cc >> I want to introduce
Dr. Aubrey De Grey from the Methuselah Foundation.
( applause ) >> Thank you very much Justin.
Now I'm very pleased that so many of you turned up.
I hope I can entertain you a little bit for the next hour and
tell you a little bit about what we do and why and about in
particular the science. I have the impression that
there's quite a variety of expertise in the audience here
that some of you are scientists some of you know quite a bit of
this sort of biology. A lot of you don't know anything
about it. So I'm going to try to
accommodate that in the range of things I talk about and we'll
see whether I manage. I'm going to put this on.
I also should emphasize before I start that I'm going to be here
for the rest of the evening. I have to fly out to New York
tomorrow morning but I'm perfectly happy to spend as long
as anyone carries on buying me beers talking about everything
that I'll be speaking about in the next hour.
And indeed anything that I don't have time to speak about.
So you're all very welcome to give me a hard time for the rest
of the evening. I should probably mention that
there's plenty that I won't have time to speak about.
And for that reason I published a book about six months ago that
is a pretty detailed account of the science behind the way that
I think aging will be defeated. I wrote it jointly with my
research assistant Michael Ray who has a real gift for putting
really tricky scientific concepts into a form that holds
the imagination. He's really good at imagery.
So I have been told that it's a pretty good read.
Though I say it myself having written some of it myself.
And I encourage you certainly to try to get a hold of a copy it's
not very expensive as you can see.
Now a lot of people when you talk about defeating aging
entirely they say well, hang on this is obviously impossible.
But let's face it, it's certainly not obviously
impossible. Because we have an abundance of
evidence of actual, you know, examples out there.
Of pretty remarkable phenomena with regard to aging.
First of all, we have a variety of simple animals that don't age
at all. And when I say don't age at all
I really mean this. The have been studied -- some of
them anyway -- have been studied very carefully in this respect.
Hydra is probably the one that's been studied most thoroughly.
And there is abundant confidence in the gerontology community
that these animals just don't age at all.
There's the existence proof there is a way to avoid aging.
Now these as I did say are simple organisms.
They don't have, for example, a central nervous system and you
know, I'm quite of my central nervous system and I would not
relinquish it even in favor of immortality.
But that's not the whole story. Some vertebrates which have of
course have a central nervous system very much like our own.
very slow aging at least and maybe truly non-aging and a lot
of them do it because they grow throughout adulthood.
This turns out to be quite useful because it means that
they retain the ability to lay down new cells in all of their
tissues. A lot of the problems that we
have with aging, in fact, the hardest problems that we have in
respect to our biology is that since we don't grow throughout
adulthood, several of our tissues, in particular the brain
-- and the heart and a bunch of others, but the brain is the
most important -- have lost the ability to do adequate
replacement of cells when cells die.
And the evolution has pushed us in a different direction instead
in the direction of simply being pretty good at keeping those
individual cells alive for a very long time without
replacement but a very long time is not forever.
So that's a big part of the problem that we have with aging.
However, there are some pretty damn good examples, even within
organisms that do not have indeterminate growth during
adulthood, that seem to be better at aging than we are.
Whales -- well certainly some species of whales -- live
considerably longer, perhaps twice as long as we do, maybe
even longer than that. These organisms I mention here,
parrots and naked mole rats, live a very long time given
their size. You probably know that larger
species, especially larger warm blooded species, tend to live a
longer time than smaller warm blooded species and that's for
plenty of good biochemical and metabolic reasons that we think
we understand. These animals seem to do better
than us that way. Taking that into account.
So that's again, you know, interesting.
Then if we come back into the laboratory, we've actually been
able to intervene again with relatively simple organisms.
But, you know, not ridiculously simple.
The ones we're talking about here do have a central nervous
system for example. You know we can multiply the
life span of simple organisms in the laboratory by a large
factor. This is pretty good news.
Now today I'm going to talk about a whole bunch of things
that I think are going to work in humans.
And, therefore, I want to emphasize that I put this list
up really as a sort of series of strong man.
On the one hand to say, listen we do have plenty of
superficially relevant -- superficially impressive
examples of the ability that we might have to control aging.
But when we try to get beyond the superficial and we say what
actually matters, what actually is likely to be promising for be
doing something about aging, it turns out that none of these are
particularly promising. What's really promising is the
fact that regenerative capacity exists in some pretty
complicated organisms, vertebrates, that can do amazing
things. Now the regeneration that we see
in lower vertebrates like Amphibia especially and
salamanders are the most high profile example.
That regeneration is not what I'm going to talk about today
but it's a -- if you like it's a spectacular example of the same
sorts of cellular molecular processes that exist naturally
that we have a respectable chance of introducing
biomedically in the foreseeable future.
So this is how the rest of the talk is going to run.
I'm going to introduce you first of all to the general
philosophy, the top level description of how I think we're
going to be able to go about combating aging seriously in the
foreseeable future and why it's foreseeable.
Then I'm going to drill down a little bit to describing it in
more detail. I'm going to describe the
structure of this plan. Now even at that point I'm going
to have to be pretty superficial because there's a lot of detail
here. It's a really pretty complicated
business. That's why I had to write a
whole book about it. And for that reason I want to
make sure that you don't think I'm bull --.
I want to go down to proper detail in one example, in one
component of this grand plan just so you can see the lower
substance there. Then towards the end of the talk
what I'm going to do is talk about the more distant future.
And when I say more distant I do not mean less relevant to people
who have the misfortune to already be alive.
I mean only slightly more distant.
And you'll see what I mean. I will be introducing you to the
reasons why I think that the relatively imperfect technology
that I think we have respectable chance of developing in the next
few decades will lead to, in fact, much much more impressive
results than that technology can itself directly provide.
That's the concept of longevity escape philosophy which I'll
introduce towards the end of the tour.
And then I'll just close with a couple of minutes about the
foundation about what we're doing, how we're doing it, how
we're progressing and what we're going to do next.
All right, the SENS philosophy. Well, I'm going to start by
describing the problem. Before you describe the solution
to a hard problem, you have to describe the problem in ways
that should be instructive. And the problem of course here
is aging. What is aging from a biological
point of view? Even a lot of biologist have
pretty profound misconceptions about this question.
So I'm going to be fairly elementary here.
The first thing that we have to understand about aging is that
we don't have genes for it. Aging is -- well this particular
description of the nature of aging is actually due to a
colleague and a very well known gerontologist, Len Hayflick.
And what this says is simply we don't have data for aging.
Aging has not been developed because evolution found it to be
selectively advantageous for organisms to age rather than not
age. Rather it was a case of it's
disadvantageous but it's not sufficiently disadvantageous for
evolution to have taken the trouble to get rid of it.
In evolution you have, obviously, from one generation
to the next, a mutational process.
Every sperm, every egg has a certain number of mutations in
it. And those mutations have to be
purified out again at the same rate they're occurring or else
they'll take over. That purification can only
happen if the mutation is bad for the organism in terms of the
number of offspring that that organism can have and the number
of subsequent descendants. Aging just isn't bad enough from
the point of view of evolution. You and I care about aging.
But evolution only cared about organisms that are still alive.
And if we were in the wild a thousand years ago then a very
small proportion of the people in this room would still be
alive at the age that we are because of -- and hypothermia
and starvation and all those things.
So evolution just doesn't care very much about aging organisms.
That's actually bad news. So I want to explain why this is
such bad news. Supposing there were genes for
aging. Bingo we just turn them off and
I'm not saying that turning them off is easy but it's fairly
easy, it's just you know, a bit of gene therapy or genetic
manipulation or pharmacological manipulation even.
And certainly we live longer. Unfortunately there aren't any
genes for aging so it's much harder than that.
Right then. So what is aging?
Well that's why we have aging because evolution couldn't be
bothered to get rid of it. What is aging?
The best way to describe aging at the top level is described on
the next two lines. Aging is a side effect of being
alive in the first place. There's no question about that.
We, you know, our metabolism is this extraordinary complex
network of biochemical and metabolic and cellular processes
that keep us alive, keep us intact from one day to the next
and those processes have side effects.
Those side effects are initially harmless.
They just accumulate in the body throughout life, even starting
from before we're born and of course I'm going to be talking
shortly about what exactly those side effects are in proper
concrete terms but for the moment just stick with the
abstract. Those types of side effects
accumulate and eventually they accumulate to a level of
abundance that is bad for it. They get in the way of
metabolism's ability to keep us going from one day to the next.
That impairs physiological function.
And that of course is what I mean by the word pathology here.
Age related decline of function including age related diseases
but not restricted to age related diseases.
So this is what aging is. It's the ongoing accumulation of
changes to the molecular and cellular structure of the body
that are eventually prejudicial to the continued functioning of
the body. And of course as soon as this
starts to emerge, things start to go down hill at an
accelerating rate that's the point I'm making at the bottom
line here. The worse you get, the faster
you get worse still. Right then.
So what does that mean in terms of intervention?
Well, classically this is what it means.
There are two games in town as far as most people have
historically thought. One game is the geriatrician's
approach. In other words, when pathology
starts to emerge, you attack it. You try to hold back the sands
of time and you try to slow down the accumulation of diabetic
problems or the growth of arthrosclerotic plaque or the
growth of cancer or whatever. And that's definitely better
than nothing, don't get me wrong.
