
him in Sydney in 1993. And I said, I want to do that. I want to study aging in yeast cells and cut a long story
short, a famous scientist Doug Melton interviewed me for a fellowship for Helen
Hay Whitney fellowship. They'd never given it
to a foreigner before and I just argued that they
should give it to me anyway. And they did. And the rest is I guess, history. - Well, terrific, David. One of the most interesting aspects of your book was in early
in the book, the delineation of the information theory of aging. And I say that because I
think from that conceptually comes absolutely fascinating hypotheses. So can you explain simply,
and in layman terms just what that means? And I'll say it's also interesting because you made the
fascinating point that aging is easier to deal with than cancer is. And this all comes out of the
information theory of aging. - That's right Yeah, so I've been studying
aging since I was at MIT. This is now 1995. And the first set of genes
that we were working on in Lenny's lab came out of a random screen for any gene that would make a yeast cell more stress resistant and longer lived. And out of that came the discovery that there are certain genes,
which we now call sirtuins they didn't have that
name in the beginning. But the interesting thing
about the name is that the SIR in the name stands for
Silent Information Regulator. And at the time we really had no idea why a Silent Information Regulator, in other words, something
that controls the expression of other genes turning other the genes off why would that be controlling aging? At the time, the idea was that and still for the most part is that
just things break down and there's not much you can do about it. You could try to slow it down but we're basically all going to fade away and be corrupted and degenerate. But that information, part of that that acronym is very important. And so I've been focusing on what is it about information
that's relevant to aging? And we did a lot of work in yeast and then in mammals in my lab at Harvard. And so I've always been trying
to think about information and one of the breakthroughs came when I realized I was reading about information theory, Claude Shannon, big disciple of his, and he's a professor from MIT in the 1940s. And he came up with the mathematics of information preservation and
actually his mathematics led to the internet among other things. And his idea was that
things degenerate over time including signals such as radio signals because of introduced noise. And that really, it clicked with me. I could see that we could
be the biological equivalent of a radio signal that degenerates, and has introduced noise. And it fit well if most of the work that was being done in
my lab, if not all of it. And so I came up with the
information theory of aging as I call it. And really the idea is that we are born with a relatively pristine
set of information. Our DNA is a digital code
four bases four letters instead of digital zeros and ones, but nevertheless, it's digital. But there's another type of information that's just as important for our survival. And that's called the
epigenome that controls how the DNA is expressed. In other words, which
genes are on and off. And you need that because
the brain has a different set of genes required for a
liver cell and a skin cell. And that's what the epigenome does. And the analogy is excuse
the old fashionist, but a DVD or a compact disc
has digital information, but the reader which is the
head that moves and use the laser is analog and the
cell have two types. They have the DNA, and
then they have the reader. And it seemed to me that
everything we were learning was at the readers, the readers of the DNA and the control systems were
going awry during aging. And that led to the
realization, if that was true then here's the really
interesting corollory is that there might be a backup copy of the original information,
the genetic information and even the epigenetic information. And we published a paper in December that we were pretty excited
to even receive the cover of that issue that said
that we could actually tap into a backup copy of the
original epigenetic information in a cell or in a tissue. In this case, we
rejuvenated the eye of mice and made them able to see again after suffering from
glaucoma or just being old. And so what I think is this
could be a turning point you know, dare I say
at risk of being wrong, but if I'm right, then
there really is the ability of truly not just slowing aging but resetting the body to an earlier age and aging out multiple times
and resetting multiple times. - Yeah well, I think the
really important conclusion from that experience was there are actually two aspects to aging. It seems to me, one is,
can we slow it down? And the second is, can we reverse it? And it's never been shown
to be reversible before. I think your paper that you described was one of the very first. And I think a fascinating question is how far can we reverse it? And another interrelated
question I'll leave you with these two is when
should we start thinking about aging and actually
doing things which will slow or even begin to reverse the process? - Right. Well, like all
science, I mean, seriously I'm standing on the
shoulders of giants there. Of giants that figured out
that you can reset the age of sematic adult cells to be zero. So Jon Gordon and Shinya
Yamanaka did those experiments in tadpoles and in skin
cells, respectively and won the Nobel Prize
deservedly in what was it? 2012, I think. So that was part of the
initiative of reversing aging. But we needed to do that. We needed to reset the
age of cells, not to zero but by 50 or 75% without causing
the cells to become tumors. And that was the challenge.
We spent, oh, about three years trying different
genetic combinations, trying genes that come on
in embryos, trying genes that are helpful to cancers,
but not causing cancer. And finally hit upon a
three gene combination that resets the age of
the cell by about 75%. And you might say, well, how
do you know how old a cell is? Well, we actually now
have a very accurate way of measuring the age
of a cell or the body. Some people call it the Horvath clock. It's also known as the
DNA methylation clock. We can read the chemicals that change over time that are on
the DNA called methyls. And that gives us a really
accurate measure of age. So we can now take those
mice that had restored vision and truly ask are those
cells just acting young or they literally young. And the answer was, they
are literally young again. And that was the first, I
think the first discovery that in a living organism
you could safely reprogram and reset the age of the body. How soon is this available to humans? While we're working towards
doing our first clinical trial in the next couple of years we've already got two years
of work under our belt there. - Wow. - Yeah. But what about other parts of the body? I think that it's gonna be possible to reset most parts of the body. The question is, you know,
the safety issue of course but my lab has now had some early results resetting other parts of the body, muscle is looking promising. We've got other labs doing the brain. Actually we've got some early results with Alzheimer's disease
and old age, dementia and there's another lab at Stanford. I should shout out Sebastiano's
lab and it's all constitute. I should credit One Kalispell Monte for showing that you can reverse the age of cells that you take out of
a mouse and put them back in. And that also also beneficial. So you don't just have to reprogram cells that are in existence. Ultimately, where is this going? Well, that'd be like
asking the Wright brothers how soon do we get to Mars? It's doable. I just don't know when, but I can see now if the information theory
of aging is correct we will be able to one day
perhaps have an injection of a virus that carries
these reprogramming genes and turn them on with an antibiotic. In the mice, we use doxycycline it's a pretty inert drug
and turn on these genes for four to six weeks,
reverse the age of the body. And then, then your doctor will say come back in another decade. We'll do another treatment. - Yeah, yeah. So you, in your book
discuss "Longevity Genes" do you want to describe what this does and their role in this
information theory of aging? - Yeah, these are fascinating genes. They came mostly out of the 1990s and early 2000s discoveries in yeast and worms and flies. Labs like Cynthia Kenyon,
Gary Rodkin, Lenny Guarente, of course, where I was. And these are genes that
you might not suspect are actually controlling
aging, but were discovered through just looking across
the genomes of these organisms. And what we've discovered is that they do is that
they're built for survival. They're not built for longevity but what they do is they respond to when organisms are perceiving adversity or future adversity. For instance, in yeast, we
showed in a nature paper, 2003 that if you restrict
the amount of calories that a yeast cell gets
or raise the temperature or give it a little bit too
much salt or lack amino acids it'll live longer through
a set of longevity genes. These sirtuins I alluded to and that is a defense
response trying to survive. And so you can think of
longevity genes in that way. These are like the Pentagon
that you can call up and say there's an emergency send out the troops. Even if there isn't an emergency. And that's what our
bodies are actually doing when we exercise and we go
hungry, we're making a call to our body's Pentagon to
send out the repair troops. And if you do that routinely you're going to have longer life. This is what has been
shown time and time again. The question is, when should you start? Well, we're starting to age from actually even before we're born. This clock is ticking. So even if, even if you look in the mirror and you don't have wrinkles yet, trust me you are getting older and
you're heading towards, you know to decrepitude. So I'm not saying to, you
know, have intermittent fasting if you're a teenager or a young adult, you've got a lot of activity
for your longevity genes. But for me, by the time I hit my thirties I was already feeling like I
needed something to assist me. And so that's when I started but so that there are two answers. It's good to start early. The animal studies suggest and
actually show, but it's also I wouldn't say it's never too late, but it's ... you can start late. We can intervene in a
mouse that's equivalent of a 70 year old and have a lifespan extension
of 15 or more percent. So it's in that window,
but I wouldn't go too old. I don't think once you're
a hundred years old you're gonna go back to 20
unless our science improves. - So how do the longevity
genes then relate to these, these now classic nine hallmarks of aging? Again, that seems that whole process is a
part of this simplicity we spoke about that marks aging as a contrast with something
more complicated like cancer. - Right, so, yeah,
cancer has been described as a hundred different diseases. Aging is really just in my view a relatively simple process. There are three levels. We've got the environment and
what we eat and how we live. So this is external and internal inputs. And I've already mentioned that
putting yourself in a state of adversity, walking,
not eating this kind of stuff does that. Second layer of the longevity genes that sense that adversity and
control the systems below it. So what's below that at
the very fundamental level? Well, of course, there's the epigenome which I've explained is not my best theory so far to explain the fundamental causes. But tied up with that, perhaps
influenced if not controlled by the epigenetic changes
are what you mentioned which are the hallmarks of aging. Many viewers will remember telomere loss, the ends of chromosomes, get shorter. We have, we lose STEM cells. We have senescent cells, the
zombie cells that accumulate in the body to make us old. These about 10 years ago,
we in the field agreed on nine hallmarks that
contribute to aging primarily. And what they do is that
they control the troops. They are the various divisions
in the Pentagon that go out. There's the Army, the Navy,
the Air Force, Space Force. That's what these whole, these longevity genes will control. Now what I don't know yet, but
what's exciting is that maybe if we can reset the age of
the cell through the epigenome these other hallmarks
of aging will vanish. And we have some evidence that some of them do actually go away. Meaning that the information
theory is perhaps valid. But that doesn't mean that
we're just going to be able to I think just tackle the epigenome. These other things need to be addressed. And so there are many researchers and companies working towards
finding ways to address each of the individual hallmarks as well. - Yep, so you spoke about the environment being the higher level
that starts the whole chain of the aging process. What are the environmental manipulations that we can use to influence
the hallmarks of aging that ordinary people, you and me can actually incorporate
into the way we live? - Yeah well, it's not that
hard to live another 14 years on average, if you just
do the right things, which is don't become obese,
do some exercise, eat good food what are the other ones? I think it's get sleep. And don't stress that,
that the basic stuff that in itself will give you 14 years. It's been calculated, you know,
bad luck, not withstanding but you can go beyond that. That's just, that's just the minimal. If I could recommend one
thing for people to try, it would be to eat less often. You know, I've totally changed
my life about around this. So as my father, who's 81 without
any medical issues at all, we now eat one meal a day. I might have a bit of lunch, but not much. And the rest is just warm
drinks, which I love. Anyway, there was some really
good experiments that show in many different species. And we've known this for 80
years that reducing the amount of calorie intake, particularly
if you're restricted during certain times of
the day, it's beneficial. One of the best experiments
I could point to it's a set of experiments is by
Raphael de Cabo at the NIA which is the National
Institute on Aging in Bethesda. And he did a very interesting
set of experiments in mice, admittedly, but
it was really telling. He was trying to figure
what are the differences between diets and you can
give mice small calories in form of fat or protein or carbohydrate. And he did all those
combinations, 10,000 mice but he did something also interesting which was fed the mice either all during the night
when they typically eat, called ad libitum feeding, or
only at, for a little window during the day or during
the night, I should say. And the mice ate almost
the same amount of food because you can imagine
if you're a hungry mouse you're going to gobble
it down really quickly within that hour of feeding. The only ones that lived
longer were the ones that had the time restricted feeding. It didn't matter what they were eating. So what that tells me most likely and there's epidemiological
evidence, this is true in humans, that it's not as
important about what you eat. You know, of course you can't
eat terribly horrible diet and expect to live longer, but within reason it's more important when and how often you eat. And so that's what I do. I've really cut back a lot.