But it's only a little bit better than nothing.
And it always will be only a little bit better than nothing
because, by definition, it's a short-termist's problem
attacking a downward spiral. Because the precursors of the
pathology are continuing to accumulate.
These are, as I said, ongoing accumulating side effects of
metabolism and therefore the geriatrician's problem is going
to carry on getting more and more difficult as the patient
gets older. This is definitely better than
nothing but only slightly better and that's how it will always
be. Now gerontologists have known
this since forever. Gerontologists have known that
they have to take the view that if they really want to do
anything about aging in the long term then prevention is better
than care. Simple as that.
Prevention is better than care. So they say right let's not wait
until pathology's emerging, let's clean up metabolism in the
first place. Let's get in here and actually
stop metabolism from laying down these various types of damage,
these various cellular and molecular changes, at the rate
that they would naturally be laid down.
If you can do that, then bingo you've achieved the same
objective, you've delayed the age at which the damage reaches
the level of abundance that is pathogenic but you don't have
the vicious cycle problem, the downward spiral of the
geriatrician. So this is a great idea, in
principle. But there are some problems.
So I explained that the problem with the geriatrician's approach
is that it's a downward spiral. It's attacking the problem too
late in the game. I just thought I would emphasize
that by pointing out how complex it is.
And you don't need to be a biologist to know what's on this
slide of course these are just a small subset of the things that
go wrong with us during aging. And, as I mentioned, the more
seriously wrong they go, the faster they go wronger still.
So that's bad news. What's wrong with the
gerontology approach? This is what's wrong.
Metabolism is rather complicated.
In fact, it's incredibly complicated.
This here is a depiction of a small subset of what we know
about the way the metabolism works.
That's not the problem. The problem is that this is a
depiction of a small subset of what we know about how
metabolism works. The big problem is, as any
biologist will tell you, what we don't know.
Any biologist -- the more you know about biology, the more you
appreciate that we have hardly scratched the surface of how
cells work let alone how organisms work.
We have an unbelievable amount to find out.
And that's just the stuff that we know that we don't know.
I'm ignoring the stuff that we don't know that we don't know.
So it's just not -- the time for the gerontologist's approach to
postponing aging has not come. In order to intervene and clean
up and minimize the side effects of a system that's really
complicated, you have to understand the system pretty
well. Otherwise you'll dive in and,
you know, 90% of the time metabolism would just get on, do
what it was doing anyway and laugh at you.
And the rest of the time if you do have some effect that you
wanted to have it's guaranteed that you will have a whole bunch
of effects that you didn't want to have.
The serious consequences will outweigh the benefits that you
may achieve. So gerontologists are more or
less -- well I will go as far to say they are virtually unanimous
that cleaning up metabolism is not something we're going to be
able to do systematically and comprehensively anytime soon.
So why am I standing here today? Well, basically it's because I
realize that the two options that I described for
intervention so far are not the only options.
This is a picture that appeared on the front of "Scientific
American" a number of years ago, a few ago.
It was advertising an article in that issue written by my good
friend and a couple of his colleagues.
And essentially it was making fun of the idea that we could
ever do anything about aging. It was a sort of tongue and
cheek description of how the human body would have to be
built if we were going to live any longer.
And they called it -- this is what they called it.
"If Humans Were Built to Last. " And there were a whole bunch
of things here about building the spine better so that we
could carry heavy weights and building the eye in such a way
that the light doesn't have to go through a whole system of
blood vessels in order to reach the retina and all those sorts
of things. And that was all very humorous
accept that some journalists actually took it seriously.
But the thing is, you know, it was basically a tongue in cheek
description by these people who were trying to make fun of the
idea that you could ever do anything about aging.
Saying well, you couldn't. Now, the human body is a
machine. It's a very, very complicated
machine. And we have the misfortune that
we don't have the plans. But it's still a machine.
So maybe we ought to be able to learn something about the
extension of the life span of the human body and the extension
in particular of the fully functioning healthy life span by
examining other machines. For example, simple manmade
machines like cars. Now, here is a car that was
built to last. It -- you know, corrosion
resistant metal, that sort of stuff.
And sure enough it has lasted. This particular car is probably
50 years old. It might be worthwhile if
someone could actually dim the lights a little bit.
I mean, it's okay I guess I don't have any particularly dark
slides but if there is possibility to dim the lights a
bit that would be great. Anyway, so this car is doing
fine. It's more than 50 years old.
But it was built that way at the beginning.
The question is, is there any other way to keep a car going?
No. My title of course is treading
carefully. I didn't say, you know, if your
average car was built to last. Here is a car that is the same
age as the car on the previous slide.
And it's just as functional. It's working just as well as it
did when it was first -- yeah, yeah whatever.
What's going on? Fantastic.
Thank you so much. It's working just as well as it
did when it rolled off the production line.
Why? Not because it was built to last
but rather because it's got style and so its owners fell in
love with it and have been doing an exceptional amount of
maintenance on it ever since so that it's still working.
Maintenance is another way to get machines to work properly
for a longer time than they otherwise would.
And that can now come back to look at the aging problem.
There is a third way. It's a maintenance approach.
I like to call it the engineering approach.
Maybe the maintenance is even a better word.
I'm not really sure. I claim -- as you can see at the
bottom here -- that the engineering approach is a much
more attractable and therefore a much more foreseeable approach
to postponing the -- or extending the healthy life span
of human beings. It has the best of both worlds
of the other two approaches. On the one hand, it's
intervening sufficiently early in the game that it doesn't have
this problem of the downward spiral.
There isn't by definition -- damage is the immediate ongoing
side effects. Side product of metabolism and,
therefore, intervening on to target damage itself does not
have the problem of some precursor of damage that's
accumulating. I should explain perhaps a
little bit more clearly what I mean by the engineering
approach. What I mean is you don't
interfere in the process whereby damage translates into
pathology. These flat-headed arrows, by the
way, are a notation taken from the genetic literature.
They just mean inhibit. So that's what the
geriatrician's approach does. It inhibits the process whereby
damage becomes pathology. The engineering approach doesn't
do that. It also doesn't intervene in the
process whereby metabolism translates into damage.
And that's really important because if you're letting
metabolism do what it naturally does, in other words, if you're
letting it lay down the various types of damage at the rate that
it naturally lays them down, then you don't have to
understand it. You're not interfering with it.
The engineering approach says let's let that happen, let's let
the metabolism lay down these various types of damage but
let's then get stuck in and repair the damage and restore
the structure of the body to a biological younger state.
Thereby, of course, having the same affect stopping the damage
from getting to the point where it's got -- where there's so
much of it that it's pathogenic. So in other words the
engineering approach uncouples metabolism from pathology.
That's the theory. And because it's intervening
earlier in the game than the geriatrician but later in the
game than the gerontologist it has the best of both worlds and
I think it's got a respectable chance of achieving a healthy,
human life extension pretty soon.
That's one reason why I think the engineering approach is
good. That it targets the right point
in the chain of events, but there's more.
The big reason why I think that the engineering approach is so
promising and why I talk about foreseeable life extension for
people who are already alive today is that damage isn't
nearly so complicated. I've shown you a couple of
slides already emphasizing how complicated pathology is and how
complicated metabolism is. Here's your damage.
The big breakthrough -- the big conceptual breakthrough that I
made that really got my research agenda going back in 2000 was to
appreciate to begin to realize that all of the various
molecular and cellular phenomena that qualify as damage by the
definition I'm using this evening, in other words, ongoing
consequences of metabolism. They're eventually pathogenic
when they accumulate to sufficient abundance.
All of those things fit into this very straightforward simple
categorization. Stuff, you know, indigestible
molecules that are accidentally made inside cells sometimes.
And if they're made at a high rate, than that has been a
problem for evolution because it kills organisms when they are
young, when they're still alive and reproducing and so on.
So evolution has done something about it.
But lots of different types of molecules accumulate at slower
rates and evolution has said well who cares.
So we care and that's one aspect of aging.
Junk accumulates outside cells. Amyloid plaques in Alzheimer's
disease are probably the best examples of this.
Cells die and sometimes they're not naturally replaced by the
division of other cells and that causes problems eventually.
That's essentially what stem cell therapy is for.
I'll come on to intervention in a second actually.
But you get the idea. Now, this is a pretty outrageous
statement that you can actually classify all of the things that
go wrong with this ongoingly during life into just certain
categories. But the more I thought about it,
the more I thought well it's actually pretty good evidence in
favor of this. First of all, you can take --
you can start from the simple tenet that damage can only
accumulate in long lived structures.
In other words, say you've got a cell and it makes a protein and
the protein does some job and then it gets damaged in some
way, it gets oxidized or whatever.
It gets broken down. The damage then is gone.
So that's not damage by the definition I'm doing because
it's not accumulating. So you can just look at long
lived structures. You can look at DNA.
You can look at molecules that are sequestered in the cell
rather than destroyed or excreted and so on.
And that's how you can get this sort of list.
There's another way you can get this sort of list.