During COVID I've lost, what is it? Nine kilos? What's that? It's a lot of pounds. I'm down to the weight that
I was when I was 20 now. And I feel great. There are plenty of other
things you should be doing. Lifting weights especially if
you're a male, an older male to keeping up the muscle
strength, but even for women keep your muscles tone because falling over is the quickest way to dying. Actually, as somebody in the
US falls over every 19 seconds and breaks their leg or their hip, and that's eventually fatal
for most elderly people. - So a really interesting question. I mean, intermittent
dieting, intermittent fasting is presumably stressing the body and it activates the longevity genes and sets in place this
whole anti aging process. So my question to you, it seems to me the most challenging aspect of that is how do you persuade people
to change their behavior and adopt activities that are really good for them in the longterm? I mean, that is, I'm very
interested in wellness and the issue is exactly the same there. So I'd be curious about your thoughts on how can we get people to change? - Yeah, you are right. You and I, we've talked about this and it's really difficult. What I find helpful is information. And even thinking about my own life, if I didn't get any feedback,
positive or negative, I gave up, right? You step on the scales,
but that's about it. Once you start measuring
things and getting feedback I find it makes the world of difference. You know, not everyone does this but wear an Oura ring
for sleep and motion. I monitor my blood work as well just to know what's happening. So that's the future. So that people won't just
go for an annual checkup. They'll actually be constantly seeing when they did this or
they took that supplement. If things are working now,
that's still futuristic. We still have, you know, close
to 50% of the US overweight. So how do you reach those people? It's really hard. And it's one of the
reasons I wrote my book is to hopefully reach more people and make those people
that hear or read my book, realize that 80% of our
longevity in our health in old age is based on how we live. And only 20% is genetic. So you really can control how long and how healthy you are an old age. So there's the education part there's the feedback,
positive feedback, hopefully. But other than that,
Lee, I'd be interested in hearing what your thoughts are on how to have people
more interested in this. - Well, I would agree with you. I think, I think there are
two really important aspects. One, is you have to give people a metric that show they're succeeding or failing and the metric can show, they
can change their behavior. And I think being able
to measure something like biological age, the
age your body says you are as opposed to your
birthday, I think is one of the most valuable
tools we're going to have in convincing people that
this is a unique opportunity. Did you want to talk a
little bit about that? - I'd love to. Yeah, so we've been
working behind the scenes in my lab on trying to
democratize that test. Now that test if you haven't heard of it, I mentioned it earlier,
it's the Horvath clock typically it's called. What we can measure are the chemical changes on the DNA itself in blood or in a cheek swab. And that will quite accurately
tell you your real age not your birthday candles. I like to joke that, I mean, who cares how many times the earth
has gone around the sun? That's not what's determining your health. It's really more about
your true biological age. And so in my lab we've been able to develop new technologies
to be able to read that test. And, you know, I'll say publicly for the first time that we're planning on making this commercially
available to the public, because I think it's so
important that everyone who wants this test should
have a cheap way to do that. And I totally agree. It changes your mindset
when you can really measure how well you're doing and also see if you can improve it. - I'll tell you the second thing, David, I think is really important is education at the K through 12 level. So for example, ISB is putting
together a program on health where we have 20 units that are based on this vision of health,
that's predictive and preventive personalized and participatory. And one of those units
is going to be on aging. And wouldn't it be wonderful
if all high school seniors came out of a school with an
understanding of the kinds of things we're talking about
now, and for young people it's easy to change for a lot
of the things in older people. The easiest way to get them to change is to have them die off
and let their kids change. So anyway, but I think education and I think metrics are, but you know, there is a third really
interesting opportunity. I'd love you to talk about,
and that is, you know Americans really like the idea. I mean, your big new
idea is that age, aging is really a disease and
we know how we can deal with the disease. And the way Americans like to deal with disease is with pills. So do you wanna talk about pills and aging and where that's
going in the future? - Yeah, it's a really hot area right now. Going back when I started my
first company, 19- no, 2004 it was crazy to think
that you could develop a medicine that would
tackle the root causes of aging or slow it down. And people didn't even
understand how to think about it let alone build companies out of it. I think we showed that it was possible. And we're now in a world
actually where longevity research and longevity development of drugs - development
of longevity drugs - is one of the hottest
areas in biotechnology. You know, I sit in the center
of a tornado of activity and I see that it's really gone almost vertical in a graph
of interest of investors. I'm part of a group actually that recently said we were going to invest in a company related to longevity. We haven't picked out which company yet and there was a billion
dollars of interest. So this is you know, it's a zeitgeist. In other words that I think the science has reached a point where Wall Street and Main Street increasingly has realized that the science has
come of age and that we can truly develop medicines
that will use this knowledge. Not only to treat aging,
but to treat the effects of aging and actually 85%
of all suffering on planet including most major
diseases are due to aging. We were in denial that
aging is not important but actually it's far more important for lung cancer than
smoking is for example, by at least an order of magnitude. So this is a major issue,
but I'm optimistic now that we've seemingly
turned a corner similar to use the Wright Brothers
is a good example. You know, we're talking, we're now in the 1920s where people have seen that the Wright flyer works
and there's a lot of interest in building, you know,
eventually a Boeing 747. - You know, I think one
of the most exciting ideas I extracted from your book was this idea that aging is the dominant cause of virtually all chronic diseases. Let's say you can control aging. Then we can begin to think about controlling all these diseases. So the argument is why
don't we spend the 6 pr 7 billion on cancer and the
11 billion on whatever else, why don't we spend it on figuring
out how to control aging? Wouldn't that be more efficient than taking diseases one at a time? It's as I would say, a systems,
integrative global approach and very powerful one you're advocating. - Right well, what I wrote in my book, I still believe which is I'm not going to try to rob Peter to pay Paul. I think that all medical
research is important and there isn't enough of the funding. The amount of money we spend
on aging research though, if you just look at the biology of aging and if you don't include Alzheimer's and other things, which is
sometimes included unfairly I think it's really
just a few fighter jets in the US has spent on this. And so I would say that as a country US can afford to put more money into understanding the
biology of aging, even without robbing, not robbing,
but taking from other places. But I definitely agree
with you that the impact of this could be far greater than tackling one disease at a time. One of the problems with the approach that we have right now is
that we've been effective at treating some areas of
aging, such as heart disease. We've got the statins for cholesterol. We've got very good blood
pressure lowering medicines. And so we're generally
living longer because of that but the brain still ages. And now there's an increase in dementia and that's the wrong way
to approach medicine. I would rather try to keep
all parts of the body younger and healthier for longer
and have an extension of our health span rather
than just our lifespan. - Yeah well, look this
discussion really brings us to a fascinating point you
and I have discussed before. And that is our determination
to push forward in the vision we have, your vision
for aging and so forth. So my question is to you, where do we go beyond government funding
to get the resources to be able to do the science that really is going to transform aging? - Well, I've seen a lot more interest from philanthropists and
non-profit organizations. So I think that that's an area where people can make a big difference. - Yep. - George Church and I talk a lot about this just for a
couple of million dollars. You can have a big impact in a lab. You can develop basically
a drug that's almost ready to go into humans. If you're very efficient with capital. And often people who have the
wealth to fund these kinds of things are shocked
that such a relatively small amount can have
such a big difference, but it really can at the early stages discoveries can be made
just by graduate student who's staying up at night dreaming. And this is what changes the
planet, not the billion dollars of investment at the
late stage of technology. - Yeah well, I think another approach that you and I share is this idea. We can take useful knowledge
and spin it off to companies which can generate enormous
resources for the maturation of the ideas and that amplifies enormously the kinds of things that you can get done. And you've certainly been very successful in taking that approach as well. - Oh, thanks. You know, I have a few idols,
and you are one of them Lee, I'm not kidding. It was very difficult as a
young scientist in my thirties at Harvard spinning out
companies in the 1990s especially in 1990s and even in the 2000s it was just not something
that assistant professors did. How could you do that? Let alone go in the media and
talk directly to the public. That was totally frowned upon. I look to people like you as inspiration and to give me the courage to do that. And I'm so glad I did. And fortunately, now we live in a world where it's quite acceptable- - It's pretty common. - For us to do that but
it wasn't always the case and you were doing it before me and you had the courage to do that. And I assume it's because you didn't want
to just publish papers. You wanted to change the world. - And that's where we both are, I think. So one of the things
that's utterly necessary for changing the world
is convincing the CEOs at every level, healthcare,
industry, the high level people in government of the
validity of the vision. And you have ideas about how to do because that is one of
the most challenging. If you can get to leaders,
you can change organizations. But getting to leaders and
changing their thinking is enormously challenging. Yet, there are approaches
one can use, obviously. - Yeah so there are leaders in industry. There are leaders in government, leaders in regulatory
authorities, such as the FDA. And I think we have to talk to all of them and you and I have been
doing that actually in my estimation I haven't
been that good at it. It's been quite difficult
to change the world from the top down. I'm actually having better
success from the bottom up. But I do think we have to
take both approaches to be- - Both approaches, yeah. - And the FDA surprisingly
a few years ago said that they were open to calling
aging a treatable disorder. If we could just prove that it was and that those experiments
are actually ongoing with a drug called Metformin which many of you will have heard of. It's a frontline diabetes
- type two diabetes drug for the elderly and people
who have high blood sugar. And that drug seems at least
based on tens of thousands of patients who've taken
that drug had protection not just against their blood
sugar, but also cancer, and heart disease, and even
Alzheimer's, frailty for sure. And so this could already be a drug for longevity that's available. It's very cheap. It's probably a few cents per pill. It's available over the
counter in many countries not here in the US, unfortunately. But if the FDA allowed
doctors to prescribe Metformin before you had type two diabetes that would be revolutionary. This would be the equivalent
of having the statins for heart disease or
blood pressure medicine. This would be a massive
change, but right now doctors, most doctors are either ignorant or reticent to prescribe such a medicine that would prevent multiple diseases. - How would you categorize
rapamycin in that regard? Another drug that is it
manipulates a major one of these central systems to set up the defense that leads
to a reducing agent. - Yeah well, what you said
really resonated earlier which is that you and I believe,