Which is more circumstantial but still quite compelling.
It's been the same list for a quarter of a century.
All of these things have been major topics of conversation and
discussion within gerontology since at least the early 1980s
and in many cases the '50s or '60s and we've come a long way
since 1982 in terms of our ability to analyze biological
systems and figure out what's wrong with them.
And this list should have got longer if there were much to add
to it. So there's pretty good reason to
think that we're really right about this.
But of course the really good news is that we know how to fix
it. And when I say we know how what
I mean is we know how in enough detail that the respectable just
basis for confidence that we can actually implement these fixes
within the next few decades. So I've written up here just in
one liners the sort of approach to fixing these various
problems. And this is actually the reason
why this particular classification on the left is a
useful classification. It's because within each of
these seven categories you can ask well there are lots of
examples within one or another tissue that are affected the
general approach to fixing the problem is essentially the same
for each of those various examples within the category.
Only the details are different. Like stem cell therapy, for
example. Okay it's a big field and the
reason it's a big field is because cell loss has different
problems associated with it in different tissues and different
fixes but lots of things in stem cell therapy are the same across
all tissues. For example nuclear transfer or
dedifferentiation of adult cells.
So you get the idea. And it's the same across the
whole thing. Now as I say the reason why I'm
confident about the time frames here is because of the detail.
If you get my book then you'll find that each one of these
things has an entire chapter describing the detail.
Obviously I don't have time today to go into all of that.
I'm just going to spend a little while talking about one example
which happens to be a rather glamorous one so that you can
get some idea of the sort of novelty that's involved here.
But also the fact that this is really based on very solid
science just science that hasn't necessarily been applied to this
problem before. Stuff that accumulates inside
cells is a big problem in some of the most important aspects of
aging. In Alzheimer's disease you get,
as I mentioned a moment ago, stuff accumulated in the spaces
between cells but you also get serious problems inside cells.
This is a cross section, in the electron microscope, a cross
section through the long part of a neuron.
The axon. And as you can see it's a bit of
the mess. It's not very pretty at all.
There's a lot of stuff in here that should be getting broken
down isn't getting broken down. There's a lot of evidence here
of failure of degradation. In arthrosclerosis, in
cardiovascular disease, you have the same sort of phenomenon,
here we are. Where the Fbam cell This is a
cell that used to be a perfectly functioning immune cell.
White blood cell. Migrated into the artery wall
and did what it was suppose to do which was to engulf bits of
cholesterol in the related molecules that was stuck in the
artery wall. And it was able to process that
stuff pretty well at first. But unfortunately a small
proportion of the stuff that it was suppose to metabolize was
recalcitrant, resistant to metabolism and accumulated
inside the macrophage and turned that macrophage into sort of an
undead macrophage called a phone cell.
This is a phone cell. Where it can't really do the
things that it was able to do before let alone the things can
couldn't do. And this is the beginning of an
arthrosclerotic plaque. You get the idea it's not very
nice. What are we going to do about
it? Well I had this crazy idea.
It was a bit of lateral thinking.
This is back in 1999. I happen to have a colleague in
my department in Cambridge who worked in environmental
decontamination. And specifically he worked in an
area in that field called bioremediation.
Bioremediation arose about -- well it arose from a hypothesis
that was put forward may be 50 years ago called -- the
wonderful name -- microbial infallibility hypothesis.
And here is the hypothesis -- the guy who thought it, Ed Gale,
said to himself well, hang on now, some microbes grow faster
than others. So growing fast is a fine way to
out compete your competitors in some environment.
So if you can grow fast, you ought to be the only -- if you
can grow faster than anyone else in the environment, you ought to
win. You ought to dominate the
environment. And if you look at a given chunk
of soil, for example, you'll see one or two species of bacteria
that can grow really fast and that's all you'll see.
But in practice that's no what you see.
If you get any sample of soil you find the most immense degree
of microbial diversity. So Gale thought about this and
he said to himself well maybe there is an explanation which is
there's another way to carve out your ecological niche if you're
a bacteria. Rather than growing faster than
your other competitor, there may be something in the environment
that you can metabolize and grow on -- extract energy from -- and
they can't. And in particular, what Gale
thought to himself was that well if there is something in the
environment that is really pretty hard to metabolize but if
you can then you can grow off it because its energy rate, then
that's going to really impose serious selective pressure on
the microbial ecology to develop such ability -- the ability to
break this stuff down. So he said well let's suppose we
go to some environment that's got let's say a just used air
field that's got TNT in the soil, which is a common thing.
And let's suppose we want to get rid of that TNT in order to
let's say build a housing estate onto the airfield.
You're not going to be able to do it at the moment because TNT
is toxic. How do you get rid of the TNT?
He said, well, maybe you can just go and have a look at the
soil and we'll find that there are bacteria in the soil that
can eat TNT. And you know what?
He was right. The only reason that there's TNT
in that soil is because there was not enough of those
bacteria. So he said you can just get
those bacteria out, expand them in the laboratory, put them back
in the soil in greater numbers and your TNT goes away.
And he was right. And it's not just TNT, plastics,
dioxins, rubber, you can go to the side of the highway and
you'll always find bacteria that can eat rubber because
pulverized rubber is coming off tires all the time.
All right, what the hell has this got to do with aging?
This is my idea. I realize that there are
environments that are enriched in human remains.
And those environments, therefore, will be enriched in
precisely the energy rich compounds that we can't break
down when we're alive. But mysteriously those
environments, those graveyards do not accumulate these things.
They do accumulate some parts of human remains, bones and teeth.
But hey, brilliant -- that's consistent with the hypothesis
because of course bones and teeth are not energy rich.
You can't live off bones and teeth.
So it seemed very probable to me that in fact graveyards would be
a fine source of microbes that would be able to break these
things down. Now what use is that
biomedically. We're not going to inject
bacteria into our bodies are we. Let's face it.
But that wasn't my idea. My idea was that we could figure
out what the genetic basis for that capacity was.
Why -- how these bacteria were able to break these things down.
We can find the genes that were encoding the enzymes that were
doing the jobs. And then we could use those
genes with straightforward -- well, relatively straightforward
molecular biology gene therapy and so on to actually have a
therapeutic affect. This is the idea put
graphically. You've got this process in the
human body that turned young people into old people and
eventually into dead people and then you've got this other
process that's completely outside the human body and it's
encoded -- and that turns dead people into decomposed people
and the idea is to take that and do standard molecular biological
work basically and translate that capacity into human cells
-- this is my pitiful picture of a neuron.
And thereby slow down -- you see this flat-headed arrow again --
slow down the process that turned young people into old
people in the first place. All right, so that's all very
well in theory. Does it work?
Well the answer is yes. We've actually -- the Methuselah
Foundation that I'm going to be at, that I run that I'm going to
be talking a little bit about later on.
We have been funding some work in this general area for a
little while now. For a couple of years.
Especially in two laboratories -- one in Arizona and one in
Texas. And these laboratories are
getting good results. We have actually publications
now on this stuff. The first target that we looked
at most intensely was this thing called -- cholesterol which is a
particular variant of cholesterol that appears to be
the public enemy number one when it comes to arthrosclerosis and
possibly Alzheimer's as well. And here you can see the sort of
experiment that gets done. Over ten days, you've got a
whole bunch of different bacteria being exposed to this
stuff and being given this to grow on and not being given
anything else to grow on. And most of them don't know what
to do. They haven't got the genes to
break this stuff down so the stuff just sits there.
The amount of the cholesterol that's in the culture.
And it stays constant. But I'm sorry about the lighting
here, it's my fault for the colors on this thing but there's
a couple of trajectories here, a pale blue one and a yellow one,
in which the stuff completely goes away after ten days.
Okay. So this really says these
bacteria are able to break the stuff down and you don't need a
microscope to see this. Here's a petri dish with the
stuff, before and after and it's pretty glamorous really.
So that's pretty good news. Now I'm not saying this is easy,
you understand. This is an extremely ambitious
approach to the cure and prevention of cardiovascular
disease and arthrosclerosis and so on.
But it is going to be so much more effective when it works
than anything that we have today or indeed anything that is
coming down the pike that it's worth it.
We have to go through all these steps obviously identify the
enzyme, put then into mammalian cells, make them work.
There are a whole bunch of tricks that we may have to play
in order to make sure they're not toxic and don't break down
things that we want to protect but we have a lot of tricks for
that. We have to do the same thing in
life before we go to human trial, the usual deal.
It's going to be a long project but it's worth it.
All right, now that's all I'm going to talk about tonight with
regards to the detailed science that of course as I've said here
I'm absolutely abundantly happy to answer as many questions as
anybody has later on. What I'm going to talk about now
is I'm going to switch from science to technology.
And in particular to the history of technology.
Because those of you who have come across me in the media and
so on will know that the thing that I tend to be most famous
for is that I discuss not simply the postponement of aging by a
little bit but by a lot, an awful lot.
And being reasonably, you know, realistic about biology I know
perfectly well that the sorts of technology that I've written
about in my book and that I've given you a taste of just now
will not do that. They're going to have an impact
on each of the various types of damage that accumulate with age.