well, I certainly believe I think you believe that
that aging is simpler and easier to treat than
cancer, which is a bunch of different diseases. When it comes down to it,
aging is not that complicated. Yes, the effects downstream and all of the various things
you see in old people older people are complicated, but at the core of what's
controlling all of that are really just three main
systems that we've discovered. There may be a few more,
but we know of three. One is the sirtuins that I work on. Another is called AMPK or MP kinase which Metformin works on. And now Lee, you've brought up the third leg of the stool,
which is a protein complex that senses amino acid intake called mTOR. And so mTOR, which is
little m capital TOR. If you eat a steak that's full of leucine, isoleucine valine. And it, this protein complex
will sense that and say, oh times are good. We just killed a mammoth. Let's build more, more skin. Let's make more. - Let's reproduce. - Yeah, exactly let's reproduce. But there's a, trade-off
the trade-off is that the body shuts down its defenses such as recycling proteins
called autophagy, a very important hallmark of aging
that declines with time. And so by taking this drug rapamycin which is definitively shown
to, or selectively shown to selectively target mTOR which is used actually to
modulate the immune system, it's in low doses, it
looks really promising as a longevity molecule. In rodents it's probably
the most successful molecule for extending lifespan even late in life. The problem with rapamycin,
the way it turns out is that if you take doses that are high I think higher than 10
milligrams for a long time, it can damage kidneys
and among other things. So it's not a perfectly safe drug which you'd want for
something that you'd use for longevity. That said rapamycin taken once a week or in low doses three milligrams are things
that people are talking about. And I'm aware of people who are trying it, you might say, well why
would you try something if it's not proven to work? Well, if we wait till it's
all proven to work, you know a lot of people listening to
this and watching will be dead. So there there's a risk reward ratio calculation that goes
on in people's minds. And that it's all done
under doctor supervision because it's a prescribed
medicine, but we're actually at that turning point,
I think in human history where we are able to say
that there's a pretty good likelihood that some medicines that are already approved could affect the aging process in a positive way. - Right, well, you know, one thing we promised to have a conversation with one another about it
in the future is my idea if we can measure in
patients, enormous amounts of data that I say all the
major systems and everything in clinical trials, like
we're talking about with aging we can one, reduce the number of patients that give you a compelling results. And two, we can see
results much more quickly because we're looking at
many more features to see if there are subtle changes and so forth. And it seems to me, this is
going to be a really key part for accelerating the acceptance of some of the kinds of things
we've talked about here. So my last question,
because we've got to turn to the audience now is
if you had to prioritize for the audience, things
that they could do now what would be your priority list for them to live in a
healthy aging manner? - All right, well, I've
mentioned eat less often. I think the three meals a
day plus snacks is misguided and I'm happy to debate
nutritionists on that. Other things you can do
is make sure that you keep your muscle mass. We lose a percent or so
every year as older males females too, as well, females
have to particularly watch about watch their bone loss as well. So doing exercise whether - - So is the exercise primarily
to keep up muscle mass or does it do other things too? - Oh, it does lots of good things. Some of which I'm not
even going to mention but testosterone will go way up if you build up the big
muscles in your body. So I exercise my quads. So my leg muscles, my back
muscles are the main ones. You know, that the rest is
just probably mostly just for vanity, but the big
muscles are really important in males and females. If you have strong hips and
there's a piriformis muscle, which holds your hips
basically your legs together, the problem with current
lifestyle is that sitting all the time causes those
muscles to degenerate. And it's very easy to just be weak there. And most people don't
realize they're weak. One of the things I'll get back to the question Lee in a second, but there there's an easy way to tell
how old you are roughly it's called the sitting-standing test and it'll test these muscles. You sit cross-legged and if you can get up without touching the
floor with your hands and stand up, you're
young, a middle-aged person like me might need to
use a hand to get up. And an elderly person will have to get on one knee to get up. And that's really just
testing your muscle strength. I think doing 20 push-ups
is considered really good at my age too, but those are
not very accurate compared to the other things we've talked about. But you're right that making your muscles
stronger has multiple benefits. It's increased testosterone for males and to a lesser extent,
females, the muscles give out hormones that are beneficial. That are what you know,
Lee are called myokines which we think circulate throughout the body and provide
improved health as well. We don't know all of them,
but we know some of them. The other thing that muscle
strength and aerobic exercise in particular will do is it'll make sure that blood glucose levels
don't get high in your body. And when you eat a meal the levels of sugar in
your blood don't spike and having high blood
glucose levels is that is one of the rapid ways to suffering and death. Anyone who's had type two diabetes in a bad way will tell
you that, including lack of circulation, heart disease,
et cetera, and dementia. - Yeah. - So that there's all those benefits besides just feeling great
and being able to still walk in old age and make sure that if you fall over,
you're bounce back up. - Yep, yep. Okay well with that, I'll
start reading some questions from the chat box that
the audience has asked. So the first is when do you plan to have the Horvath clock test
available for consumers? - Oh, that's hilarious. Only because that's one of the questions that
somebody was just asking me before I got on. All right, so this is public information. So let me think what I can say. We are right in the process
of making that happen the test will be coming
down a lot in price. And I mean, I hope to be
able to have something available conservatively speaking before the end of this year. Yeah that's probably all
I should say at this point but it is coming and it will be it'll be backed by my
science and be backed by my reputation and also provide feedback and suggestions on how
to improve your score. - Well, you know, I will make
one comment on a, I guess competitor now called
Longevity that has a test for biological age that
uses blood analytes. - Yeah. - And again, it is now available. So you can look up Longevity
and read about that. But I think both possibilities
are absolutely fascinating. Second question. What is the ideal window for eating with intermittent fasting? You eat just a single meal,
does that mean the window is just one to two
hours of eating per day? - Not even that. I'm like everybody, I'm a regular person. I like eating cheesecake, you know, but what I've realized is
that I feel so much better. I'm more alert, I'm excited. I'm I have a better
outlook, I'm optimistic. If I don't constantly eat I've never been big on breakfast. So that's just my physiology. Some people need breakfast I don't. But then I started skipping lunch and having a hot tea instead, I might eat a piece of
fruit, but that's about it. And then at dinner time, you
know, I'll look at a dinner. If I go out to dinner socially, I'll just eat normally that's fine. I'm not gonna reduce my joy in life. But most dinners are small. They are more like what a
rabbit would eat than a lion. I eat fish. I try not to eat big steaks, but generally I've reduced the portion
sizes really way down. And you know, I've never felt better. I, you know, I'd boasted
probably a little too much that I've got my 20 year old
body back, but I really do. And it's invigorating to be like this. And it wasn't that hard. I really started in earnest in February and you know, we're now in April. It wasn't that hard. I hope that everybody can consider it. If they are not already doing
it, I would encourage you to to do it for at least two
weeks before you give up because it takes two
weeks to get used to it. You know, we've all got habits. We go to the fridge we eat snacks. And once you get over
that psychological thing just have warm drinks, hot water, tea whatever you feel like, then it's easy. I definitely don't feel hungry. In fact, I feel way better
not having all these meals. One question I get though,
is should I fast longer than 18 hours, which is
what I tend to go for. And you can do that. I'm not that good at it actually. I don't have a lot of
willpower to be honest. A lot of people are better than me. So some people go for three
days, maybe every few weeks if you go for three days,
you get real deep cleansing by this process called autophagy the body will start to
recycle more proteins than it normally would using
a system called a chaperone mediated autophagy, or CMA. I would love to try three days. I just haven't been able to do that yet. And then there's the extreme version which is a colleague of ours. Peter, Dr. Peter Attia, who's become pretty well known for this. He does a week of fasting just with water. And he does that, I think
every, every few months. And apparently that's extremely good for you according to his
estimations, but it's hard to do. I would say at least try not
to eat three meals a day. That's a good start. - And then if you can get
to one, that's even better. - Yeah, you really do
start to appreciate food that's for sure. But it doesn't dominate your life. I lived a childhood where
my mother used every meal to discuss what was for the next meal. And I'm pretty happy that I
don't live like that anymore. - Great, so in your book you write about Resveratrol,
NMN and other supplements. What does the latest
research say about these? Would you give advice
to people that are ... what advice would you give to people interested in adopting them? - All right, so the technology
in my lab has been improving steadily resveratrol was a
very early discovery back into the early 2000s. What we were trying to
understand was can you activate these longevity
pathways mechanisms with a safe molecule? And at the time we didn't know that, now it seems obvious of course
everyone's talking about it, but we didn't know. And so what we discovered co-discovered with my coauthors was
that plant polyphenols, these are a variety of
molecules that are made by plants when they're
also under adversity. And one of which is resveratrol which is found in grapevines and red wine was pretty
effective at activating one of the sirtuin enzymes that my lab and others has shown to
be beneficial for health in mammals and even in humans. So resveratrol got a lot of hype, actually it was kind of unavoidable. There were a couple of things going on. The red wine industry loved it. Sales of red wine went up 30 plus percent and have stayed up. And then there was the commercial entity. So I started a company called
Sirtris which, you know had a professional team of
people talking to the media. So all of that, you know, 60 minutes Barbara Walters interview,
all that was pretty fun. But what really came out
of it was the realization that a safe, small molecule could be used to mimic the benefits of fasting. So we fed resveratrol to mice that were on a high-fat Western diet,
and they lived as long and were just as healthy
as the mice that were lean. So that in itself was I
think, a radical departure from what people were thinking. Why do I take resveratrol? Well, I do still take resveratrol. I take a teaspoon full
of it every morning. I take it with a tiny bit of yogurt just because it needs to dissolve. It's like brick dust. Otherwise it doesn't dissolve. And I've been doing that since my thirties and I'm still alive. So it's, we don't know if it's going to make me live longer, but- - You are the good test subject yes. - Well, I'm an Australian. So as you know, that there's a tradition of Australian scientists
experimenting on themselves. Like Barry Marshall discovered that the ulcers in the stomach
are caused by bacteria. He actually drank the bacteria and was himself and then cured himself. - But he won a Nobel Prize,
so sometimes it works. - Yeah well, instead of waiting 30 years for
the clinical evidence, but you know I'm not doing
this to try and live forever. I don't really worry about that but I am very curious and I do
like to learn things quickly. My father's been on resveratrol
for the same amount of time. And as I mentioned, he's
81 and is as fit or fitter than I am, but I don't, I
don't recommend supplements. I'm not an MD and we don't know if
these are going to work but there is a lot of evidence I would say in animal studies that
resveratrol is relatively benign and also can be beneficial to your metabolism and