But they're not going to solve them completely.
Because within each of these categories there are things that
are relatively easy to fix and there are things that are
relatively harder to fix. We have a respectable chance, it
seems to me, of perhaps halving the severity of each of these
problems in the next few decades but we won't solve the problems
completely. And if we only halve them, then
I reckon we're problem going to get may be 30 extra years of
healthy life. We're going to be able take
people who are middle age, let's say 60 years old when we start,
and we might be able to rejuvenate them for a while but
eventually the things that the therapy just doesn't work on
well enough will catch up with those people.
So what's the catch? How do I get out of this?
How do I say that people are actually going to live
indefinitely? Well, the fundamental four-word
answer to that question is here. It's the third reason why the
engineering approach is such a good idea relative to the other
approaches. Repairing damage buys time.
Here I'm giving you a very, very schematic description of what
I'm talking about. So don't read too much into the,
you know, quantitation into this.
This is really just to give you the conceptual idea I'm putting
forward. But, you know, it's an important
thing to get across and it's not always easy for a lot of people
here. This word reserve that I'm using
on the Y axis is not a new concept I'm introducing.
It's the inverse of damage. You can think of reserve as the
amount of additional damage that someone can afford to accumulate
before pathology starts to hit. So you've got on the red line a
very schematic just sort of representation of what normal
aging consists of. You start off at age zero with
not much damage, lots of reserve.
Damage accumulates -- damage in all these various sorts that
I've been talking about -- in other words, reserve goes down
and eventually you hit this thing I'm calling the frailty
threshold, this dotted line and at that point pathology begins
to emerge and it's all, you know, you're going to have in a
hand basket. Now supposing you had a therapy
that halved the rate of accumulation of damage.
I told you earlier that cleaning up metabolism is basically
impractical. But let's forget that it's
impractical for a moment. Let's just think hypothetically
supposing we had a therapy that could slow down the accumulation
of damage by a factor of two for the sake of argument.
And let's pretend we start applying it to someone when
they're here. Let's say middle age.
Let's say 55-60 years old. So that's the blue line.
Eventually you hit the frailty threshold.
And at that point I'm drawing the line as revealing it's
previous gradient, and the reason I'm doing that is because
the frailty threshold is a bad thing to get to.
Once it gets to that point you've got this downward spiral,
you've got this auto catalytic accumulation of damage and so
the therapies are basically not going to have much effect
anymore. Right now.
What's going to happen if we now consider a comparably effect
reversal therapy. I said that here we are halving
the rate of damage. In other words, we're having a
50% effect on the accumulation of damage starting from the
point that we apply the therapies.
Now, if we start reversing the damage and again we reverse half
the damage, what's the result? Well, this is the result.
You're going to be able to take someone up to here to rejuvenate
them effectively. So I'm calling the damage the
therapy works on the easy damage and the damage the therapy
doesn't work on is the hard damage.
Now because we're not intervening at the rate at which
the damage is laid down the rate of aging as determined by damage
as determined by a lot of reserve is the same after the
therapy has been applied as it would be in the absence of the
therapy, the red line. But then of course we can
reapply the therapy and again and again and so you get a lot
more efficacy than you do if you only retard the damage.
But you do have only a finite amount of improvement.
And this is the sort of trajectory that I call robust
human rejuvenation. The addition of maybe 30 extra
years of healthy life to people when you start the therapies at
middle age. The reason you have diminishing
returns is of course because the hard damage, the damage that the
therapies don't work on is continuing to accumulate
unabated and eventually on its own irrespective of the
thoroughness and frequency with which you apply the therapy,
it's going to be enough to tip the person over the frailty
threshold. So that's what I call robust
human rejuvenation. And it's a lot better than
retardation but it ain't immortality.
It isn't even indefinite life span.
Addition of 30 extra years of healthy life and total life to
the lives of people who are already in middle age when the
therapy's begun. So I still haven't answered the
question. How can I talk about four digit
life spans? How can I talk about the total
elimination defeat of aging? If we were mice, I would not be
able to. If you and I were mice, then I
would have reached the end of my story because on the X axis here
where I've carefully put no numbers we will be talking about
in like in a year, two years, three years.
Okay? But we're not.
We're humans. So the X axis is maybe 25-30
times as long. In particular the interval
between the first two applications of this therapy,
this punitive therapy. Here and here.
May be as much as let's say 20 years.
Now, what's so special about that?
Well the answer is 20 years is one hell of a long time in
technology. It is enough time, in
particular, in biotechnology for these therapies to be
considerably improved. Not just in the cost and the
convenience but in their comprehensiveness.
So it means that we can be very confident that the second time
that someone who was here when the therapies first arrived goes
back for his re-rejuvenation, he will not be receiving the same
therapies that would only give this amount of rejuvenation.
He'll be receiving therapies that will fix not only the type
of damage that could be fixed the first time 20 years
previously. But also let's say for sake of
argument half the damage that could not be fixed previously.
That's why I'm dividing the hard damage now into hard and very
hard. So this brown line, this orange
line is the depiction of that. Now, most of you can probably
see where I'm going with this. The orange line -- the thing
about it is not only the person is rejuvenated to a greater
level than they would have been if they'd been using the
20-year-old therapies, they're also rejuvenated to a greater
level than they were 20 years previously when they were
chronologically 20 years younger and that, of course, iterates.
It means that the diminishing returns problem does not occur.
All you need to do is continue to improve the therapies at a
sufficient rate to keep one step ahead of the problem to make the
therapies sufficiently comprehensive to keep the
overall level of damage of all the various types down to a
tolerable level, a sub-pathogenic level, And you
never hit that frailty threshold.
You don't have to apply the therapies increasingly more
frequently. You don't need the therapies to
become -- you don't have the therapies becoming increasingly
ineffective. That's what I call longevity
escape velocity. It's the rate at which these
rejuvenation therapies need to be improved following that
initial breakthrough where we could fix roughly half the
damage. And we get this thing I'm
calling reversed human rejuvenation.
The rate at which the therapies must be improved thereafter in
order to outpace the accumulation of the various
types of damage that they can't yet fix.
Is it's a bit of a mess and it took me five lines to write it
down but conceptually it's a very simple idea.
Longevity escape velocity. Now, I said earlier that if we
were mice this would not be realistic because we need to
double the efficacy of the therapies every year or
something. But every 20 years or 30 years
sound all together more realistic.
Is it realistic enough? Well I thought it might be
useful to try to ramify that. To try to get more data on that.
To try to get more of a solid argument that it really was a
realistic scenario. So I work with an excellent
computer programmer from New York called Chris Phoenix and we
published a paper last year which gave a summary of our
results. Essentially we wrote a pretty
faithful simulation of all of this.
Since this is the nature of aging, metabolism ongoing
recording these various types of intermediate that eventually
cause pathology, we should be able to simulate that.
We should be able to write a computer program that
essentially, you know, just recapitulates that process.
And that's what we did. We wrote a simulation in which
there were various types of damage each of which could
individually kill us, that's a very important component.
However, within each of which there are additive subtypes,
contributions from things are easy to fix and things that are
hard to fix. We built in this concept of the
downward spiral. We built in the concept of
different people aging at somewhat different rates.
Which is, of course, actually true.
And we also built in the fact that you don't just die of
aging, you die of the combination of aging and your
external environment. If you're unlucky and you get
the flu when you're a 30 year old then you might die sooner
than you otherwise would and so on.
And this is the simulation I won't be talking about that.
This is the validation of the simulation first of all we want
to see whether we could actually describe the distribution of
ages at death that is seen in the real world using this
program. And the answer is yes we
certainly could. The orange line here, which you
can hardly see, is the distribution of ages at death.
Although I think it was U. S. mailed in 1999 just happened
it the first data I could get my hands on.
The yellow line which you see fits the orange line fairly well
is the best that a typical demographic analysis would
achieve. Demographers like to use
something called the Gompertz curve -- the Gompertz
relationship. Which is essentially saying that
the mortality rate is an exponential function of age and
this is a pretty good fit in most populations.
In fact pretty much all populations not just human ones
and it worked pretty well here too.
But the green line is what we got for our simulation.
And as you can see it fits it like a glove.
It's even better than the Gompertz curve.
So this was nice good news. It showed that we were
representing reality here. This was also useful.
The fact that the damage seemed to accumulate in a reassuringly
realistic manner. Here we have simply a vessel --
a plot of how each individual's rate of accumulation of damage
goes throughout life. And you can see a couple of
important things here. First of all, the degree of
variability in the population looks about right.
People who are aging nice and slowly and healthily reach a
level of damage at the age of let's say 85 that's about the
same as rapid agers reach at the age of 70.
That seems about the right degree of variability.
Another thing that's good about this is that the rate of
accumulation of damage seems to follow the right sort of
trajectory. The rate is perhaps twice as
fast at old age as it is at young adulthood.
If it was 30 times as fast, we'd know there was something wrong.
If it was 1. 01 times as fast, we'd know
there was something wrong. We didn't get that.
So that's good news. So then the question is having
reassured ourselves that we're talking about a simulation
that's pretty realistic, what do we see when we look at
interventions? Well, first of all, let's look
at the damage. So here we have a bunch of
curves, each of which documents a cohort.