protecting the organs. So I continued to take it until I see evidence that
it could be dangerous. And I haven't seen anything
like that in 20 years. I do take another molecule that's fairly prominent in the media, which is called an NAD booster. You can buy these, they're
called either NR or NMN. I certainly don't sell anything at all. I don't promote anything, but I find that a lot of people are interested in it. So I'm mentioning it tonight. NAD boosters are ... came out
of research out of my lab, as well as Lenny Guarente's. We discovered that the
sirtuin enzymes are controlled by the level of NAD. This is a molecule that our bodies make for metabolic reactions but also control the sirtuins' activity. And when you're hungry, if
you're a yeast cell or a human your levels of NAD will rise. And, but as you get older, it declines. And so what we were trying to
do is to artificially boost up the levels of NAD in the body. And that's why I take
the molecule called NMN which is a precursor to NAD. Interestingly, and what's very
rarely recognized is that one of the companies that I
founded, co-founded called Metro Biotech has been
doing clinical trials in people for over two years now with an NAD boosting
molecule that is related to NMN and found really
great results so far. I'm not at liberty to
say what they are yet but I'm still taking NMN,
having seen all the data. But I don't want anyone to
get the impression that I'm a a cowboy who's just
experimenting on himself. It's not that, you know I only take very calculated,
you know, barely risks but I also, at the same
time do clinical trials on these molecules to try and rapidly find out A, are they safe? And B, are they effective? - Okay, I love this question. Is it totally a good thing to get younger? Wouldn't that over populate the world with a bunch of newly young people? - Well, so I don't think that the world is a pie that has only a
certain number of slices. I think we can keep growing the pie. Now, the world has limited
resources of course, we can't keep burning oil and
we can't keep overpopulating and continuing to populate
a growing population. But as I explained in
the last part of my book when you actually do the math and I've, we're actually going to publish a mathematical model in
the journal Nature Aging, soon on this. What happens is it doesn't
... if you stop aging or slow it down, certainly
if you slow it down it doesn't appreciably
contribute to global population. Despite what you might think, there aren't that many people dying from old age, actually the problem is birth. Unfortunately, fertility rates, or at least reproductive
numbers in families are steadily declining across the planet and is even in the negative
for most developing countries or developed countries. The US would go negative if
it didn't have immigration. So don't worry. I don't think you should
worry about population. Well, resources, yeah, we need to solve that,
but I'm hugely encouraged by for instance, the energy
transition to renewable resources. I drive a Tesla for
good reason, and I think that humans are capable
of engineering themselves and innovating themselves
out of really any problem. It's just a matter of will and the investment and
we can solve any problem. - I think the other point is to be younger means you're vital,
energetic, curious, creative. I mean, it's hard to believe that virtually anybody wouldn't
like those, those traits. - Another question, if
someone were interested in a career changing into a field of aging from
a business related field where would you recommend starting? - Yeah what the, let me start. If you're in high school, have
a great interest in science. You want mathematics, you want
a bit of physics, chemistry. You want biology. When you get to college, I
would do some basic biology. I would do some philosophy. I would do some history
if you're interested, get a broad education it'll help you greatly
in the rest of your life. And when you get to my age, it's very difficult to do those kinds of
broad thinking and learning. So do that, but then start
to focus maybe in your second third year on genetics, which
now covers molecular biology as well as, you know,
even nanotechnology kind of stuff that Lee has
developed in his career. We're now in a revolution,
both in our ability to read and write the genome to
read and write the epigenome and to do experiments
by the millions per day, just as as one person, something
that took me a whole PhD which was to discover three genes read the code can now be done. Well, it wouldn't even be done. It would, the whole genome can be done in an hour by a graduate
student of a yeast cell. So we're at a point
where it's a great time to join molecular biology
and genetics and science in general, because we've
got these tools that people like Lee have built for us that we can now do a
million experiments a day. So that's a long way of saying
also get some experience in bioinformatics because
being able to analyze all of that data is invaluable. And I cannot find enough
good bioinformaticians at this point. - Yup, absolutely. Presumably you currently
do your own sequencing for your methylation age calculations. Is this the kind of things
somebody could do themselves today on a regular basis
with their own DNA sequencer? - Who has their own DNA
sequencer for goodness sakes? If you had a DNA sequencer, okay. - With Olink you can
actually have a little DNA sequencer that doesn't cost. I mean, with the single
cell sequencing technology from England yeah. - Yeah MNI you mean, or
is this something else? - Yeah, MNI that's right. - Right, a little candy bar size sequence. So you can do that for sure. If I think you can do
your own test at home you'd need a bench and
you'd need a central fusion. You'd need a pipette
and a kit probably don't want to make your own reagents, but- - And it would probably
cost you a thousand times as much as getting it from
somebody who is a pro. - It would, it would. So, you know, come to Lee or come to me, we'll get it done routinely and be able to help you
interpret the results as well. But I think it's an
interesting point that science has reached, genetics has reached a point where you can edit the genome
and read the genome even in your garage or your
kitchen, if you want to. - Absolutely yeah. You can take a DNA
sequencer out on field tests and look at organisms in the field. So it's amazing. What is the most accurate
way to measure NAD levels after consumption of precursors? What is your perspective on
NAD+ via IV for longevity similar to what we've done
for addiction detoxification? - Well, for IV NAD, I haven't
seen any solid data yet. I'm aware of it being offered. I went to the, one of the hotels in Hollywood and they offered it to me at the reception