That's to say a group of people of the same age.
Now, these cohorts are ten years apart.
Each is ten years apart in age. And in particular the top curve,
the top blue one, is people who are already 80, 8-0 years old,
at the point where the first therapies start to arrive.
Start to knock down half the damage of various types.
And you can see it's up and down a bit for a little while because
the thing is not very comprehensive.
But eventually since we're above longevity escape velocity, the
people start getting biologically younger as they're
getting chronologically older and eventually they end up being
biologically very useful. Now, there's one thing I want to
emphasize before you miss it which is that we're looking very
conservatively here. We're talking about therapies
being improved in terms of the doubling of efficacy on at half
as fast as the schematic description I was giving a few
slides ago. Every 40 odd years.
Really slow. And yet we're still way ahead of
longevity escape velocity. The second curve is people, as I
said, are ten years younger. These little circles document
the point at which the therapies arrive.
So this is the people 80 years old when their first therapies
arrive. These people are 70 years old
when their therapies arrive. Before the therapies arrived
you've got the exponential accumulation of damage and after
that you have the gradual bringing the thing under
control. I suppose you'd like to know it
what it means for life span. Well, unless on the next slide I
don't have anything about life span limitations due to things
other than aging. These curves are going to be
just probabilities of death caused by aging.
But they're quite good news. The black curve is what happens
in the real world as we know it today when we don't have
anything that can do about aging.
The blue curve as on the previous slide is therapies --
is what happens to the group of people who were already 80 years
old roughly here. Half of them, pretty much half
of them were dead before we begin when the therapies arrive.
And as you can see not a lot of good.
It's, you know, it's going to give a few people the longest
survivors, a few people perhaps, you know, ten or 20 years.
That's all. But if you're just ten years
younger than that, 70 years old when the therapies arrive.
Which would be about here. Then again you only pull
gradually away from the line -- from the non-therapy line.
But you pull further and further and further away and eventually
you get down to here and your chance of dying of aging is
getting rather low. And as you can see eventually
once some of these people get out to the age of maybe 200 at
which point they are biologically so young that their
chance of dying of aging is basically nil.
And 10% of them do that. 10% of people who are 70 years
old at the time that the therapies arrive.
And if you are ten years younger than that.
That's the brown line -- these are people who are 60 years old
when the therapies begin to arrive.
Nearly half of them make it. Pretty damn good news.
So that's life extension escape velocity in practice.
And as you can see -- and I'll repeat again -- I'm talking
about a very conservative estimate for the rate at which
these therapies arrive. Why am I saying it's so
conservative? Would you like to me justify
that? Well, let me justify it.
Let's look at other technologies.
These are just for illustration, I can certainly make the same
argument using cars or using computers or using, you know,
combating infectious diseases or anything you like.
You know, when the Wright brothers got off the ground in
1903 they probably didn't think it would be terribly likely that
anyone would be flying across the Atlantic any time soon but
it only took 24 years for Lindbergh to get to Paris.
From there, you know, Lindbergh probably wasn't thinking in
terms of commercial jetliners. This is 22 years between
Lindbergh and the first commercial jetliner.
Only 20 years from there until concord.
Now you may say, well, okay, yes it got that far, didn't it?
But where are our flying cars? The answer is not flying cars
are really hard. The answer is we can't be
bothered. Just in the same way that you
know we could have obviously got to mars by now if there had been
the same degree of national pride attached to it that there
was with regard to the moon in the '60s.
We know that. We couldn't be bothered.
Public pressure, enthusiasm for this is not going to be in short
supply in respect of fixing aging.
So we should look at this sort of trajectory in order to judge
whether the scenario, the rate of progress that I'm talking
about fought incremental improvements after we make the
initial breakthroughs is going to be fast enough.
It's even better than that. This is my last point about
longevity escape velocity. You may think well yeah, okay,
so we might -- it looks pretty, pretty easy that we're going to
be able to double the level of efficacy of these therapies,
half the amount of damage that we can't fix.
Every 20 years or every 40 years.
That looks pretty reasonable. But it's going to go up and down
isn't it? There's going to be some times
when progress is fast and sometimes not and maybe sometime
in the future we're going to have a really bad century and
everybody's going to die because we make no progress.
Right? Now, I mean, that would be bad,
yes but hey we got that far so that's good enough in and of
itself. But also it turns out that
argument doesn't even work because it turns out that we can
slow down. Here's a scenario in which we
fix half the damage in order to get to robust human rejuvenation
in the first place. But the second time around 20
years later we're not fixing half of the remaining damage in
this scenario we're only fixing a third of it and the third time
around another 20 years later we're only fixing a quarter of
what we couldn't fix previously and so on.
And as you can see that's still good enough.
The people are still staying nice and healthily above the
frailty threshold. So it gets easier, it actually
gets easier with time. And that means that it's really
extraordinarily difficult to argue against the conclusion
that -- rejuvenation therapy is giving a few decades of extra
life will, in fact, give an indefinite degree of extra life
as a result of the rate of subsequent progress.
And you want to believe that just again go back to cars.
Now here's a vintage car. It's not 50 years old it's well
over a hundred years old taking part in a London rally which is
an annual car rally. It happens in England every
year. And this car, of course, is
getting a lot of maintenance, no question.
But the critical point is it's getting no more maintenance, no
more sophisticated maintenance than it was, let's say 30 or 40
years ago when it was only 3 or 4 times old as it was designed
to be. In other words, longevity escape
velocity for cars is already negligible.
We're not having to, you know, to get more sophisticated.
So I'm just going to complete with a couple of minutes on the
Methuselah Foundation. This is the foundation that I
run. I used to be at the University
of Cambridge but I quit because I was able to get paid to do
this stuff full time. And basically what we are --
we're a 501 charity based and registered in Virginia.
And we promote and fund, sponsor the hastening of just what I'm
talking about. When we began back in 2002-2003
we had no money whatsoever. And that didn't stop us.
We decided that we would get stuck in and get public
enthusiasm going raise the profile of life extension
research in a legitimate, you know, respectable way that
didn't in any way demean it and so we launched the prize called
the Methuselah Mass Prize, as we called it back then.
We call it the M prize now. It's simply -- we offer you
money if you can get, if you can make mice that lived longer than
any mouse had lived before. Very simple idea.
Gets the message across to people who go to sleep when you
talk about science to them for more than 10 seconds.
And, you know, it really worked. It got the word out there.
And we didn't have to spend very much money.
We only put $5,000 in it in the beginning.
And now as you can see it's got quite a lot.
And that's just because of people like Justin, for example.
And people around the world who have put money in and you can
still do it. And anyone with a credit card or
a PayPal account can add to that part.
The research part is the other thing we do.
When we got the M prize really going properly we a couple of
years ago started funding research directly in just the
same way that any standard funding agency would do accept
because we're very small -- well still fairly small -- we don't
have standard grant solicitation procedure.
We just fund stuff that I think is cool.
Which is fun because I know what's cool.
And we are spending that money as fast as we fill it.
The project that I told you about a moment ago, the
introduction of microbial genes into cells to get rid of stuff
that we can't naturally break down is something that we're
funding at three universities now around the U.
S. in Arizona state, at Rice University in Houston and also
Columbia in New York. Going very nicely.
Funding's going up all the time. The group is fantastic.
They're really committed to all of this.
They're the best graduate students you could possibly
imagine and the PIs that we're funding are also really
committed to it so it's a glorious situation from point of
view of the grant administrator, so to speak.
Also over the past year or two we've been funding one of the
other major really challenging components of the sense program.
The obviation, rather than reversal, of the accumulation of
mitochondria mutations. And again a comparable amount of
funding which again is going up all the time.
We're funding that not in the U. S. this time but in Paris.
Because we are a very much a global enterprise.
We expect to be funding at least three probably more like five
projects in the next few months. Again at the same sort of level
one or two people. Where are we getting all this
money from? Well our number one donor at the
moment is a guy you may have heard of Peter Thiel who was the
cofounder of PayPal and is now the spearhead of probably the
most successful hedge fund in the world, in terms of its rate
of growth, clarity and capital. He's very good at making money
and he's got a lot of it. But he's got slightly less than
he would otherwise have had because he gave some of it to
me. To fund some of this stuff.
And a lot of what he gave was not straightforward
unconditional but rather as a challenge pledge, in other words
we have to get money from other people in order to extract his
money from him. And we're doing our damnedest to
get that money. Eventually we want to be quite a
lot bigger than what we are now. I've told we we're funding maybe
half a dozen people at the moment plus we've got maybe a
half dozen or a few more in the foundation itself.
We'd like to be up around 500. Both employed by the foundation
and funded by the foundation. This is the sort of structure we
expect to have. It will include work like this
around universities around the world and it will also include a
stand alone facility in which especially the integration of
multiple different interventions into the same mice will be
pursued. We hope to be there as soon as
possible. We're not there yet.
But we're working on it. A year ago we were at this sort
of 6-digit level of budget. We're now very much at the
7-digit level. And we're moving through that as
fast as we can. Next step will be along the
order of magnitude bigger than that.
We will set up a standard grant solicitation and administration
and application procedure. So that we can find out about
and fund work that I haven't come across myself already.
And eventually we'll get to the point that I described a moment
ago where we have a stand alone facility as well as funding
extramural work. So we're talking about a pretty
pitiful amount of money really given the scale of the problem
that we'd like to solve. We're talking about really a
drop in the ocean of biomedical research.
The reason we're talking about such a small amount of money is
because all the work I've described to you here is work
that we want to do in the next several years up to a maximum of
ten years on mice. It's after we break through to
what I like to call robust mass rejuvenation where we can take
middle aged mice and seriously postpone their aging, that the
serious money will be needed in order to translate that
technology to humans. But that's the easy part.
Because after we get sufficient proof of concept that the
gerontological community in general are saying yes, it's
only a matter of time before we do it for humans, then Oprah
will be up there saying let's do it.
And then -- [LAUGHTER] Money will be no object.
It will be impossible to get elected except on a manifested
commitment to fund this. So we are focusing on the
shortest but the relatively short term, relatively cheap
order of nine digit funding to get to that proof of concept in
the laboratory in mice. And I'll stop there.
Thank you. ( applause )
I imagine there's a few minutes for questions if
anyone's got any. >> What will the benefit to
society be of extending life? >> Aging is really bad for
people. It doesn't just kill people.
It kills people really horribly. It causes suffering.
We generally agree among ourselves that suffering is bad,
right? God said so.
You know, most people feel this. Ageism is also generally
considered to be a bad thing. You know, we are actually
suppose to regard old people as people too.
So, you know, putting two and two together we have a moral
obligation to do this. And yes, there will be a degree
of restructuring of society that will be required after results.
Just as there was with the industrial revolution.
I don't know many people who would like to go back to the
pre-industrial world and the world before we had hygiene and
vaccines and so on when 40% of infants died before the age of
one. Progress does cause upheavals
but get over it. Progress is progress.
And progress that alleviates suffering is unfailingly good
progress. >> I have two questions for you.
One is do you practice caloric restriction?
If not, why not? >> I don't.
I don't and there are two reasons.
First of all I already look as though I do and that's not a
frivolous point. I have a feeling that the people
who might find calorie restriction easiest to do are
precisely the people who will get the least benefit from it.
However, that's a detailed point we can go into it more later if
you want. The other reason I don't do it
is because I don't think it's going to do anyone much good.
I published something on this a few years ago.
But essentially my reasoning is that the -- even though we --
all organisms seem to have genetic pathways in them that
respond to nutrient deprivation by hunkering down to one degree
or another. The shorter lived you are the
more impressive the metabolic acrobatics is that occurs in
response to nutrient deprivation.
For example, worms and flies can live several times as long as
they normally would if they're starved at the right time of
their development. Whereas, mice can quite only
live 40 or 50% as long. Now there is good evolutionary
reasoning to suggest that this is actually not surprising.
That actually the only reason we have these pathways is to the
extent that they're useful. And long famine much longer than
a year just don't happen often enough to apply enough selective
pressure to retain the ability to survive them.
Second question then is of the beliefs and attitudes that
people have that are posing the greatest resistance or barrier
to you, what are they that are really preventing them or
blocking them from buying into your vision?
And by buying into, I mean literally by giving more money.
So, first of all, let's get the wealthy people out of way
because the problem the wealthy people don't deserve all the
blame for not getting me money. Because they're just members of
the general public. And they, too, have the
misfortune to have televisions on which they don't receive the
right message and so on. So, you know, it's a social
problem. It's not a problem just of
wealthy people not being sufficiently visionary.
Basically, it's the same problem like when I just gave a fairly
scathing answer to the previous question.
Nobody clapped. You've all got this problem,
right? It's what I call the pro-aging
trance. People have made their peace
with aging. Aging is something that we've
had to live with all our lives. All civilization's life, so to
speak. And the reason we rationalize it
away is because until now, that's been our only option.
It's been this grim thing that's going to happen to you and it's
not going to happen to you for quite a long time, okay, but
there's nothing you can do about it.
Then what's your choice? You can spend your life, you
know, obsessing about it and not having much of a good time or
you can put it out of your mind and get on with your miserably
short life, you know, and make the best of it.
And obviously that's the thing to do, right?
And given that that's the thing to do, it doesn't matter how
irrational your rationalization is.
Okay, so the people are very good at and coming up with and
believing and swallowing irrational rationalizations
about aging and, you know, worrying about things if they
applied the faintest sense of proportion to the problem they
would not dream of considering to be arguments against this.
So what I spend my time doing is essentially, well, to varying
degrees of aggressiveness, ridiculing that and getting
people to grow up and take this problem as seriously as they
would take any other problem. >> I have two questions, as
well. My first question is do you
think your anti-aging technology will be able to keep stride with
ecological solutions to basically deal with the fact
that humanity is beginning to reach -- well, it will
eventually reach carrying capacity.
It's whether the ecological -- societal, you know, whether
we as society will keep pace with the anti-aging stuff.
So the anti-aging stuff will happen and the question is how
soon will it happen and we will be able to cope.
A large part of why I'm fairly strident about these things is
because I need -- I feel a need, not only in order to hasten the
technology but also to hasten the anticipation of the
technology so that there's a certain amount of forward
planning that goes on and we don't just get -- get surprised
when suddenly people announce that they've made these mice.
It seems to me that it's probably going to be okay.
But I don't say that it's going to be okay immediately.
I think that the transition to a post-aging world is going to be
pretty damn turbulent just as the transition to a
industrialized world was pretty turbulent.
But that's not the question we have to ask ourselves.
The question we have to ask ourselves is it worth it?
And my second question is given the complexity of the
metabolic processes and the fact that, you know, they're going to
basically inflict various kinds of damage on the body, how do
you account for, you know, how you're going to target that very
damage and especially -- my main interest is in the brain.
How are you going to, for example, target a decreased
cognitive abilities into old age?
So first question is why do we have decreased cognitive
abilities with old age in the first place?
And the biggest reason I think pretty clearly is the sort of
things that I put up on the screen, the fact that the brain
accumulates crap. Inside cells and outside cells
get in the way and stop neurons from communicating so well with
each other and from working so well.
And a more advanced rate they'll die at an accelerating rate and
they, therefore, can't do much when they're dead.
So we're fixing those -- we're going to fix those things.
Now that's almost certainly not the whole story with regard to
cognitive decline. There are two other things.
Number one is -- and the biggest one -- is we don't learn so well
because there are too many distractions.
It's often -- you know, people have done quite interesting
psychological studies on what people can remember in their
lives. And they found that there is a
phenomenon which they've given the wonderful name to the
reminiscence bump. Basically what this says is that
however how old, whether you are 40, 50, 60, 70, 80, that the
time of your life that you're going to remember best is your
adolescence. And everything else is more of
an equilibrium. And if you think about it,
that's not surprising. Even people, you know, at middle
age are probably forgetting things as fast as they are
learning new things because the process of recalling a
recollection -- a memory -- reinforces it.
So you basically remember the interesting things -- a lot of
which happened during adolescence -- rather well, more
or less indefinitely. Whereas, the things that were
not so interesting tend to be the ones that are forgotten.
That's fine. If it's fine between 40 and 80
then it continues to be fine. In the blue T-shirt.
The process which you are working on, is it going to be a
completely experimental stimulus to the --
I can't hear. >> What kind of a treatment are
you working on would it be just external stimulus to the body or
would it require conscious effort for people to do?
Certainly it's clear that having a good frame of mind, you
know, especially being able to cope well with stress, is good
for longevity. Lots of people have determined
that. However, these therapies will
certainly be straightforward biomedical therapies.
If, for whatever reason, you're aging faster than average,
either because you haven't got the right attitude or because
you smoke or because you really like Big Macs, or whatever, you
know, that's going to be fine. But the thing about rejuvenation
therapies is that the only difference between someone who's
aging a bit faster or a bit slower is the frequency at which
the therapies need to be applied.
The same therapy should work on anybody.
I think that answers your question.
( inaudible ) >> So what?
A conscious effort on the part of the human.
You got to go to the hospital or whatever, you know, it's not
going to happen in your sleep. We're not going to chain people
down and rejuvenate them by force, if that's what you mean.
How would you solve the problem of space?
Clearly the birth rate and the death rate have to more or
less match. That's clear.
So if we're lowering the death rate by using these therapies
very widely then we will end up lowering the birth rate as well.
How will we do it? Who can say?
I have no idea. But I do know that first of all
it's not for us to ask. We have the duty, a moral duty
-- a very clear moral obligation to develop these therapies as
soon as possible so that humanity in the future has the
choice between the high death rate that we have today and the
low birth rate. And that may be a dilemma but a
dilemma that they are entitled to choose between for themselves
rather than have us impose these values on them by saying, you
know, you got to have the high death rate.
That's the first thing. Second thing is if we look, you
know, pragmatically at the what the problem really is and how
bad it is -- well, first of all, let's remember that the
population, the fertility rate is already plummeting across the
whole developed world and indeed the pre-developed world.
China and India are fine examples as well.