desk, which was funny, but and also it seems to be
helpful, at least anecdotally with helping with
addiction on their clinics around the country,
particularly in Florida. But I can't say as a scientist
that I've seen convincing, you know placebo controlled
kind of experiments that would tell you if
that's working or not, and I'm open to it. I certainly think it's possible. And if anyone has data that
they'd like to share with me please go ahead and send it to me. And I'll judge it as I
would any other study. - Okay I think we have to close
down with the last question. I'll ask you, David. I know from our conversation that you're writing another book and I'll offer you a chance
to make some comments about it or to decline at this point
in time, whichever you choose. - Right, well it's late in the night over here on the East Coast. So, you know, maybe I'm
in a talkative mood, but yeah I'm excited that
the first book "Lifespan" was a New York times bestseller. It was super exciting. I've enjoyed the process the feedback that I've received
from you Lee and many others but particularly your
voice was very meaningful to me has prompted me to
want to do it again, right? You get enjoyment, you find
fulfillment you do it again. So I am writing another book
with my coauthor, Matt LaPlante who's a genius at bringing
together a whole bunch of disparate, crazy stuff in my mind. And I know Lee, you've worked with Matt so you know what I'm
talking about. My new book, we're still not disclosing
exactly what it's about but I can tell you that a
I'm very excited about it. It's going to be as
interesting and revolutionary as the first book. We like to take what seems obvious to the world and look at it from behind the mirror and actually
see what's what's going on. And it's going to be a journey of understanding where we've come over the last few million years as humans. Why do we exist with, with
crazy hands like this? Why do we look like this? Why are we a lollipop, physique? That's pathetic. You put us in a cage with a chimpanzee and
one hit and we're dead. We're pathetic as a species. Why did we evolve genetically
to be this pathetic? And then what happened to the world that we've made around us? Obviously we've got technology to try and make our lives easier to cope with all of the faculties that we've
lost over time since we've been out in the wild, but
we built a world that, that isn't perfect for our physiology. And I'm staring here into lights. I'm not going to sleep well tonight. You know, we suffer from social media. We've got a lot of depression
and anxiety in our young kids. We've got other problems. We sit all day, you
know, time and time again our technology solves one
problem and causes another. And I call this the
treadmill that we're on. And really ever since
humans have picked up a rock and used it to bang an animal
on the head, or maybe one of their enemies on the head
we've been on this treadmill. And the question is, can we ever get off? And what does the future hold? And that's what I'm writing about. - Yeah well, David, I want to thank you for an absolutely stimulating
and wonderful conversation. I thought you did a terrific job in bringing the world
of aging to everyone. And I just say, if you will lessons that I took home
when I read your book was something we haven't talked about is that this aging process David and others have discovered
is conserved all the way back to the simplest of
single celled organisms. And I think there are
two interests with regard to that conservation. One is it underscores the idea
of simplicity and elegance and something that's
shared in all creatures. And number two was the idea
we can use model organisms like mice and yeast to
discover fundamental things that apply in very straight
forward fashion to humans. And that's really an exciting idea. I think number two, the
idea that aging is a disease and that we really have
powerful tools for curing and slowing and even potentially
reversing that disease. And I think number
three, if we can do that we can begin to think of a very powerful way for
attacking the broad set of chronic diseases whose
major predisposing factor is in fact aging itself. And I think finally with all
of the revolutionary changes that David has discovered
in the next 10 years, we're going to see remarkable
opportunities presented to each of us for fundamentally
changing our lives. And presumably moving us into the eighties and nineties and hundreds
physically, capable mentally alert, enthusiastic about life. Now that poses other
really interesting issues about where are we going
to get enough money to do all the fun things we like? How can we, are we going
to have multiple jobs all sorts of exciting things. Anyway, I want thank Town Hall for allowing us to do these
wonderful, exciting programs. I think to the audience please we'll have other exciting programs in the future that combined
together ISB and Town Hall. And if you're interested in
keeping up with all of these go to our website at ISB,
which is www.isbscience.org. So thank you, and especially you, David have a great evening. We really appreciate your contributions and your expression of them. - Well, thank you, Lee. And thanks to everybody,
the Town Hall folks and everyone who tuned in tonight I thought it was a wonderful discussion. And Lee, thanks for everything you've done for science and technology as well. - Sure.
Worth having a read about the interviewer (Leeroy Hood), who is an absolute scientific giant.
Very, very promising that such a scientist is supportive of aging research and understands it well - he recognises that it makes sense to target aging rather than one disease at a time, and is aiming to add an aging module to the Institute of Systems BIology to educate youths in high school/undergrad.
Interesting interview because the interviewer is able to ask good questions as a fellow biologist
New info I learned: Sinclair is looking to commercialize blood tests so we can easily monitor ourselves; FDA is open to consider aging a disease as long as it can be proven (and actually studies are going on right now for exactly that purpose).
One of the best interviews, if only for good questions being asked. Sounds like weβll have access to Horvath clock analysis as soon as the end of this year. Also we got to hear that he takes metformin, nmn, and resveratrol. Personally Iβm still on the fence about taking supplements (pls donβt attack me in the replies) but heβs pretty persuasive.
This was a great interview! David says he is working on making his βbiological ageβ test available to the public at a reasonable price before the end of the year. Thatβs a big deal!