And that's going to continue. Furthermore, there's a good
reason to believe that it may accelerate.
In the west, we see that not only are women having fewer
children but they are having them later.
And that's very interesting because we have to ask why are
they having them later? And of course there are
different reasons for different individuals but the point is
they are, for whatever reason, choosing to do other stuff with
their lives until the mid '30s or whatever.
Then why are they having the children then?
Answer of course, it's then or never.
Right? It won't be that way anymore.
That's one thing we're going to fix.
So if you know you're going to be perfectly capable of having a
child safely, you know, at the age of 70 then maybe you will
choose to postpone your birth for a bit longer if you're
enjoying yourself at age 30 and 40 and 50.
And that won't happen really early on in the process before
the resulting from the death rate being low, right?
So if you look at the actual math of that the demographic
trajectory is a really powerful influence.
Red T-shirt. >> Hearing all these examples of
how this would adversely effect society and how these changes
come about, isn't this theory kind of vague as seeing how the
effects improves your life or effects one person but adversely
effects many or could? >> Who is the one person you're
thinking about? ( inaudible )
But everyone is yourself. It's going to benefit everybody.
The question is are the benefits to health more important than
the social dangers? >> What about people that have
to change their life and don't want to?
They don't have to. Okay, consider the Amish.
The Amish are a perfectly respectable, stable community
that reject a bunch of existing modern technology.
Now, that's fine. We don't resent them for it,
they don't resent us for it. We get along.
It may very well be in the future that some sections of
society choose to stay where they are and not to go this way
and others sections choose to go this way.
And that's fine too. What's not fine is to say today
overpopulation or whatever let's not go there let's impose our
values and make everyone Amish in the future.
That's not fair. Go on.
The first you showed for the therapies where you have this
kind of like you mentioned about like you have to apply the
therapy to like reach half of the one third and like that.
But I'm kind of curious what I could see is that like you're
more or less having the same amount of -- same amount of like
recovery rate need to do each time because the pink curve is
exponentially decreasing so it becomes almost flat and so each
time you have applied a therapy there person you're actually not
decreasing -- >> If you think it through
that's what you would expect. This is the limit.
This is the slowest that you could get and still stay above
the frailty threshold. Because what's happening here is
that each time you're knocking off the a certain chuck of the
amount of damage that you're not repairing, right?
So the rate at which the overall amount of damage is increasing
is slower than it was previously because there are less types of
damage that are increasing. So each of these lines has -- is
increasingly closer to horizontal and so you expect to
have to do less each 20 years. It's what you would except.
So the damage is not the orange line but the blue line?
Yes, that's right. The blue line.
The reserve, the Y axis, is the amount of damage that you can
afford to accumulate before frailty happens.
So, yes, each of the blue lines is the trajectory of how much
damage you have or equivalently how much reserve you have left.
And the orange line is the individual, you know, what's
happening. So the orange line is, for a
particular individual, how much damage they actually have.
And the blue lines are the trajectory of the damage that
the therapy doesn't yet repair. So back here, for example, okay,
this chunk of damage here could be repaired but none of this
could. And so these blue lines are just
notional at that point. But down here they become less
notional because -- yep? >> Like have you taken has
something new if like you can? ( inaudible )
I think that-- Okay, so this is actually
something that I used to, I guess, misjudge in terms of
people's reception of the whole thing.
It's perfectly clear to me that the hardest part of all of this
is going those first 40 years. Going to this point.
That's really tough. And I think we got a 50/50
chance of going there within maybe 30 years.
But I think we've got at least a 10% chance of not going there in
a hundred years if we just hit a lot of problems.
What I'm much, much more certain about is that once we get to
here this is going to happen. We're going to have no trouble
staying ahead of the longevity escape velocity.
I think that answered your question.
In the back. >> I was just wondering how you
would assess fixing or engineering the damage that
occurs -- the quote-unquote damage that occurs with every
replication. ( inaudible )
yeah, okay. So this is something that I've
published on but it's pretty controversial and a lot of
people don't agree with me on this but I reckon my logic is
pretty sound. There are a bunch of things that
can happen to a cell when it accumulates mutations.
One thing that can happen is that it can die.
Okay? We've got a solution to that.
Stem cell therapy. Cell loss right?
Another thing is that it can get into a state where can refuses
to die. Okay?
So the immune system has this problem.
You accumulate cells that are not doing anything.
They won't proliferate when they should but they also won't die
and they get in the way they inhibit the proliferation of
other cells. The third thing that can happen
is that it will die quite easily but it will also proliferate
really easily. And that's, of course, cancer.
Uncontrollably. Now it may surprise you to learn
that I think cancer is a really good thing.
It's a really good news that we get cancer.
Here's why. Cancer is so bad that just one
cell going wrong can kill us fairly quickly in a fairly short
order like ten or 20 years later.
Anything else that goes wrong in a cell has to effect a lot of
cells in order to matter. Now that means that the problem,
the main problem that evolution has had in getting us to live as
long as we do is cancer. And if we look at the nature of
aging closely, we find that a lot of the aspects of aging are
side effects of making sure that we don't die of cancer even
younger than we do. In particular, the accumulation
of mutations in the genome that have nothing to do with the cell
cycle, is constrained, in terms of its race, simply by the fact
that DNA repair and maintenance has to be incredibly good in
order to stop us from dying of cancer at the age of four.
So actually cancer is an enormous help.
It has forced evolution to make a DNA repairing machinery
unnecessarily good for other purposes.
In other words, if we can just really, really fix cancer, then
we're done. The other mutations are going to
accumulate but they're not going to matter in terms of pathology
until we're a lot older than we can ever get at the moment.
So, yes, we're going to have to fix that in order to maintain
longevity escape velocity in the long run but we're talking off
the curve. We're talking over here.
That's my view. >> Are there any types of damage
that we'll never be able to repair and does that imply that
as life span increases we're continuously dependent on
synthetic or artificial technologies organs, bones and
teeth. >> I don't agree with the
structure of your question, because I think that what you
call synthetic or non-biological technologies sort of blend into
the biological ones. I think that at the moment we
will almost certainly reach longevity escape velocity and
robust human rejuvenation in these first few decades in fact
almost overwhelmingly by using straightforward biotechnology,
biomedical approaches to this. But I also think that
increasingly we will use non-biological approaches.
We already use them for some things of course, cochlear
implants, you know, things like that.
I think that as a non-biological sophistication improves that
more and more things, more and more problems of aging will
become easier to tackle by non-biological solutions than by
biological solutions. So I think there will be a
continuum and eventually we'll get to the point where yes,
we'll be using a lot of non-biological solutions.
Is the slope on this curve -- exclusive of science and
exclusive of technology -- is the slope on that curve
dependent on money more than anything else today to reach
robust regeneration? >> Yes, it is.
I think at this point, you know, lots of research is happening
that's useful. So it's not entirely that
progress is zero. Certainly not.
Lots of stuff is happening in stem cells, for example.
But most of the seven -- that I'm talking about are definitely
not proceeding as fast as they could if people -- if there were
more appropriately directed funding.
There are in each case really, you know, absolutely world class
scientists who work in this general space and who have all
the expertise necessary and who are interested in working on
these particular things but they don't work on them because other
things are easier to fund or easier to get publications for
and, you know, the sort of things that scientists tend to
have to prioritize. That why I started the
Methuselah Foundation because with a bit of change, I can --
with a bit of money I can change that.
I used to give up somewhat slip and slide that said scientists
will do anything interesting for food.
And that's more or less true. Certainly, I mean, I'm well
integrated into I know personally all of the world
leading scientists in all of these various fields.
I'm constantly communicating with them and trying to control
them into doing stuff when I can't pay them as well as now of
course increasingly actually paying them.
So really at this point I've done all the hard work other
than getting enough money sent in the direction of the
appropriate project. Far side.
( inaudible ) >> Specific treatment is going
to change extremely fast. It's going only when these
things come along clearly there's going to be massive
pressure to engage in incremental refinements that do
not simply do this sort of thing in terms of the
comprehensiveness but also improve the cost.
No question about that. However, even at the beginning
when these things are very expensive indeed, I do not
foresee any significant delay between the point where they're
available to anyone and the point where they're available to
everybody. That seems, you may think, to be
a very unrealistic and optimistic prediction.
But here's why. There's going to be this gap
between the point where we get proof of concept in mice and the
point where we get these therapies in humans.
That gap is going to be a absolute minimum of ten years
and it's very likely to be 15 or 20 years and it might be a lot
longer than that. That's a long time for society
to get its head around the whole thing.
And, in particular, it's time for society to have a few
general elections in which it's going to be impossible to get
elected unless you have a manifesto commitment not only to
put enough public money in, as well as, of course, encouraging
private money, to get the research done but also to get
all of training of the medical personnel and sufficient numbers
and all of the building and factories and so on so that when
the therapies do finally arrive, the serious decisions have been
made -- the serious money's been spent.
This is going to be straightforward for a bunch of
reasons. First of all it's going to
matter to people. You know, it's not going to be
the economy stupid in the famous Clinton phrase.
It's going to matter more. It's going to be a wartime
mentality when people are willing to embrace a certain
amount of -- of standard of living in order to end the
slaughter as soon as possible once they actually see it that
way. But more than that even from an
economic point of view it's going to be easy to justify.
Because being frail is not just risky, it doesn't just kill
people, it's really expensive. I don't know if you know the
statistic but the average person in the west consumes a lot more
medical expenses in their last year of life than in the whole
of the rest of their life put together.
And that's irrespective of how old they are when they die.
So we won't have that anymore. We won't have frail people
anymore with these technologies and all that money is going to
be saved. Even at the beginning when these
therapies are very expensive. That expense will be absolutely
dwarfed by the amount we save by not having to keep people alive
in a grisly state for an extra year or two.
All right now this is more of an opinionated type of answer.
You can tell I don't like that.
How do you think that the whole psychological process is
going to be different because, I mean, someone thinks differently
when they're 25 versus 45. So 150 versus 100.
I mean, how do you think that's going to differ.
Well I'm 44. I was 45 yesterday.
Okay, so I mean I can see some changes in both myself and my --
you know, people of my age with regard to how they behave toward
-- in terms of youth and so on. So I, for example, I feel that
in some ways I'm absolutely as much of a child as I ever was.
You know, I still enjoy the same sort of informality.
I still live like a student. But on the other hand I despise
most of modern music. I still listen to stuff that was
from the '60s and '70s and '80s, right?
So there's plenty of things that I can see even in myself, let
alone in society, that are clearly aged structured.
The question is will that actually be to the extent that
that might be a good thing is it going to go away?
And to the extent that it might be a bad thing, you know, the
people are sort of old before their time if you like.
Will that go away? And I again I feel pretty good
about this. I think that the more health you
have, the more vigor you have, the more options you have to
change to choose to go to discos with your granddaughter if you
want to. You know, things like that which
people just don't have at the moment.
So I think there inevitably will be a greater degree of variety
among society with regards the sorts of people that people are
at given ages but I think that's fine.
And equally there will be more mixing between those groups.
You know, age will matter less. And there's another question.
Yeah, you have one. >> Sort of an evolutionary
ambivalency in terms of how there hasn't been a lot of --
Evolution is a function-- Sorry, aging is a function of
evolutionary neglect, yeah. >> And so in the future as you
proposed, more in terms of things that then --
( inaudible ) Do you think that there could be
the potential of evolutionary ambivalency in the other
direction? >> No.
Basically evolution of the human race is, at this point, already
overwhelmingly under our own control.
We're actually, at the genetic level, we are evolving far
faster now than we ever did before and we're doing so
because the evolutionary pressures the selected pressures
on the individual genes and genetic pathways are being
altered by technology, by civilization.
The immune system is a fine example.
A lot of the -- it's pretty much accepted now that a lot of the
reasons why people's immune systems tend to be worse now
than they used to be -- and more allergies and stuff like that --
is because of the absence of selective pressure imposed by
infectious diseases. You can get away with having a
weak immune system whereas previously you would die before
having any kids. So that would happen even in a
accelerated rate especially when we get to the point of being
able to have good and effective and safe gene therapy.
We will be doing our own evolution.
Their own treatments in the future.
Do you think that will be limited at all by own only
intellectual capacity -- ( inaudible )
That's a pretty hard question.
I think probably not. Simply because we're so good at
enhancing our intellectual capacity at all with computers
and so on. >> What about species that have
no predators. ( inaudible )
You mean why don't they age? ( inaudible )
They do of course live, in general, a lot
longer than organisms that do have natural predators.
That is the dominant determinant.
But it's not the only determinant.
Because even the organisms that have no predators they still
have other causes of death that are not age related.
Things like starvation and especially hypothermia,
accidents, infections, all these things count for the same thing.
Anything that's extrinsic contributes to the determination
of how much evolution cares about aging.
Is there some sort of, you know, evolutionary sort of
pressure for aging that we haven't quite comprehended yet?
There are still a few gerontologists who look at that.
Who are interested in the possibility that that might be
so. Because there's so much data out
there which in some way looks a bit like, you know, an aging
program. The fact that all of everything
goes wrong more or less simultaneous, for example, is
often brought up. But in each of these cases, one
can see that actually is indeed what you expect from the absence
of an aging program. But at this point, very few
gerontologist take seriously the idea that there is an aging
program. Essentially in order for there
to be a aging program you have to have a model for how the
aging program would not only evolve but also be retained.
In other words, how it would actually be a good thing for the
species. And people just haven't
succeeded in finding a model for that.
( inaudible ) >> Speak up, speak up.
Are these therapies going to get rid of things like wrinkles
and gray hair? >> Yes, they are.
If we can fix the inside than it's going to be pretty damned
easy to fix the outside. >> Are there categories of
diseases that will be difficult to deal with like auto-immune
diseases. >> There are plenty of diseases
that will be difficult to deal with but luckily they, the point
in the train of events where we're targeting, in other words
these ongoing types of damages, the precursors of various
diseases, right. The cause and effect
relationship is very complex and indeed not really known and, in
fact, it probably won't be well known for a while.
But that's fine. If we fix all the various types
of damage then by definition since structure defines
function, we are fixing all the consequences of the damage.
So auto immune disease -- well, sure, that's important but what
will they come from? They come from inadequacy of the
immune system. And certainly to the extent that
auto immune problems are age related.
That people's allergies get worse, for example, then yes,
that will be something that will be fixed by the rejuvenation of
the immune system even though that rejuvenation is being done
for more life threatening reasons.
I've exhausted you all. Oh, no I haven't.
One more. >> If you were to fix something,
you need to know what's broken. >> That's not necessarily true.
Carry on. >> Well, how do you propose to
do surveillance in realtime of entire organisms in order to be
able to target different therapies?
All right, good question. So the question is -- it's quite
a profound question so I want to make sure everybody heard it.
The objection that the questioner gave is okay how do
you know -- in order to fix something you got to know that
it's broken. You've got to know that the
thing is in some way -- you know, would be better in some
other way. How are you going to know this?
You mentioned surveillance of the organism in some way.
The thing is we can sidestep all of our ignorance about that by a
very simple trick. All we have to do is look at the
difference between younger people and older people.
And I don't mean children and really old people here.
I'm talking about, let's say between 25 and 40.
Now the difference is at the molecular and cellular level
between someone who's 25 and someone who's 40 are pretty
small. I mean, I'm 45 now and I can
still run more or less as fast as I could when I was 25 and I
can still think more or less as fast.
I'm functionally more or less intact.
But as things stand I've got a considerably shorter remaining
life span and that's of course got to be a function of what I'm
made of. Of my of composition at the
molecular and cellular level. Now, therefore, if we look at
the composition of an older person and we find differences
and we know differences between that person and a younger person
and we can say if we reverse those differences, that's going
to be a good thing. We can't say that if we reverse
some individual difference it's going to be a good thing because
a lot of those individual differences may be adaptations,
may be compensations but they'll be compensations for other
differences. So if we put everything back the
way it was at a younger age, we know we're going to have the
result we want even though we don't know which of the things
were actually bad for us and which were not.
I'm all for fixing things that might not matter.
All right. ( inaudible )
The issue of evolution and the objective of evolution.
Yeah. >> So if the objective of
evolution, survival of species, it seemed like that there may be
some innate aging mechanism going on that hasn't been
identified and still hasn't been identified.
Because you've got two different possibilities to sustain the
species. One is you have a higher
turnover rate, right? Faster death rate.
Or you have a very, very slow turnover rate.
Either of those strategies will result in survival of species
but so far it appears evolutionary from our experience
we're on a high turnover rather than a slow turnover objective.
So that doesn't work. And the reason it doesn't work
is because you're thinking about turnover in an environment
that's protected. You're thinking about an
environment in which most organisms die of decrepitude.
Most organisms in the world do not die of decrepitude.
In a typical ecological niche in the wild, most organisms --
nearly all organisms die of starvation or hypothermia or
whatever. Okay.
Evolution has to work within that.
Evolution can't change that. Okay.
Evolution has -- for a particular species evolution is
going to work on that species to maximize the number of offspring
that the species has and so on in order for the species to
survive. And it's going to do so in the
context of the mortality rate that's going to happen anyway.
And therefore in the context in the fact that not many organisms
are going to have offspring at the age of 50 because they're
all going to be dead from other causes than aging.
So that's why aging doesn't matter at those ages.
But evolution does not -- the evolutionary pressures are not
restricted to just creatures in the wild.
We're subject to evolutionary pressures --
You're right, and I mentioned that earlier in respect to the
immune system ago. But that's very recent.
We age now simply because we always did age when we were in
the wild. Which was actually not very long
ago in evolutionary terms, remember.
So eventually we'll fix it. But yes, at the moment, you're
quite right, at the moment our environment, our protected
environment is imposing evolutionary pressure to live
longer. And for just the same reason
that, you know, if you took a species that lived a very short
life span and you put it in a protected environment the same
pressure would exist. But that pressure has only been
applied very recently and it hasn't done the job yet because
it's a very hard job to do. I think we really ought to stop.
I'm desperately thirsty so anyone who wants to ask more
questions can follow me.